HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis

Abstract

Background

Cardiovascular disease is the most frequent cause of death in people with early stages of chronic kidney disease (CKD), and the absolute risk of cardiovascular events is similar to people with coronary artery disease. This is an update of a review first published in 2009 and updated in 2014, which included 50 studies (45,285 participants).

Objectives

To evaluate the benefits and harms of statins compared with placebo, no treatment, standard care or another statin in adults with CKD not requiring dialysis.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies up to 4 October 2023. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. An updated search will be undertaken every three months.

Selection criteria

Randomised controlled trials (RCTs) and quasi‐RCTs that compared the effects of statins with placebo, no treatment, standard care, or other statins, on death, cardiovascular events, kidney function, toxicity, and lipid levels in adults with CKD (estimated glomerular filtration rate (eGFR) 90 to 15 mL/min/1.73 m²) were included.

Data collection and analysis

Two or more authors independently extracted data and assessed the study risk of bias. Treatment effects were expressed as mean difference (MD) for continuous outcomes and risk ratios (RR) for dichotomous benefits and harms with 95% confidence intervals (CI). The risk of bias was assessed using the Cochrane risk of bias tool, and the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results

We included 63 studies (50,725 randomised participants); of these, 53 studies (42,752 participants) compared statins with placebo or no treatment. The median duration of follow‐up was 12 months (range 2 to 64.8 months), the median dosage of statin was equivalent to 20 mg/day of simvastatin, and participants had a median eGFR of 55 mL/min/1.73 m². Ten studies (7973 participants) compared two different statin regimens. We were able to meta‐analyse 43 studies (41,273 participants). Most studies had limited reporting and hence exhibited unclear risk of bias in most domains.

Compared with placebo or standard of care, statins prevent major cardiovascular events (14 studies, 36,156 participants: RR 0.72, 95% CI 0.66 to 0.79; I² = 39%; high certainty evidence), death (13 studies, 34,978 participants: RR 0.83, 95% CI 0.73 to 0.96; I² = 53%; high certainty evidence), cardiovascular death (8 studies, 19,112 participants: RR 0.77, 95% CI 0.69 to 0.87; I² = 0%; high certainty evidence) and myocardial infarction (10 studies, 9475 participants: RR 0.55, 95% CI 0.42 to 0.73; I² = 0%; moderate certainty evidence). There were too few events to determine if statins made a difference in hospitalisation due to heart failure. Statins probably make little or no difference to stroke (7 studies, 9115 participants: RR 0.64, 95% CI 0.37 to 1.08; I² = 39%; moderate certainty evidence) and kidney failure (3 studies, 6704 participants: RR 0.98, 95% CI 0.91 to 1.05; I² = 0%; moderate certainty evidence) in people with CKD not requiring dialysis.

Potential harms from statins were limited by a lack of systematic reporting. Statins compared to placebo may have little or no effect on elevated liver enzymes (7 studies, 7991 participants: RR 0.76, 95% CI 0.39 to 1.50; I² = 0%; low certainty evidence), withdrawal due to adverse events (13 studies, 4219 participants: RR 1.16, 95% CI 0.84 to 1.60; I² = 37%; low certainty evidence), and cancer (2 studies, 5581 participants: RR 1.03, 95% CI 0.82 to 1.30; I² = 0%; low certainty evidence). However, few studies reported rhabdomyolysis or elevated creatinine kinase; hence, we are unable to determine the effect due to very low certainty evidence. Statins reduce the risk of death, major cardiovascular events, and myocardial infarction in people with CKD who did not have cardiovascular disease at baseline (primary prevention). There was insufficient data to determine the benefits and harms of the type of statin therapy.

Authors' conclusions

Statins reduce death and major cardiovascular events by about 20% and probably make no difference to stroke or kidney failure in people with CKD not requiring dialysis. However, due to limited reporting, the effect of statins on elevated creatinine kinase or rhabdomyolysis is unclear. Statins have an important role in the primary prevention of cardiovascular events and death in people who have CKD and do not require dialysis.

Editorial note: This is a living systematic review. We will search for new evidence every three months and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Plain language summary

Statins can help reduce risk of death in people with chronic kidney disease who do not need dialysis

What is the issue?
Adults with chronic kidney disease (CKD) have a high risk of cardiovascular events, with elevated serum cholesterol and triglycerides, a factor that contributes to cardiovascular disease. Statin therapy helps to lower the level of bad cholesterol (low‐density lipoprotein) and has cardiovascular protective effects beyond cholesterol reduction. For people not needing dialysis, statin therapy has been shown to reduce death and cardiovascular events. Still, studies in this population have shown unclear effects on stroke, kidney failure, and harms such as muscle damage (rhabdomyolysis).

What did we do?
We looked at 62 studies published before 4 October 2023 concerning statins in over 50,000 people with CKD who did not need dialysis treatment. This review is a living systematic review. A search for new evidence will be conducted every three months, and the review will be updated accordingly.

What did we find?

We found that compared to placebo, statin therapy reduced death and major heart‐related events, with one in 13 people receiving statin therapy avoiding heart‐related events and one in 26 people avoiding death. Statin therapy probably had little or no effect on stroke and kidney failure (when people would benefit from dialysis or a kidney transplant). The benefits of statin therapy were also evident in patients with CKD but not heart disease. Statins have some potential harms; however, we found there was probably no effect on cancer, liver function or withdrawing from treatment due to adverse events. There was limited reporting of muscle damage in the studies.

Studies did not identify a preferred type or dose of statin in treating people with CKD not requiring dialysis.

Conclusions
Statins decrease death, major cardiovascular events, and myocardial infarction in people with moderate CKD. Limited data related to treatment toxicity resulted in uncertain effects.

Editorial note: Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Summary of findings

Summary of findings 1. Statin therapy versus placebo or standard of care for people with chronic kidney disease not requiring dialysis.

Statin therapy versus placebo or standard of care for people with chronic kidney disease not requiring dialysis
Patient or population: people with chronic kidney disease not requiring dialysis Setting: primary and tertiary care Intervention: statin therapy Comparison: placebo or standard of care
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or standard of care	Risk with statin therapy
Major cardiovascular events (MACE) follow up: mean 46 months	6 per 1,000	5 per 1,000 (4 to 5)	RR 0.72 (0.66 to 0.79)	36156 (14)	⊕⊕⊕⊕ HIGH	Statin therapy reduces major cardiovascular events
Death follow up: mean 40 months	3 per 1,000	2 per 1,000 (2 to 3)	RR 0.83 (0.73 to 0.96)	34978 (13)	⊕⊕⊕⊕ HIGH	Statin therapy reduces death
Rhabdomyolysis follow up: mean 64 months	1 per 1,000	2 per 1,000 (0 to 59)	RR 3.07 (0.13 to 75.37)	2618 (2)	⊕⊝⊝⊝ VERY LOW 1 2	The evidence is very uncertain about the effect of statin therapy on rhabdomyolysis
Myocardial infarction follow up: mean 39 months	3 per 1,000	2 per 1,000 (1 to 2)	RR 0.55 (0.42 to 0.73)	9475 (10)	⊕⊕⊕⊝ MODERATE 2	Statin therapy probably reduces myocardial infarction
Stroke follow up: mean 40 months	13 per 1,000	8 per 1,000 (5 to 14)	RR 0.64 (0.37 to 1.08)	9158 (7)	⊕⊕⊕⊝ MODERATE 3	Statin therapy probably results in little to no difference in stroke
Kidney failure follow up: mean 34 months	2 per 1,000	2 per 1,000 (2 to 2)	RR 0.98 (0.91 to 1.05)	6704 (3)	⊕⊕⊕⊝ MODERATE 2	Statin therapy probably results in little to no difference in kidney failure
Hospitalisation due to heart failure follow up: 54 months	75 per 1,000	53 per 1,000 (28 to 99)	RR 0.70 (0.37 to 1.32)	579 (1)	⊕⊕⊝⊝ LOW 1 4 5	Statin therapy may result in little to no difference in hospitalisation due to heart failure
*The risk in the intervention group (and its 95% CI) is based on the baseline risk of outcomes from observational studies (and its 95%CI) . The relevant studies in the Summary of Findings Table are listed below: Major cardiovascular events and death ‐ Go 2004 Rhabdomyolysis ‐ based on the assumed risk of outcomes in the comparison group Myocardial infarction ‐ Meisinger 2006 Stroke and hospitalisation due to heart failure ‐ Bansal 2017 Kidney failure ‐ Dalrymple 2011 CI: Confidence interval; RR: Risk ratio; MACE: Major Adverse Cardiac Events
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

¹ Very few events

² Inadequate sequence generation/ generation of comparable groups, resulting in potential for selection bias

³ Effect estimates were on both side of the null

⁴ Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, Inadequate concealment of allocation during randomisation process, resulting in potential for selection bias,

⁵ Only one study

Background

Description of the condition

The incidence and prevalence of chronic kidney disease (CKD) are increasing, with a global prevalence estimated at around 10% (Global Burden of Disease CKD Collaboration 2020). CKD is a known risk factor for cardiovascular disease (CVD) (Go 2004). Overall cardiovascular deaths are more common than progression to kidney failure in patients with CKD (Gargiulo 2015). For patients with severe kidney disease on long‐term dialysis, 39% of deaths are attributable to cardiovascular causes (USRDS 2019). People with moderate CKD not on dialysis experience risks of death or complications from CVD equivalent to people with heart disease (Go 2004; Henry 2002).

Description of the intervention

HMG‐CoA reductase inhibitors, known as statins, are a commonly prescribed class of cholesterol‐lowering medications used in the primary prevention of atherosclerotic CVD and secondary prevention for those who have developed CVD (Sidebottom 2020). Ezetimibe is another cholesterol‐lowering medication class which has been examined in combination with statins in clinical trials (SHARP 2010).

How the intervention might work

Many traditional and non‐traditional cardiovascular risk factors are prevalent in people with CKD (Muntner 2005; Shilpak 2005). The majority (60%) of people with CKD have elevated serum cholesterol and triglycerides levels and an even higher proportion in those with nephrotic syndrome (Harris 2002). Abnormal lipid levels may contribute to the development of CVD and the initiation and progression of CKD (Drueke 2001; Schaeffner 2003). In the Atherosclerosis Risk in Communities Study (ARIC) and Physicians Health study, elevated lipid levels were associated with lower kidney function (Manjunath 2003). Apart from their lipid‐lowering function, it is plausible that statin use may result in improved kidney function by decreasing urinary protein excretion and inflammation and reducing fibrosis of tubular cells (Kasiske 1988). Ezetimibe prevents intestinal cholesterol absorption through inhibition of the synthetic 2‐azetidinone agent at the brush border of the small intestine (StatPearls Textbook), while statins could reduce kidney disease progression and CVD incidence in people with kidney dysfunction (Massy 2001). Clinical studies in people with CVD have shown that statins safely reduce the five‐year incidence of death or major cardiovascular events by about 20% (Baigent 2005).

Why it is important to do this review

In previous versions of this review published in 2009 and 2014, statins proportionally reduced the risk of death and major cardiovascular events in people with CKD. However, the risks of stroke, adverse events (muscle or liver damage), and kidney failure in these studies were uncertain due to few reported events (Palmer 2014). The previous version of this review relied on the post‐hoc analysis of larger general population studies. Additional studies have been published, warranting a review update. This review has transitioned to a living systematic review. Clinical practice guidelines recommend using statins with or without ezetimibe for people with CKD, not on dialysis (CARI 2013; KDIGO 2013). The Caring for Australian and New ZealandeRs with Kidney Impairment (CARI) Guideline is being updated, and this review will form the underlying evidence review for guideline recommendations.

Objectives

To evaluate the benefits and harms of statin therapy compared with placebo, standard care without statin therapy, or another different statin in adults with CKD who were not on dialysis. A secondary objective is to maintain the currency of the evidence using a living systematic review approach.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) that evaluated the benefits and harms of statins in adults with CKD who were not on dialysis. The first period of randomised cross‐over studies was included. We excluded studies of fewer than eight weeks duration as these studies were unlikely to enable detection of death or cardiovascular outcomes related to statin therapy (Briel 2006).

Types of participants

Inclusion criteria

We included studies enrolling adults with CKD (estimated glomerular filtration rate (eGFR) 90 to 15 mL/min/1.73 m²) (defined and staged according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines) (KDIGO 2012) who were not on dialysis, including people with persistent urine abnormalities (proteinuria or albuminuria) or structural kidney disease with normal kidney function. Studies were included irrespective of whether participants had CVD at baseline.

Exclusion criteria

Studies of adults with kidney failure treated with dialysis (peritoneal dialysis or haemodialysis) and recipients of a kidney transplant were excluded. Other Cochrane Reviews have specifically reviewed these populations (Palmer 2013; Palmer 2014a).

Types of interventions

We included studies that compared statins with placebo, standard care without statin therapy, or another statin. We excluded studies where a statin was compared with a different lipid‐lowering strategy, including fibrate therapy and ezetimibe.

Types of outcome measures

Standardised Outcomes in NephroloGy (SONG) is currently developing a core outcome set for CKD. This finalised core outcome set will be incorporated in updated versions of this review.

Primary outcomes

1. Major cardiovascular events

2. Death

3. Rhabdomyolysis

Secondary outcomes

1. Cardiovascular death

2. Myocardial infarction (MI) (fatal and non‐fatal)

3. Stroke (fatal and non‐fatal)

4. Hospitalisation due to heart failure

5. Kidney failure

6. Doubling of serum creatinine (SCr)

7. Acute kidney injury (AKI)

8. Elevated creatine kinase

9. Elevated liver enzymes

10. Withdrawal due to adverse events

11. Cancer

12. Onset of diabetes

13. Revascularisation procedure

14. End of treatment creatinine clearance (CrCl) or GFR (any measure)

15. End of treatment proteinuria

16. Serum lipid levels

    1. Total cholesterol

    2. Low‐density lipoprotein (LDL) cholesterol

    3. High‐density lipoprotein (HDL) cholesterol

    4. Triglycerides

17. Fatigue

18. Life participation

19. Memory loss

Search methods for identification of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Register of Studies to 4 October 2023 through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources:

• Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

• Weekly searches of MEDLINE OVID SP

• Searches of kidney and transplant journals and the proceedings and abstracts from major kidney and transplant conferences

• Searching of the current year of EMBASE OVID SP

• Weekly current awareness alerts for selected kidney and transplant journals

• Searches of the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, and a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website.

See Appendix 1 for search terms used in strategies for this review.

Living systematic review considerations

An updated search of the Cochrane Kidney and Transplant Register of Studies will be undertaken every three months.

Searching other resources

• Reference lists of review articles, relevant studies and clinical practice guidelines.

• Contacting relevant individuals/organisations seeking information about unpublished or incomplete studies.

• Grey literature sources (e.g. abstracts, dissertations and theses) in addition to those already included in the Cochrane Kidney and Transplant Register of Studies will be searched.

Living systematic review considerations

References lists of newly identified studies from updated searches were checked, and relevant individuals and organisations were contacted if appropriate. Grey literature sources screening will not be periodically undertaken during the living evidence surveillance period.

Data collection and analysis

Selection of studies

The following processes were used in the current update and previous versions of the review. The search strategy described was used to obtain titles and abstracts of studies relevant to the review. Title and abstracts were screened independently by two authors (BC and DJT), who discarded studies that were not eligible. However, studies and reviews thought to include relevant data or information on studies were retained initially for full‐text review. Two authors (BC and DJT) independently assessed retrieved abstracts and the full text, where necessary, to determine which studies satisfied the inclusion criteria. Disagreements between authors were resolved in consultation with a third author (SP).

Living systematic review considerations

The 2023 review update undertook study selection in Covidence (https://www.covidence.org/). Two independent authors (BC and DJT) immediately screened the retrieved citations from three monthly searches. Disagreements were resolved in consultation with a third author (SP).

Data extraction and management

Data extraction was carried out independently by authors (DJT, BC) using Robot Reviewer (https://www.robotreviewer.net/). Data extraction was checked independently by authors using standard data extraction forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study existed, reports were grouped. Data were obtained from all relevant reports, including long‐term follow‐up data if the attrition rate was less than 80% of randomised participants. Any discrepancies between published versions were highlighted.

Assessment of risk of bias in included studies

The following items were independently assessed by two authors using the Cochrane risk of bias assessment tool (Higgins 2022) (Appendix 2).

• Was there adequate sequence generation (selection bias)?

• Was allocation adequately concealed (selection bias)?

• Was knowledge of the allocated interventions adequately prevented during the study?

  • Participants and personnel (performance bias)

  • Outcome assessors (detection bias)

• Were incomplete outcome data adequately addressed (attrition bias)?

• Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

• Was the study apparently free of other problems that could put it at risk of bias?

Measures of treatment effect

For dichotomous outcomes (major cardiovascular events, death, rhabdomyolysis, kidney failure, doubling of SCr, onset of diabetes, revascularisation procedure, memory loss, elevated liver enzymes, elevated creatine kinase, withdrawal due to adverse events, and cancer), results were expressed as risk ratios (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (lipid parameters, proteinuria, kidney function (CrCl or eGFR), fatigue, and life participation), the mean difference (MD) was used, or the standardised mean difference (SMD) where different scales were used for outcome measurement.

Unit of analysis issues

Cross‐over RCTs were analysed using only the data from the first period. Studies with multiple treatment arms were included. When considering these studies, we tried to combine all relevant intervention groups into a single group when appropriate, i.e. high‐ and low‐dose statin, to allow a single pairwise comparison. If appropriate, we compared the intervention arms against one another. It was planned that cluster RCTs were not included in the meta‐analysis and were analysed and reported separately. However, no cluster RCTs were included in the review.

Dealing with missing data

Any further information required from the original author was requested, and relevant information was included in the review. Evaluation of important numerical data, such as screened or randomised patients and intention‐to‐treat, as‐treated, and per‐protocol population, was performed. Attrition rates, such as drop‐outs, losses to follow‐up, and withdrawals, were investigated, including the balance between treatment groups. Issues of missing data and imputation methods (e.g. last observation carried forward) were critically appraised (Higgins 2022).

Assessment of heterogeneity

We first assessed the heterogeneity by visual inspection of the forest plot. We then quantified statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies likely due to statistical heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values was as follows.

• 0% to 40%: might not be important

• 30% to 60%: may represent moderate heterogeneity

• 50% to 90%: may represent substantial heterogeneity

• 75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depended on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P value from the Chi² test or a CI for I²) (Higgins 2022).

Meta‐regression for age and GFR was undertaken for outcomes with more than 10 studies in which meta‐analysis demonstrated evidence of substantial or considerable heterogeneity.

Assessment of reporting biases

To assess potential bias from small‐study effects, we constructed funnel plots for the log risk ratio in individual studies against the standard error of the risk ratio. Statistical assessment of funnel plot asymmetry with the Egger regression test (Harbord 2006) using R (R Core Team 2013 ‐ http://www.R-project.org/) to assess publication bias if required or sufficient data is available).

Data synthesis

Data were pooled using the random‐effects model, but the fixed‐effect model was also used to ensure the robustness of the model chosen and susceptibility to outliers.

The anticipated absolute effects have been calculated from baseline risks reported in published observational studies that examine the incidence of cardiovascular outcomes, death, and kidney failure in people with CKD (Bansal 2017; Dalrymple 2011; Go 2004; Meisinger 2006). These studies were selected as they were large multi‐national observational studies conducted on people with CKD that may be generalisable to the populations in the identified RCTs in this review. When no published data was available, the assumed risk of the outcomes was given by the event rates in the comparison group.

Living systematic review considerations

All included studies in future review updates will undergo data extraction and critical appraisal by two authors (BC and DJT) independently, using Robot Reviewer (https://www.robotreviewer.net/) as a supportive tool. Whenever new evidence (i.e. studies, data or other information) relevant to the review is identified, we will extract the data and assess the risk of bias as appropriate. We will wait until the accumulating evidence changes one or more of the following components of the review before incorporating it and re‐publishing the review.

• The findings of one or more primary outcomes

• The credibility (e.g. GRADE rating) of one or more primary outcomes

• New settings, populations, interventions, comparisons or outcomes were examined

• New serious adverse events.

Formal sequential meta‐analysis approaches will not be used for updated meta‐analyses.

Subgroup analysis and investigation of heterogeneity

For outcomes with more than 10 studies, we planned to conduct subgroup analyses to explore potential sources of heterogeneity in modifying estimates of the effects of statins if substantial or considerable heterogeneity or significant heterogeneity (P < 0.1) was present in the primary analysis. We planned subgroup analyses according to participant, intervention, or study‐related characteristics when subgroups contained four or more independent studies (statin type, statin dose (equivalent to simvastatin, baseline total cholesterol (< 230 mg/dL versus ≥ 230 mg/dL), age (≤ 55 years versus > 55 years), the proportion with diabetes (≥ 20% versus < 20%), presence or absence of CVD (primary versus secondary prevention), or adequacy of allocation concealment. Additionally, post‐hoc analyses were conducted on the impact of baseline kidney function on the following outcomes: kidney failure, doubling of SCr, end‐of‐treatment kidney function, and end‐of‐treatment proteinuria.

We conducted meta‐regression using a mixed‐effects model with the Metafor package for R (R Core Team 2013) for primary outcomes with more than 10 studies and substantial or considerable heterogeneity. Age and kidney function were considered covariates for meta‐regression.

Sensitivity analysis

The following sensitivity analyses were considered to explore the influence of the following factors on effect size.

• Repeating the analysis, excluding unpublished studies

• Repeating the analysis taking into account the risk of bias

• Repeating the analysis, excluding any very long or large studies to establish how much they dominate the results

• Repeating the analysis excluding studies using the following filters: diagnostic criteria, the language of publication, source of funding (industry versus other), and country.

However, there were insufficient data for sensitivity analyses for unpublished studies, risk of bias, the language of publication, and country.

Summary of findings and assessment of the certainty of the evidence

We presented the main results of the review in the 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schünemann 2022a). The 'Summary of findings' tables also include an overall grading of the evidence‐related main outcome using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach (GRADE 2008; GRADE 2011). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of the within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, the precision of effect estimates and risk of publication bias (Schünemann 2022b). We presented the following outcomes in the 'Summary of findings' tables.

• Major cardiovascular events

• Death

• Rhabdomyolysis

• Cardiovascular death

• MI

• Stroke

• Hospitalisation due to heart failure

• Kidney failure

Methods for future updates

Living systematic review considerations

The conduct and production of this living systematic review will be overseen by the CARI Guidelines Living Evidence Working Group and the Statins in CKD Guideline Working Group. We will review the scope and methods when updating the review in light of potential changes in the topic area or new evidence (e.g. when additional comparisons, interventions, subgroups, outcomes, or new review methods become available). At every three‐month search, we will consider the necessity for the review to be living. By assessing the questions' ongoing relevance to decision‐makers and determining if continuing uncertainty in the evidence is present, we will determine whether further relevant research is likely to change recommendations for clinical practice via the CARI Guidelines Statins in CKD Living Guideline.

Results

Description of studies

The following section contains broad descriptions of the studies considered in this review. For further details on each individual study, please see Included studies; Excluded studies; Studies awaiting classification; Ongoing studies.

Results of the search

Previous versions of this Cochrane review (Navaneethan 2009; Palmer 2014) identified 47 studies (39,738 participants) compared statin therapy with placebo or no treatment, and three studies (5547 participants) compared a statin with another statin (Table 2).

1. List of included studies according to Cochrane review update.

Statin versus placebo studies identified in the 2009 and 2014 version of the Cochrane review	Statin versus placebo studies identified in the updated 2023 Cochrane review	Statin versus statin studies identified in the 2009 and 2014 version of the Cochrane review	Statin versus statin studies identified in the updated 2023 Cochrane review
4S 1993	Abe 2011c	IDEAL 2004	Abe 2015
AFCAPS/TexCAPS 1997	ASUCA 2013	PANDA 2011	Ikeda 2012
ALLIANCE 2000	Cha 2015	TNT 2004	Kimura 2012
Aranda Arcas 1994	Masajtis‐Zagajewska 2018		PLANET I 2006
ASCOT‐LLA 2003	Ohsawa 2015		PLANET II 2006
Bianchi 2003			SAGE 2004
Buemi 2000			Yi 2014
CARDS 2003
Di Lullo 2005
Dummer 2008
ESPLANADE 2010
Fassett 2010
Fried 2001
Gheith 2002
Goicoechea 2006
Hommel 1992
HPS 2002
JUPITER 2007
Imai 1999
Lam 1995
Lee 2002
Lintott 1995
LIPS 2001
LORD 2006
MEGA 2004
Mori 1992
Nakamura 2002
Nakamura 2005
Nakamura 2006
Nielsen 1993
Panichi 2006a
PPP 1992
PREVEND IT 2000
Rayner 1996
Renke 2010a
Samuelsson 2002
Sawara 2008
Scanferla 1991
SHARP 2010
Stegmayr 2005
Thomas 1993
Tokunaga 2008
Tonolo 1997
UK‐HARP‐I 2005
Verma 2005
Yasuda 2004
Zhang 1995

2023 review update

For this update, we searched the Cochrane Kidney and Transplant Register of Studies (4 October 2023) and identified 134 new reports. Thirteen new studies (22 reports) were included, 20 (50 reports) were excluded, and one ongoing study was identified. One new study is awaiting classification (recently completed; no data available). We also identified 61 new reports of existing included studies and studies awaiting classification.

We reassessed and reclassified seven ongoing studies: three studies have been included (Ohsawa 2015; PLANET I 2006; PLANET II 2006); four studies were excluded (Mose 2014a; Mose 2014b; Weinstein 2013; Zinellu 2012); and one study has been moved to awaiting classification as no data have been published (NCT00768638). Eighteen previously excluded studies were deleted because they were not randomised (4), enrolled the wrong population (4), or did not use statins (10).

A total of 63 studies were included (336 reports, 50,725 randomised participants), 32 were excluded, two are awaiting classification, and there is one ongoing study (Figure 1).

1.

Flow diagram showing study selection

Included studies

Details are provided in Included studies.

Fifty‐three studies (42,752 randomised participants) compared statin therapy to placebo or no treatment. Nine studies compared high to low‐dose statin (7851 randomised participants), and one study (122 randomised participants) compared continuous‐release versus intermittent‐release statin. Of the 63 included studies, 11 studies provided post hoc data for subgroups of 31,315 adults with CKD within larger studies that compared statins with placebo or no treatment (4S 1993; AFCAPS/TexCAPS 1997; ALLIANCE 2000; ASCOT‐LLA 2003; CARDS 2003; HPS 2002; JUPITER 2007; LIPS 2001; MEGA 2004; PPP 1992; SAGE 2004). Two comparisons provided post hoc data for 5428 adults comparing two statin regimens (IDEAL 2004; TNT 2004). Overall, 43 studies (41,273 participants) contributed to the meta‐analyses.

Statin versus placebo or no treatment

Studies varied in sample size (median 55 participants; range 14 to 3107 participants). Seven comparisons that included more than 1000 participants (4S 1993; ASCOT‐LLA 2003; HPS 2002; JUPITER 2007; MEGA 2004; PPP 1992; SHARP 2010).

The median statin dose (equivalent to simvastatin) was 20 mg (range 5 to 80 mg/day). Twelve studies used simvastatin, 10 studies used atorvastatin, nine studies used pravastatin, nine studies used fluvastatin, four studies used pitavastatin, four studies used rosuvastatin, two studies used lovastatin, one study used cerivastatin, one study used simvastatin with ezetimibe (SHARP 2010). One study used simvastatin or pravastatin (Scanferla 1991) (Table 3).

2. Studies classified by type of statin therapy.

Atorvastatin (dose)	Cerviastatin (dose)	Fluvastatin (dose)	Lovastatin (dose)	Pitavastatin (dose)	Pravastatin (dose)	Rosuvastatin (dose)	Simvastatin (dose)	Simvastatin and ezetimibe (dose)
ALLIANCE 2000 (10 mg/d)	Nakamura 2002 (0.15 mg/d)	Buemi 2000 (40 mg/d)	AFCAPS/TexCAPS 1997 (20 mg/d)	Nakamura 2005 (10 mg/d)	Aranda Arcas 1994 (20 mg/d)	Abe 2011c (5 mg/d)	4S 1993 (20 mg/d)	SHARP 2010 (20 mg/d and 10 mg/d)
ASCOT‐LLA 2003 (10 mg/d)		Cha 2015 (20 mg/d)	Lam 1995 (20 mg/d)	Nakamura 2006 (10 mg/d)	ASUCA 2013 (mean 12.5 mg/d)	JUPITER 2007 (20 mg/d)	Dummer 2008 (20 mg/d)
Bianchi 2003 (40 mg/d)		Di Lullo 2005 (80 mg/d)		Ohsawa 2015 (20 mg/d)	Imai 1999 (mean 7.5 mg/d)	Sawara 2008 (2.5 mg/d)	Fassett 2010 (10 mg/d)
CARDS 2003 (10 mg/d)		ESPLANADE 2010 (80 mg/d)		Tokunaga 2008 (40 mg/d)	Lee 2002 (10 mg/d)	Verma 2005 (10 mg/d)	Fried 2001 (10 mg/d)
Goicoechea 2006 (20 mg/d)		Gheith 2002 (20 mg/d)			MEGA 2004 (15 mg/d)		Hommel 1992 (15 mg/d)
Inukai 2011 (10 mg/d)		Lintott 1995 (40 mg/d)			Mori 1992 (10 mg/d)		HPS 2002 (40 mg/d)
LORD 2006 (10 mg/d)		LIPS 2001 (20 mg/d)			PPP 1992 (40 mg/d)		Nielsen 1993 (15 mg/d)
Masajtis‐Zagajewska 2018 (20 mg/d)		Samuelsson 2002 (40 mg/d)			PREVEND IT 2000 (40 mg/d)		Panichi 2006a (40 mg/d)
Renke 2010a (40 mg/d)		Yasuda 2004 (20 mg/d)			Scanferla 1991 (10 mg/d)		Rayner 1996 (25 mg/d)
Stegmayr 2005 (10 mg/d)					Zhang 1995 (20 mg/d)		Scanferla 1991 (10 mg/d)
							SHARP 2010 (20 mg/d with ezetimibe 10 mg/d)
							Thomas 1993 (40 mg/d)
							Tonolo 1997 (20 mg/d)
							UK‐HARP‐I 2005 (20 mg/d)
High‐dose statin versus low‐dose statin
PANDA 2011 (80 mg/d versus 10 mg/d)						PLANET I 2006 (40 mg/d versus 10 mg/d)
TNT 2004 (80 mg/d versus 10 mg/d)						PLANET II 2006 (40 mg/d versus 10 mg/d)

The median follow‐up duration was 12 months (range 2 to 66 months). Studies reporting death outcomes that could be included in meta‐analyses had a median follow‐up duration of 44 months (range 5 to 65 months).

Although three studies enrolled participants with established acute or stable coronary artery disease (4S 1993; ALLIANCE 2000; LIPS 2001), 12 studies excluded participants with clinical coronary artery disease (Abe 2011c; AFCAPS/TexCAPS 1997; CARDS 2003; Fried 2001; Imai 1999; JUPITER 2007; Lam 1995; MEGA 2004; Nakamura 2002; Nakamura 2005; Ohsawa 2015; SHARP 2010). Median baseline LDL cholesterol was 143.9 mg/dL (range 108.5 to 189 mg/dL) (3.72 mmol/L; range 2.80 to 4.89 mmol/L)

Ten studies included only participants who had diabetes (Abe 2011c; CARDS 2003; Hommel 1992; Inukai 2011; Lam 1995; Mori 1992; Nakamura 2005; Nielsen 1993; Tonolo 1997; Zhang 1995); and people with diabetes were excluded from eight studies (Bianchi 2003; Gheith 2002; Lee 2002; Nakamura 2002; Nakamura 2006; Ohsawa 2015; Panichi 2006a; Renke 2010a). Stegmayr 2005 combined outcome data for adults not on dialysis with those on dialysis; data from this study were not included in the meta‐analyses.

Effects of statins on adverse events data from SHARP 2010 could not be included in analyses because disaggregated data for 6247 adults with CKD were not available.

The Pravastatin Pooling Project (PPP 1992) was a pooled analysis of three large data sets of participants with kidney impairment who were included in three major statin studies (LIPID 1998; Sacks 1996; Shepherd 1995) conducted in the general population and were included as a single comparison.

High versus low dose statin

PANDA 2011 and TNT 2004 compared two doses of atorvastatin, while PLANET I 2006 and PLANET II 2006 compared low‐ and high‐dose rosuvastatin. The median follow‐up was 24 months (range 12 to 58.8 months). Meta‐analysis was undertaken when two or more studies were available.

Continuous release versus intermittent release statin

Yi 2014 compared continuous‐release statin (20 mg/day) administered in the morning with intermittent‐release statin (20 mg/day) administered in the evening for two months. The study included 122 participants, with a mean LDL cholesterol of 140.5 ± 28.3 mg/day (3.63 ± 0.73 mmol/L).

Statin versus another statin

• PLANET I 2006 and PLANET II 2006 compared rosuvastatin and atorvastatin

• IDEAL 2004 compared simvastatin with atorvastatin

• Abe 2015 compared rosuvastatin with pitavastatin

• Ikeda 2012 compared pravastatin with rosuvastatin

• Kimura 2012 compared pitavastatin with pravastatin

• SAGE 2004 compared atorvastatin with pravastatin.

Sample sizes ranged from 28 to 3107 participants. The median follow‐up was 12 months (range 12 to 57.6 months). Baseline LDL cholesterol levels ranged from 123.6 to 150.8 mg/dL (3.20 to 3.90 mmol/L). Meta‐analysis was not possible because three or more studies were not available for each comparison.

Excluded studies

See Excluded studies.

Thirty‐two studies did not meet our eligibility criteria for the following reasons.

• Wrong intervention (11 studies): did not compare a statin with placebo or standard of care without a statin (Almquist 2012; IMPROVE‐IT 2008; Ishimitsu 2014; Kouvelos 2013; NCT03543774; Suzuki 2013a; UK‐HARP‐II 2006; Weinstein 2013; Yasmeen 2015; Yasuda 2010; Zinellu 2012)

• No comparator: one study (ESTABLISH 2004)

• Wrong study design: three studies (Mose 2014a; Mose 2014b; Siddiqi 2011)

• Wrong population: eight studies (Almukhtar 2021; Fotso 2021; Mackie 2008; Mohammadi 2023; PACTR202110707328144; Vasin 2021; Watanabe 2022; Yen 2022)

• Unclear duration or less than eight weeks: nine studies (Dogra 2005; Dogra 2007; Golper 1987; Golper 1989; Ott 2008; Paulsen 2010; Schmieder 2003; Torraca 2006; Van Dijk 2001).

Risk of bias in included studies

Seven studies comparing statins with placebo or no treatment were conducted according to published protocols, outcomes were adjudicated by a committee, specified outcomes were reported, and analyses were conducted using intention‐to‐treat methods (4S 1993; HPS 2002; JUPITER 2007; PPP 1992; PREVEND IT 2000; SHARP 2010; UK‐HARP‐I 2005). In placebo or no treatment‐controlled studies, adverse events were reported in 33 studies (63%) and systematically evaluated in 17 studies (33%). See Included studies for detailed information on study risk of bias assessment.

See Figure 2 and Figure 3.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Allocation

Random sequence generation

Random sequence generation was low risk in 15 of the included studies, and the remaining 48 studies were judged to have an unclear risk of bias.

Allocation concealment

Allocation concealment was low risk in 19 studies, and the remaining 44 studies were judged to have an unclear risk of bias.

In studies that examined the primary outcomes, six of 17 studies were low risk for random sequence generation, and nine of 17 were low risk for allocation concealment.

Blinding

Performance bias

Participants and personnel were blinded in 27 studies and considered low risk, and 24 studies were open‐label and hence high risk, with the remaining 12 studies did not report blinding and were judged to have an unclear risk of bias.

Detection bias

Sixteen blinded outcome assessors and four studies were high risk with no blinding of outcome assessors. The remaining 43 studies were judged to have an unclear risk of bias.

In studies that reported the primary outcome, nine of 17 studies were blinded study participants and personnel, and outcome assessors.

Incomplete outcome data

Completeness of outcome reporting was applied in 26 of the included studies, and 18 included studies exhibited a high risk of incomplete outcome reporting. The remaining 19 studies did not provide sufficient information to permit judgement and were judged to have an unclear risk of bias. Ten of the 17 studies that reported the primary outcomes exhibited a low risk of attrition bias.

Selective reporting

Selective outcome reporting occurred in four studies, and only four studies exhibited a low risk of selective outcome reporting. The remaining 55 studies had unclear reporting, with studies not reporting a protocol or clinical registry number. Only two studies that reported the primary outcomes of the review exhibited a low risk of selective reporting.

Other potential sources of bias

The risk of bias due to sources of funding was high in 14 studies, 21 studies exhibited a low risk of any other bias, while in 28 studies the risk of bias was unclear. Nine studies that reported the primary outcomes of the review exhibited a low risk for other potential sources of bias.

Effects of interventions

See: Table 1

Statin therapy versus placebo

The main findings of the analysis are presented in Table 1.

Primary outcomes

Compared to placebo, statin therapy reduces major cardiovascular events (Analysis 1.1 (14 studies, 36,156 participants): RR 0.72, 95% CI 0.66 to 0.79; I² = 39%; high certainty evidence) and death (Analysis 1.2 (13 studies, 34,978 participants): RR 0.83, 95% CI 0.73 to 0.96; I² = 53%; high certainty evidence).

1.1. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 1: Major cardiovascular events

1.2. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 2: Death

Statins had uncertain effects on rhabdomyolysis due to study limitations and very serious imprecision (Analysis 1.3 (2 studies, 2618 participants): RR 3.07, 95% CI 0.13 to 75.37; very low certainty).

1.3. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 3: Rhabdomyolysis

Secondary outcomes

Cardiovascular endpoints

Compared to placebo, statin therapy probably reduces cardiovascular death (Analysis 1.4 (8 studies, 19,112 participants): RR 0.77, 95% CI 0.69 to 0.87; I² = 0; moderate certainty evidence) and MI (Analysis 1.5 (10 studies, 9475 participants): RR 0.55, 95% CI 0.42 to 0.73; I² = 0%; moderate certainty evidence).

1.4. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 4: Cardiovascular death

1.5. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 5: Myocardial infarction

Statin therapy probably has little or no effect on stroke (Analysis 1.6 (7 studies, 9115 participants): RR 0.64, 95% CI 0.37 to 1.08; I² = 39%; moderate certainty evidence) but probably decreases revascularisation procedures (Analysis 1.7 (3 studies, 4156): RR 0.62, 95% CI 0.47 to 0.82; I² = 0%; moderate certainty evidence), and may have no difference on hospitalisation due to heart failure (Analysis 1.8 (1 study, 579 participants): RR 0.70, 95% CI 0.37, to 1.32; low certainty evidence).

1.6. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 6: Stroke

1.7. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 7: Revascularisation procedure

1.8. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 8: Hospitilsation due to heart failure

Kidney endpoints

Compared to placebo, statin therapy probably has no protective kidney effect with little or no effect on kidney failure (Analysis 1.9 (3 studies, 6704 participants): RR 0.98, 95% CI 0.91 to 1.05, I² = 0%; moderate certainty evidence), and doubling of SCr (Analysis 1.10 (1 study, 6245 participants): RR 0.90, 95% CI 0.79 to 1.02; moderate certainty evidence).

1.9. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 9: Kidney failure

1.10. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 10: Doubling serum creatinine

Statin therapy probably improves kidney function (CrCl or eGFR) (Analysis 1.11 (18 studies, 4213 participants): MD 1.83, 95% CI 0.27 to 3.39 mL/min; I² = 17%; moderate certainty evidence). No difference was found with the use of measured CrCl compared to eGFR (test for subgroup differences: Chi² = 3.11, df = 1 (P = 0.08), I² = 67.8%).

1.11. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 11: End of treatment kidney function

Compared to placebo, statin therapy may lower proteinuria (Analysis 1.12 (7 studies, 356 participants): MD ‐0.47 g/24 hours, 95% CI ‐0.75 to ‐0.19; I² = 81%; low certainty evidence) with substantial heterogeneity.

1.12. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 12: End of treatment proteinuria

Safety endpoints

Statin therapy may have little to no effect on elevated liver enzymes (Analysis 1.13 (7 studies, 7991 participants): RR 0.76, 95% CI 0.39 to 1.50; I² = 0%; low certainty evidence), withdrawal due to adverse events (Analysis 1.14 (13 studies, 4219 participants): RR 1.10, 95% CI 0.83 to 1.48; I² = 37%; low certainty evidence), cancer (Analysis 1.15 (2 studies, 5581 participants): RR 1.03, 95% CI 0.82 to 1.30; I² = 0%; low certainty evidence), and onset of diabetes (Analysis 1.16) (1 study, 3267 participants): RR 1.03, 95%CI 0.71 to 1.50; low certainty evidence).

1.13. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 13: Elevated liver enzymes

1.14. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 14: Withdrawal due to adverse events

1.15. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 15: Cancer

1.16. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 16: Onset of diabetes

Compared to placebo, the effect of statin therapy on elevated creatinine kinase was unclear because of serious study limitations and very serious imprecision (Analysis 1.17 (7 studies, 4514 participants): RR 0.84, 95% CI 0.20 to 3.48; I² = 0%; very low certainty evidence).

1.17. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 17: Elevated creatine kinase

Fatigue, life participation, and memory loss were not reported by any of the included studies.

Lipid endpoints

Statins compared to placebo probably lowers total serum cholesterol (Analysis 1.18 (27 studies, 2234 participants): MD ‐50.26 mg/dL, 95%CI ‐64.34 to ‐36.17 mg/dL (MD ‐1.3 mmol/L, 95% CI ‐1.67 to ‐0.97 mmol/L); I² = 96%; moderate certainty evidence), may decrease LDL cholesterol (Analysis 1.19 (24 studies, 2183 participants): MD ‐43.84 mg/dL, 95%CI ‐52.56 to ‐35.12 mg/dL (MD ‐1.14 mmol/L, 95% CI ‐1.37 to 0.91 mmol/L); I² = 92%; low certainty evidence) and triglycerides (Analysis 1.20 (20 studies, 1186 participants): MD ‐26.02 mg/dL, 95%CI ‐40.99 to ‐11.06 mg/dL (MD ‐0.29 mmol/L, 95% CI ‐0.45 to ‐1.22 mmol/L); I² = 82%; low certainty evidence), and may increase HDL cholesterol (Analysis 1.21 (22 studies, 1374 participants): MD 2.92 mg/dL, 95% CI ‐0.03 to 5.88 mg/dL (MD 0.08 mmol/L, 95% CI 0.0001 to 0.15 mmol/L); I² = 81%; low certainty evidence). Analyses of treatment effects on serum lipids showed evidence for substantial heterogeneity (I² > 80%) for all outcomes.

1.18. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 18: Total cholesterol

1.19. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 19: LDL cholesterol

1.20. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 20: Triglycerides

1.21. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 21: HDL cholesterol

No other secondary outcomes were reported in the included studies.

Subgroup analyses

Cardiovascular disease

When we limited analyses to studies in which CVD was an exclusion criterion at baseline, effect modification was not evident for death (Analysis 1.22: test for subgroup differences: Chi² = 1.40, df = 1 (P = 0.24), I² = 28.5%). However, the test of subgroup differences indicated potential effect modification for major cardiovascular events, but it was considered not important as the direction of the effect estimates were in the same direction, indicating a benefit of therapy and cross‐over of the 95% CIs (Analysis 1.23: test for subgroup differences: Chi² = 2.71, df = 1 (P = 0.10), I² = 63.0%).

1.22. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 22: Subgroup analysis (cardiovascular disease): death

1.23. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 23: Subgroup analysis (cardiovascular disease): major cardiovascular events

Statin dose

When comparing < 20 mg/day simvastatin equivalent with ≥ 20 mg/day simvastatin equivalent, effect modification was evident for major cardiovascular events (Analysis 1.24: test for subgroup differences: Chi² = 10.27, df = 1 (P = 0.001), I² = 90.3%) but was not important as the effect estimates were in the same direction and overlap of the 95% CIs. Test for subgroup differences found no evidence of effect modification for statin dose for the outcomes of death (Analysis 1.25), withdrawal due to adverse effects (Analysis 1.26), total cholesterol (Analysis 1.27), LDL cholesterol (Analysis 1.28), HDL cholesterol (Analysis 1.29), or triglycerides (Analysis 1.30).

1.24. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 24: Subgroup analysis (statin dose): major cardiovascular death

1.25. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 25: Subgroup analysis (statin dose): death

1.26. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 26: Subgroup analysis (statin dose): withdrawal due to adverse events

1.27. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 27: Subgroup analysis (statin dose): total cholesterol

1.28. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 28: Subgroup analysis (statin dose): LDL cholesterol

1.29. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 29: Subgroup analysis (statin dose): HDL cholesterol

1.30. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 30: Subgroup analysis (statin dose): triglycerides

Age

Comparing age (< 55 years versus ≥ 55 years), a test of subgroup difference was significant for total cholesterol (Analysis 1.31: test for subgroup differences: Chi² = 2.91, df = 1 (P = 0.09), I² = 65.6%). However, effect modification was not considered important because the subgroup effect estimates were in the same direction and overlap of the 95% CIs. Other outcomes did not demonstrate any effect modification (withdrawal due to adverse effects (Analysis 1.32), LDL cholesterol (Analysis 1.33), HDL cholesterol (Analysis 1.34), or triglycerides (Analysis 1.35)).

1.31. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 31: Subgroup analysis (age): total cholesterol

1.32. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 32: Subgroup analysis (age): withdrawal due to adverse events

1.33. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 33: Subgroup analysis (age): LDL cholesterol

1.34. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 34: Subgroup analysis (age): HDL cholesterol

1.35. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 35: Subgroup analysis (age): triglycerides

Diabetes mellitus

Effect modification was examined for DM (< 20% versus ≥ 20%) and was evident for withdrawal due to adverse events (Analysis 1.36: test for subgroup differences: Chi² = 3.60, df = 1 (P = 0.06), I² = 72.2%) but not for death (Analysis 1.37), major cardiovascular death (Analysis 1.38), total cholesterol (Analysis 1.39), LDL cholesterol (Analysis 1.40) HDL cholesterol (Analysis 1.41), or triglycerides (Analysis 1.42).

1.36. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 36: Subgroup analysis (diabetes mellitus): withdrawal due to adverse events

1.37. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 37: Subgroup analysis (diabetes mellitus): death

1.38. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 38: Subgroup analysis (diabetes mellitus): major cardiovascular death

1.39. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 39: Subgroup analysis (diabetes mellitus): total cholesterol

1.40. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 40: Subgroup analysis (diabetes mellitus): LDL cholesterol

1.41. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 41: Subgroup analysis (diabetes mellitus): HDL cholesterol

1.42. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 42: Subgroup analysis (diabetes mellitus): triglycerides

Baseline cholesterol

When baseline cholesterol at study entry was ≥ 230 mg/dL compared to < 230 mg/dL, test for subgroup differences were found for the outcomes, total cholesterol (Analysis 1.43: test for subgroup differences: Chi² = 4.47, df = 1 (P = 0.03), I² = 77.6%) and LDL cholesterol (Analysis 1.44: test for subgroup differences: Chi² = 10.02, df = 1 (P = 0.002), I² = 90.0%). The subgroup differences were not considered important because the subgroups are in the same direction and the 95% CI overlap. For the outcomes of withdrawal due to adverse events (Analysis 1.45), HDL cholesterol (Analysis 1.46), and triglycerides (Analysis 1.47), no effect modification was evident.

1.43. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 43: Subgroup analysis (baseline cholesterol): total cholesterol

1.44. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 44: Subgroup analysis (baseline cholesterol): LDL cholesterol

1.45. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 45: Subgroup analysis (baseline cholesterol): withdrawal due to adverse events

1.46. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 46: Subgroup analysis (baseline cholesterol): HDL cholesterol

1.47. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 47: Subgroup analysis (baseline cholesterol): triglycerides

Allocation concealment

We assessed if allocation concealment resulted in effect modification and found that for the outcome of death, a test of subgroup differences was significant (Analysis 1.48: test for subgroup differences: Chi² = 5.70, df = 1 (P = 0.02), I² = 82.5%). Studies with high or unclear risk of bias indicated little to no effect (5 studies, 2838 participants: RR 0.98 95% CI 0.82 to 1.16), while studies with appropriate allocation concealment demonstrated a benefit of statin therapy (8 studies, 32,142 participants: RR 0.77, 95% CI 0.70 to 0.84). Furthermore, subgroup differences were demonstrated in total cholesterol (Analysis 1.49: test for subgroup differences: Chi² = 4.83, df = 1 (P = 0.03), I² = 79.3%), but the subgroup effect estimates are in the same direction and the 95% CI overlapped and hence considered not important. No effect modification was evident for major cardiovascular events (Analysis 1.50) and triglycerides (Analysis 1.51).

1.48. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 48: Subgroup analysis (allocation concealment): death

1.49. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 49: Subgroup analysis (allocation concealment): total cholesterol

1.50. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 50: Subgroup analysis (allocation concealment): major cardiovascular events

1.51. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 51: Subgroup analysis (allocation concealment): triglycerides

Baseline kidney function

A post hoc analysis was undertaken to examine the influence of baseline kidney function on the outcome end of treatment kidney function. We found that there was no effect modification evident (Analysis 1.52: test for subgroup differences: Chi² = 0.07, df = 1 (P = 0.79), I² = 0%). Studies with lower kidney function at baseline (< 55 mL/min/1.73 m²)demonstrated little or no effect on (5 studies, 3207 participants: MD 1.56 mL/min/1.73 m², 95% CI ‐3.02 to 6.15), but studies with higher kidney function at baseline (≥ 55 mL/min/1.73 m²)indicated that there might be a small increase in kidney function at the end of treatment (12 studies, 963 participants: MD 2.24 mL/min/1.73 m², 95% CI 0.30 to 4.17).

1.52. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 52: Subgroup analysis (kidney function): end of treatment kidney function

Sensitivity analyses

We excluded SHARP 2010 from the meta‐analysis for primary outcomes because it added ezetimibe to statin therapy. We found no differences for major cardiovascular events and death. The summary treatment estimates were essentially unchanged (Analysis 1.53: RR 0.70, 95% CI 0.63 to 0.77) (Analysis 1.54: RR 0.80, 95% CI 0.70 to 0.90).

1.53. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 53: Sensitivity analysis (excluding SHARP): major cardiovascular events

1.54. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 54: Sensitivity analysis (excluding SHARP): death

Excluding studies with industry funding, we found that in studies with non‐industry funding or where funding was not reported, major cardiovascular events were decreased with statin therapy compared to placebo (Analysis 1.55), similar to the meta‐analysis with all included studies (Analysis 1.1). However, for death, studies with no industry funding or where funding was not reported, statins compared to placebo made no difference (Analysis 1.56), unlike the full analysis that found statins decreased death compared to placebo. Although the effect estimates direction indicates a decrease in death, the exclusion of studies may decrease the precision of the finding, and hence the finding should be interpreted with caution. There was insufficient data to examine the effect on rhabdomyolysis.

1.55. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 55: Sensitivity analysis (funding): major cardiovascular events

1.56. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 56: Sensitivity analysis (funding): death

Excluding large studies from the analysis (N > 3500) did not change the direction and size of the effect estimates for the primary outcomes, major cardiovascular events and death (data not shown).

The following sensitivity analyses were considered but not undertaken.

• Repeating the analysis excluding unpublished studies (due to limited unpublished studies)

• Repeating analysis taking account of risk of bias (due to limited low risk of bias studies)

• Repeating the analysis using the following filters: diagnostic criteria, language of publication, and country.

Meta‐regression

Considerable heterogeneity (I² = 53%) was found for the primary outcome of death. Subgroup analyses to explore heterogeneity among the studies found that kidney function at baseline accounted for 100% of the observed heterogeneity in the meta‐analysis for death. Additionally, subgroup analysis indicated that baseline kidney function (98.8% of heterogeneity explained), the proportion with diabetes (99.6%), and adequacy of allocation concealment (100%) modified the observed risks of withdrawal due to adverse events. These findings were exploratory and should be interpreted with caution.

Assessment of publication bias

Publication bias was assessed for all outcomes listed in Table 1, which included more than 10 studies. The funnel plots for the outcomes of major cardiovascular events (Figure 4), death (Figure 5), and MI (Figure 6) were symmetrical and indicated little concern regarding small study effects. No further statistical testing was undertaken to assess publication bias for these outcomes.

4.

Funnel plot of comparison: 1 Statins versus placebo or no treatment, outcome: 1.1 Major cardiovascular events.

5.

Funnel plot of comparison: 1 Statins versus placebo or no treatment, outcome: 1.2 Death.

6.

Funnel plot of comparison: 1 Statins versus placebo or no treatment, outcome: 1.5 Myocardial infarction.

Statin therapy versus different statin therapy

PLANET I 2006 and PLANET II 2006 compared low‐ and high‐dose rosuvastatin and atorvastatin and found both therapies were well tolerated, with few events to determine the difference between primary outcome death and secondary outcomes, doubling of SCr and AKI.

IDEAL 2004 compared simvastatin with atorvastatin, Abe 2015 compared rosuvastatin with pitavastatin, Ikeda 2012 compared pravastatin with rosuvastatin, Kimura 2012 compared pitavastatin with pravastatin, and SAGE 2004 compared atorvastatin with pravastatin. Sample sizes ranged from 28 to 3107 participants. The median follow‐up was 12 months (range 12 to 58.8 months). Baseline LDL cholesterol levels ranged from 3.05 to 3.9 mmol/L. Meta‐analysis was not possible because there was insufficient data for each comparison. It was unclear which statin therapy was the most effective and safe from these studies. IDEAL 2004 reported the primary outcome of major cardiovascular events,

Secondary outcomes reported in the identified studies included LDL cholesterol, HDL cholesterol, total cholesterol, triglyceride, MDA‐LDL, non‐HDL cholesterol, SCr, cystine C, urinary albumin/creatinine ratio, hs‐CRP, HbA1c, eGFR, adverse events, the cost to lower LDL cholesterol by 10 mg/dL, onset of diabetes, time to first occurrence of a major coronary event, any chronic heart disease event, any cardiovascular event, urinary protein excretion, kidney failure, AKI, and serum uric acid.

High versus low dose statin

PANDA 2011 and TNT 2004 compared two doses of atorvastatin, and PLANET I 2006 and PLANET II 2006 compared low‐ and high‐dose rosuvastatin.

Primary outcomes

High‐dose statin compared to low‐dose statin may have little or no effect on major cardiovascular events (Analysis 2.1 (2 studies, 3226 participants): RR 1.17, 95% CI 0.25 to 5.55; I² = 59%; low certainty evidence), and death (Analysis 2.2 (3 studies, 3465 participants): RR 1.05, 95% CI 0.29 to 3.83; I² = 56%; low certainty evidence). No events of rhabdomyolysis were reported.

2.1. Analysis.

Comparison 2: High dose versus low dose statin, Outcome 1: Major cardiovascular events

2.2. Analysis.

Comparison 2: High dose versus low dose statin, Outcome 2: Death

Secondary outcomes

TNT 2004 (3107 participants) reported high‐dose statin may decrease stroke (Analysis 2.3: RR 0.67, 95% CI 0.50 to 0.89) and hospitalisation due to heart failure (Analysis 2.4: RR 0.55, 95% CI 0.39 to 0.77; low certainty evidence) compared to low‐dose statin. High‐dose statin, compared to low‐dose statin, probably has little or no effect on serious adverse events (Analysis 2.5 (2 studies, 358 participants): RR 1.12, 95% CI 0.73 to 1.72; I² = 0%; moderate certainty evidence), but there was limited data on AKI and doubling of SCr to determine if high‐dose statin made a difference. However, high‐dose statins may increase elevated liver enzymes (Analysis 2.6: RR 20.67, 95% CI 2.79 to 153.14; low certainty evidence) compared to low‐dose statins. PLANET I 2006 (223 participants) reported high‐ versus low‐dose rosuvastatin may improve change in total cholesterol and LDL cholesterol at 12 months, but there was no difference in change in HDL cholesterol and change in triglycerides. No other secondary outcomes were reported in the included studies.

2.3. Analysis.

Comparison 2: High dose versus low dose statin, Outcome 3: Stroke

2.4. Analysis.

Comparison 2: High dose versus low dose statin, Outcome 4: Hospitilisation due to heart failure

2.5. Analysis.

Comparison 2: High dose versus low dose statin, Outcome 5: Serious adverse events

2.6. Analysis.

Comparison 2: High dose versus low dose statin, Outcome 6: Elevated liver enzyme

Continuous release versus intermittent release statin

Yi 2014 (122 participants) compared continuous‐release to intermittent‐release statin (20 mg/day). No primary outcomes of major cardiovascular events, death, or rhabdomyolysis were reported. There were few withdrawals due to adverse events in the study. Continuous‐release versus intermittent‐release statin may have little or no effect on total cholesterol, LDL cholesterol, and HDL cholesterol, but may increase triglycerides. No other secondary outcomes were reported.

There was insufficient data to perform a meta‐analysis for this comparison.

Discussion

Summary of main results

This update confirmed findings from the previous 2014 review (Palmer 2014). Compared to placebo, statins reduced the risk of death by 20% and major cardiovascular events by 28% in people with CKD not needing dialysis. Statins probably reduce the risk of MI by nearly half, but the effects on stroke and hospitalisation due to heart failure remain uncertain. Statins decreased death, major cardiovascular events, and MI in people with (secondary prevention) and without CVD (primary prevention).

Considering the estimated baseline risk of people with CKD not needing dialysis (Table 1), statins given to 1000 people with CKD for one year might be expected to prevent 32 major cardiovascular events, 10 deaths from any cause, and seven non‐fatal or fatal MIs. There was limited reporting of adverse effects of statins in people with CKD not needing dialysis. Withdrawal due to adverse effects probably occurs more frequently among those with lower kidney function or pre‐existing diabetes, suggesting that these people may be more at risk of treatment‐related toxicity. However, there was uncertainty regarding the effect on rhabdomyolysis due to the few events reported and no reporting of patient‐important outcomes such as fatigue, life participation, and memory loss.

Data comparing different statins were sparse in patients with CKD. One study reported a benefit of high‐dose statins in reducing stroke and heart failure events compared to low‐dose statins, but a further examination of this finding is required. Additionally, there was limited reporting of safety in studies comparing high‐ versus low‐dose statins.

Overall completeness and applicability of evidence

Based on current evidence, statins probably make little to no difference to CKD progression, as treatment effects were similar to placebo with more than 2000 events. However, statins probably have a slight benefit on kidney function and may reduce proteinuria due to the pleiotropic effects of statins, but the clinical importance of these outcomes is unclear. Nearly two‐thirds of the included studies did not systematically evaluate and report adverse events, such as rhabdomyolysis and elevated liver enzymes. There was no reporting of patient‐important outcomes, such as fatigue, memory loss, and life participation.

SHARP 2010 assessed ezetimibe (a drug that lowers cholesterol absorption in the intestine) combined with simvastatin. There was insufficient data to determine if treatment effects differed between combination therapy and treatment with a statin alone. There was limited data that could be used to determine the most effective and safe type of statin or dose of statin in the CKD population. Furthermore, it was unclear if treatment benefits for statins depended on treatment‐related reductions in serum cholesterol or by another mechanism of action, as there were insufficient number of studies that reported both cardiovascular and death outcomes and changes in cholesterol levels with treatment.

Quality of the evidence

Overall, the quality of the evidence in clinical outcomes (death, cardiovascular events, kidney failure) for shared decision‐making for statin with or without ezetimibe is high to moderate certainty evidence. However, the data for patient‐important outcomes, such as rhabdomyolysis is very low or not reported for fatigue, life participation and memory loss.

Current data on the effects of statins in people with earlier stages of kidney disease relating to the primary outcomes of death and cardiovascular events were derived from post hoc subgroup analyses from major studies in larger populations (4S 1993; AFCAPS/TexCAPS 1997; ALLIANCE 2000; CARDS 2003; HPS 2002; JUPITER 2007; LIPS 2001; MEGA 2004; PPP 1992; PREVEND IT 2000; SHARP 2010). Data for treatment effects in people with CKD derived from post hoc analyses of larger studies may be less reliable (Boutron 2010). The heterogeneity observed in our review was not explained by prespecified or post hoc studies of people with CKD, as the effects estimates in all studies were similar.

Potential biases in the review process

This review is reported using standardised Cochrane methods and the PRISMA checklist (Liberati 2009). It includes a highly sensitive electronic search of the Cochrane Kidney and Transplant's Specialised Registry of Studies, designed by an Information Specialist. Despite applying these best practice approaches, potential biases may exist in the review process. Incomplete reporting of outcomes in the identified studies limited the power to detect differences among interventions for important outcomes. For example, data for treatment effects on stroke and hospitalisation due to heart failure suggest a potential for benefit, but the small number of events resulted in imprecision in the effect estimate. This incomplete reporting of outcomes may also limit the statistical power to detect heterogeneity. However, the analysis of most outcomes exhibits low to moderate heterogeneity, indicating that the meta‐analysis was appropriate. Additionally, we could not include data for people with CKD not on dialysis from Stegmayr 2005 for death and cardiovascular death. Reported data for these outcomes combined results for people on dialysis with those at earlier stages of kidney disease not on dialysis; separate unpublished data for earlier stages of kidney disease were not available.

Agreements and disagreements with other studies or reviews

This update confirmed our earlier review findings that statins reduce serious cardiovascular events and death in people with CKD not requiring dialysis (Palmer 2014). The finding that statins proportionally reduce cardiovascular death by 20% is similar to the prospective meta‐analysis in broader populations of people who had or were at risk for CVD, which showed that statins lowered lipids to reduce coronary‐related death at a rate of 20% (Baigent 2005). People with CKD risk cardiovascular events equivalent to those with existing coronary artery disease (Foley 1998). The absolute benefits of statins in people with CKD are similar to people with a 20% or more 10‐year absolute cardiovascular risk, for whom statins are recommended (NICE 2014).

We also found that statins reduced death by approximately 28%, similar to the 10% proportional reduction in broader populations (Baigent 2005). The inclusion of studies conducted in people with CKD without clinically evident CVD in this review (Abe 2011c; Masajtis‐Zagajewska 2018; Ohsawa 2015) reaffirmed the previous finding that statins have a role in the primary prevention of death and major cardiovascular events (Palmer 2014). The beneficial effect of statins on cardiovascular end‐points observed in our review may be potentially explained by either cholesterol‐dependent or cholesterol‐independent effects or both. In addition to the well‐documented association between cholesterol‐lowering and cardiovascular risk reduction in non‐CKD populations (Baigent 2005), statins may modulate cardiovascular risk by decreasing inflammation, enhancing endothelial function, inhibiting smooth muscle proliferation, exerting direct anti‐thrombotic properties and stabilising pre‐existing atherosclerotic plaque (Kinlay 2003; Robinson 2005; Sotiriou 2000). Similar mechanisms may underpin the beneficial actions of statins on the progression of kidney disease, although other cholesterol‐independent renoprotective actions such as inhibition of renal cell proliferation, anti‐fibrotic effects, suppression of macrophage recruitment, anti‐oxidation, and down‐regulation of inflammatory cytokines, may also contribute (Campese 2005; Keane 2000).

Notably, the finding that statins significantly reduce adverse cardiovascular outcomes in people with earlier stages of CKD contrasts with a similar systematic review and meta‐analysis we have conducted of studies in people with advanced kidney disease on dialysis (Palmer 2013). Statin therapy in people with advanced CKD on dialysis has little or no effect on major cardiovascular events (RR 0.95, 95% CI 0.88 to 1.03), death (any cause) (RR 0.96, 95% CI 0.90 to 1.02), cardiovascular death (RR 0.94, 95% CI 0.84 to 1.06), or MI (RR 0.87, 95% CI 0.71 to 1.07) with uncertain effects on liver or muscle function or cancer, despite a similar reduction in cholesterol levels. Similarly, an individual patient‐level meta‐analysis of 28 RCTs found that the effects of statins decreased with declining kidney function, with patients on dialysis receiving little to no benefit from statins (Herrington 2016).

The KDIGO Lipids in CKD guideline recommends statins for patients 50 years or older and an eGFR ≥ 60 mL/min/1.73 m² "For patients 50 years of age and older and eGFR < 60 mL/min/1.73 m² not needing dialysis, a statin with or without ezetimibe" (KDIGO 2013). Additionally, CARI Guidelines (CARI 2013) recommend using statins with or without ezetimibe in patients with early CKD (stages 1 to 3) to reduce the risk of atherosclerotic disease. Our analysis confirms the benefits of statins in people with CKD (including primary prevention of death and cardiovascular events) and supports the present guidelines. However, there is limited data on the incremental benefit of ezetimibe combined with statins in people with CKD.

Authors' conclusions

Implications for practice.

Moderate‐to‐high‐quality evidence currently supports the widespread use of statins for people with CKD not on dialysis to prevent death and cardiovascular events, including people without existing CVD. Statins reduce death and cardiovascular events, including MI, although effects on the risk of stroke were less certain. Treating 1000 people with CKD not on dialysis may prevent 32 major cardiovascular events and 10 deaths over one year. Statins have uncertain effects on the progression of CKD and cannot be recommended to slow the progression of CKD. Currently, the toxicity of statins for people with CKD is poorly characterised in studies, and this needs to be acknowledged when commencing treatment.

Implications for research.

Available data confirms the benefit of statins in reducing lipid levels and improving death and cardiovascular death in people with CKD not needing dialysis. Future research, including post‐marketing surveillance, is required to monitor the safety of statins in people with CKD, with a focus on risks of muscle or liver damage associated with longer‐term treatment. A co‐ordinated approach to post‐marketing surveillance might be considered.

Currently, the available evidence depends largely on post hoc analyses from larger studies. Future prospective studies of primary prevention in people with moderate to severe CKD (eGFR 15 to 60 mL/min/1.73 m²), including a detailed assessment of treatment toxicity, are warranted. PLANET I 2006 and PLANET II 2006 have demonstrated that the type of statin may have different effects on kidney function, including proteinuria. A network meta‐analysis to rank the efficacy of the type of statin is warranted. Additionally, future prospective studies comparing statins combined with ezetimibe with statins alone in people with moderate to severe CKD are warranted because of a lack of certainty regarding the benefits and harms of therapy from the several small published trials. Finally, further examination of the type of statin should be considered.

Feedback

Review conclusions (2009 review),

Summary

Navaneethan SD et al (Navaneethan 2009¹) in their systematic review titled ‘HMG CoA reductase inhibitors (statins) for people with chronic kidney disease (CKD) not requiring dialysis’ came to the conclusion that “statins cause a significant reduction in the risk of all‐cause mortality and cardiovascular mortality in CKD patients who are not requiring dialysis.” We feel that this claim requires reassessment based on the following reasons.

For the outcome all‐cause mortality, the review included 21 ‘individual’ studies. The results of this outcome were driven (99%) by a pooling of three individual studies (LIPID², CARE³ and WOSCOPS⁴). These three trials were included as one entry (PPP 2004⁵) in the forest plot (analysis 1.1). The pooling of these three trials is incorrect in a meta‐analysis as it gives improper weighting to the data. Inappropriate pooling of data as one study can negatively impact the weight and precision that would be apparent had these trials been entered as separate studies. The review explained that the reason for pooling the trials is that they could not get the data in a separate form. This however, is not a sufficient reason to pool the trials together as one. Also, the review references the subgroup analysis of CARE, where the individual data is reported separately. We would like to know the attempts that were made to obtain individual trial data and see this in an updated review.

Secondly, we are concerned with how studies were identified and included in this review. While the PPP makes up 99% of the all‐cause mortality data, we are aware of many other statin trials with mortality data. For example, the Heart Protection Study (HPS 2003) was included in non‐fatal CV events (analysis 1.3), but not for all‐cause or cardiovascular mortality. We are unclear as to the efforts that were made to obtain subgroup data on kidney disease patients from all of the statin trials published. We have the same concern as above with respect to those studies that were excluded from this review. Figure 1 provides a flow diagram of the number of trials excluded, however the authors do not describe in detail the reasons for exclusion.

Third, the PPP publication separates individuals into normal, mild and moderate kidney disease (GFR 30‐59.99 mL/min/1.73m²). According to this paper, the total amount of patients that would meet the inclusion criteria of this Cochrane review (that is moderate kidney disease) would be 4,491, instead of the 16,824 that were actually analysed. This means that there were approximately an extra ~12,000 patients included in this review that who not actually meet the inclusion criteria of moderate kidney disease. We would like to know what efforts were made to extract this data and what process was done to see if the extra 12,000 patients fit the other inclusion criteria of this Cochrane review (i.e. some form of kidney disease, but normal renal function, elevated baseline serum creatinine). Upon review of two of the individual trials, we could not find any indication for inclusion of the patient data in this Cochrane review based on what was reported in the publications.

With respect to serious adverse events, this review does not specifically address all of the potential harms associated with statins. The Cholesterol Treatment Trialists’ (CTT) collaboration⁶ report an increased risk of hemorrhagic stroke with statin use, with high dose vs. low dose and compared to control. This increase although not statistically significant, is a concern of statin use that should be addressed when considering the benefit and risk of this class of medications.

Two of the three trials included (LIPID and CARE) were secondary prevention trials. That is, patients whom had already experienced an event (e.g. myocardial infarction, stroke). The benefit of statins in secondary prevention, irrespective of CKD has already been well established. The authors do outline that they were including patients with or without coronary artery disease, however the bigger question that remains unanswered is there any benefit of statins in a primary prevention patient with CKD. The SHARP⁷ trial aimed to answer this question in a dialysis and non‐dialysis population, and found no reduction in all‐cause mortality or cardiovascular mortality. Including both primary and secondary prevention trials together can bias the end result in favour of treatment for the entire population, when in fact the benefit may only exist in secondary prevention patients. Given the above issues, we cannot be certain of the benefit that is claimed for statins in non‐dialysis CKD patients.

We hope this provides some constructive feedback for the next review. We look forward to hearing from you.

Sincerely,

Megan Harbin, BSc.Pharm, Pharmacy Resident

Anthony Amadio, BSc.Pharm, ACPR, PharmD Student

Aaron Tejani, BSc.Pharm, PharmD

The authors of this letter have no known conflicts of interest to declare.

References:

1. Navaneethan SD, Pansini F, Perkovic V, Manno C, Pellegrini F, Johnson DW, Craig JC, Strippoli GFM. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD007784. DOI: 10.1002/14651858.CD007784.

2. Anonymous. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long‐Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.[see comment]. New England Journal of Medicine 1998;339(19): 1349–57.

3. Tonelli M, Moye L, Sacks FM, Kiberd B, Curhan G, Cholesterol and Recurrent Events (CARE) Trial Investigators. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Annals of Internal Medicine 2003;138 (2):98–104.

4. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. West of Scotland Coronary Prevention Study Group. New England Journal of Medicine 1995; 333(20):1301–7

5. Tonelli M, et al. Effect of Pravastatin on Cardiovascular Events in People with Chronic Kidney Disease. Circulation 2004;110:1557‐1563.

6. Baigent C, Blackwell L, Emberson J et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta‐analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376(9753):1670‐1681.

7. Baigent C, Landray MJ, Reith C, et al, on behalf of the SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus Registryibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo‐controlled trial. Lancet 2011; 377: 2181–92.

Reply

Dear Ms.Harbin,

We like to thank you for your careful review of our Cochrane systematic review titled‐ HMG CoA reductase inhibitors for people with chronic kidney disease not requiring dialysis published in 2009. Please see our responses below which answers your specific concerns:

Pooling of Pravastatin Pooling Project with other studies: We obtained additional unpublished data for the Pravastatin pooling project from Dr. Tonelli (email communication by Dr. Strippoli). As discussed in the review, we attempted to obtain individual trial data but without success. An updated systematic review that examined the use of statins in patients with varying severity of kidney disease was published in 2012 (Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Ann Intern Med. 2012 Aug 21;157(4):263‐75). This review included additional studies and reported results separately for those who were on dialysis, received renal transplant and those who had non‐dialysis dependent CKD. Cochrane reviews get updated every 2‐3 years to include any new studies that gets published. Update of our 2009 Cochrane review is in press (to be published in late 2013) and clarify some other issues pointed out by you.

Inclusion of other studies with CKD sub‐groups: Thanks for pointing out this. We have included the Heart Protection Study and other trials that provided data relating to those with CKD in the updated review (Palmer SC et al. Annals of Internal Medicine 2012) and the upcoming Cochrane Review. In the updated Cochrane review (in Press), reasons for exclusion were provided in Figure 1.

Confirmation of CKD: We reported the total number of patients included in the studies and agree that not all participants had CKD and only 4491/19700 patients in the Pravastatin Pooling Project had CKD. We did not have access to the original data for this study precluding us to assess whether others had any other forms of kidney disease (such as dialysis or renal transplant). These could be addressed by an individual patient‐level meta‐analysis that could be considered by other investigators in future.

Inclusion of stroke as an adverse event: We extracted details relating to adverse events from all individual studies. Even though few trials reported increased incidence of stroke in dialysis population, there was no increased risk for this subgroup (RR, 0.61 [CI, 0.38 to 0.98]) (Palmer SC et al. Annals of Internal Medicine 2012). These data were not included in the 2009 Cochrane Review but will be available in the update Cochrane review.

Statins for primary vs. secondary prevention: This important issue that has been discussed in the literature (Erickson et al. J Am Coll Cardiol. 2013 Mar 26;61(12):1250‐8 and Massy et al. Kidney Int. 2013 Sep;84(3):451‐6 and Updhyay et al Ann Intern Med. 2012 Aug 21;157(4):251‐62.). CKD population have significant CV disease burden with higher coronary events (Tonelli M et al. Lancet 2012 Sep 1;380(9844):807‐14) arguing for the use of statins as a primary prevention measure. As you pointed out, SHARP trial reported a statistically significant reduction in atherosclerotic events (primary outcome measure) but no significant reduction in the individual secondary end‐points. Given the limited data available relating to primary and secondary prevention with statins in CKD, primary and secondary prevention trials were pooled together in our review.

In summary, we agree with some of the issues raised by you and your team members. We have added additional details suggested by you in the updated Cochrane review (in press) and in the paper published in Annals of Internal Medicine (Palmer SC et al. 2012). However, we do have several unanswered questions that might be addressed in future clinical trials to better treat our patients. Once again, thank you for the constructive feedback.

Sincerely,

Sankar Navaneethan, MD, MPH,

Suetonia Palmer, MBChB, PhD

Giovanni Strippoli MD, MM, MPH, PhD.

Contributors

Megan Harbin, BSc.Pharm, Pharmacy Resident

Anthony Amadio, BSc.Pharm, ACPR, PharmD Student

Aaron Tejani, BSc.Pharm, PharmD

Sankar Navaneethan, MD, MPH,

Suetonia Palmer, MBChB, PhD

Giovanni Strippoli MD, MM, MPH, PhD.

What's new

Date	Event	Description
13 December 2023	Amended	Minor amendment to Plain Language Summary

History

Protocol first published: Issue 2, 2009
Review first published: Issue 2, 2009

Date	Event	Description
29 November 2023	New search has been performed	New search
29 November 2023	New citation required but conclusions have not changed	Thirteen new included studies added
8 July 2014	Amended	Sources of external support amended
7 July 2014	Amended	Declarations of interests amended
10 June 2014	Feedback has been incorporated	Feedback on original review incorporated
9 May 2014	New citation required and conclusions have changed	New studies included
9 May 2014	New search has been performed	Methods updated, new authors, new search preformed
4 March 2012	Amended	Author added (SP) and contact details updated.
1 March 2012	New search has been performed	Updated search to February 2012. 24 new trials included (14,803 additional participants). Results and conclusions updated. Conclusions generally unchanged.
13 May 2009	Amended	Contact details updated.
3 July 2008	Amended	Converted to new review format.

Appendices

Appendix 1. Electronic search strategies

Database	Search terms
CENTRAL	pre‐dialy* or predialy*:ti,ab,kw in Clinical Trials MeSH descriptor Kidney Diseases, this term only chronic kidney*:ti,ab,kw in Clinical Trials chronic renal*:ti,ab,kw in Clinical Trials MeSH descriptor Renal Insufficiency, this term only MeSH descriptor Renal Insufficiency, Chronic explode all trees (CKF or CKD or CRF or CRD):ti,ab,kw in Clinical Trials ur?emi*:ti,ab,kw in Clinical Trials MeSH descriptor Uremia explode all trees in Clinical Trials (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9) MeSH descriptor Hydroxymethylglutaryl‐CoA Reductase Inhibitors explode all trees hydroxymethylglutaryl‐CoA reductase inhibitor*:ti,ab,kw in Clinical Trials HMG CoA reductase inhibitor*:ti,ab,kw in Clinical Trials HMG Co A reductase inhibitor*:ti,ab,kw in Clinical Trials statin*:ti,ab,kw in Clinical Trials atorvastatin:ti,ab,kw or cerivastatin:ti,ab,kw or dalvastatin:ti,ab,kw or fluindostatin:ti,ab,kw in Clinical Trials fluvastatin: ti,ab,kw or simvastatin:ti,ab,kw or lovastatin:ti,ab,kw or pitavastatin:ti,ab,kw in Clinical Trials pravastatin:ti,ab,kw or rosuvastatin:ti,ab,kw or simvastatin:ti,ab,kw in Clinical Trials meglutol:ti,ab,kw or mevinolin:ti,ab,kw or monacolin:ti,ab,kw or pravachol:ti,ab,kw or lipex:ti,ab,kw or lipitor:ti,ab,kw or zocor:ti,ab,kw or mevacor:ti,ab,kw or lescol:ti,ab,kw or baycol:ti,ab,kw in Clinical Trials (#11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19) (#10 AND #20)
MEDLINE	Renal Insufficiency/ exp Renal Insufficiency, Chronic/ Kidney Diseases/ (chronic kidney or chronic renal).tw. (CKF or CKD or CRF or CRD).tw. (predialysis or pre‐dialysis).tw. exp Uremia/ ur$emi$.tw. Diabetic Nephropathies/ diabetic kidney disease$.tw. diabetic nephropath$.tw. or/1‐11 exp Hydroxymethylglutaryl‐CoA Reductase Inhibitors/ "hydroxymethylglutaryl‐CoA reductase inhibitor$".tw. ("HMG CoA reductase inhibitor$" or "HMG Co A reductase inhibitor$").tw. statin$.tw. atorvastatin.tw. cerivastatin.tw. dalvastatin.tw. fluindostatin.tw. fluvastatin.tw. lovastatin.tw. pitavastatin.tw. pravastatin.tw. rosuvastatin.tw. simvastatin.tw. (meglutol or mevinolin$ or monacolin$ or pravachol or lipex or lipitor or zocor or mevacor or lescol or baycol).tw. or/13‐27 and/12,28
EMBASE	Kidney Disease/ Chronic Kidney Disease/ Kidney Failure/ Chronic Kidney Failure/ Kidney dysfunction/ (chronic kidney or chronic renal).tw. (CKF or CKD or CRF or CRD).tw. (pre‐dialy$ or predialy$).tw. or/1‐8 exp Hydroxymethylglutaryl Coenzyme a Reductase Inhibitor/ hydroxymethylglutaryl‐CoA reductase inhibitor$.tw. HMG CoA reductase inhibitor$.tw. HMG Co A reductase inhibitor$.tw. statin$.tw. atorvastatin.tw. cerivastatin.tw. dalvastatin.tw. fluindostatin.tw. fluvastatin.tw. lovastatin.tw. pitavastatin.tw. pravastatin.tw. rosuvastatin.tw. simvastatin.tw. (meglutol or mevinolin$ or monacolin$ or pravachol or lipex or lipitor or zocor or mevacor or lescol or baycol).tw. or/10‐25 and/9,26

Appendix 2. Risk of bias assessment tool

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Appendix 3. Living systematic review protocol

Systematic review section	Methods considerations specific to living systematic reviews	Comments
Title	HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis	The title of the review will remain the same, with no indication that the review has been changed to a living review
What's New	New events including will be highlighted in the 'What's new' table at the beginning of the review. This table will highlight all updates of the living systematic review to identify changes in currency of the review.	Events may include, new citation: conclusions not changed etc, new citation: conclusions changed etc.
Abstract	Editorial note: This is a living systematic review. We search for new evidence every three months and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.	We will include the following statement in the abstract
Plain language summary	Editorial note: Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.	We will include the following statement in the plain language summary
Methods: Search methods for identification of studies
Electronic sources	An updated search of the Cochrane Kidney and Transplant Register of Studies will be undertaken every 3 months
Searching other sources	No proposed change – maintain Cochrane Kidney and Transplant Registry of studies current handsearching
Methods: Data collection analysis
Selection of studies	We will immediately screen any new citations retrieved by three monthly searches. Additionally, moderated crowd sourcing platforms may be used to support screening of the literature, for example Cochrane Crowd.
Inclusion criteria	No proposed changes
Data extraction and management, Assessment of risk of bias of included studies	No proposed changes
Measurement of treatment effect, unit of analysis issues, dealing with missing data	No proposed changes
Assessment of heterogeneity, Assessment of reporting biases	No proposed changes
Data synthesis	Decide when to incorporate new evidence All included studies future review updates will undergo data extraction and critical appraisal by two authors (BC and DJT) independently, using Robot Reviewer (https://www.robotreviewer.net/) as supportive tool. Whenever new evidence (meaning studies, data or other information) relevant to the review is identified, we will extract the data and assess risk of bias, as appropriate. We will wait until the accumulating evidence changes one or more of the following components of the review before incorporating it and re‐publishing the review: The findings of one or more primary outcomes The credibility (e.g. GRADE rating) of one or more primary outcomes New settings, populations, interventions, comparisons or outcomes studied New serious adverse events Adjustments for repeated meta‐analyses Formal sequential meta‐analysis approaches will not be used for updated meta‐analyses.
Subgroup analysis and investigation of heterogeneity, Sensitivity analysis, Summary of Findings Table	Summary of findings tables will be developed in GRADEPro and will be exported to Review Manager.
Methods for future updates	The conduction and production of this living systematic review will be overseen by the CARI Guidelines Living Evidence Working Group and the Statins in CKD Guideline Work Group. We will review the scope and methods when updating the review, in the light of potential changes in the topic area or new evidence. For example, additional comparisons, interventions, subgroups, outcomes, or new review methods available. At every three monthly search, we will consider the necessity for the review to be living. By assessing the questions ongoing relevance to decision‐makers and by determining if continuing uncertainty in the evidence is presence, and whether further relevant research is likely to change recommendations for clinical practice via the CARI Guidelines Statins in CKD Living Guideline.

Data and analyses

Comparison 1. Statins versus placebo or no treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Major cardiovascular events	14	36156	Risk Ratio (IV, Random, 95% CI)	0.72 [0.66, 0.79]
1.2 Death	13	34978	Risk Ratio (IV, Random, 95% CI)	0.83 [0.73, 0.96]
1.3 Rhabdomyolysis	2	2618	Risk Ratio (IV, Random, 95% CI)	3.07 [0.13, 75.37]
1.4 Cardiovascular death	8	19112	Risk Ratio (IV, Random, 95% CI)	0.77 [0.69, 0.87]
1.5 Myocardial infarction	10	9475	Risk Ratio (IV, Random, 95% CI)	0.55 [0.42, 0.73]
1.6 Stroke	7	9115	Risk Ratio (IV, Random, 95% CI)	0.64 [0.37, 1.08]
1.7 Revascularisation procedure	3	4156	Risk Ratio (IV, Random, 95% CI)	0.62 [0.47, 0.82]
1.8 Hospitilsation due to heart failure	1	579	Risk Ratio (IV, Random, 95% CI)	0.70 [0.37, 1.32]
1.9 Kidney failure	3	6704	Risk Ratio (IV, Random, 95% CI)	0.98 [0.91, 1.05]
1.10 Doubling serum creatinine	1	6245	Risk Ratio (IV, Random, 95% CI)	0.90 [0.79, 1.02]
1.11 End of treatment kidney function	18	4213	Mean Difference (IV, Random, 95% CI)	1.83 [0.27, 3.39]
1.11.1 CrCl [mL/min]	7	319	Mean Difference (IV, Random, 95% CI)	5.19 [0.58, 9.79]
1.11.2 eGFR [mL/min/1.73 m²]	11	3894	Mean Difference (IV, Random, 95% CI)	1.01 [0.46, 1.57]
1.12 End of treatment proteinuria	7	356	Mean Difference (IV, Random, 95% CI)	‐0.47 [‐0.75, ‐0.19]
1.13 Elevated liver enzymes	7	7991	Risk Ratio (IV, Random, 95% CI)	0.76 [0.39, 1.50]
1.14 Withdrawal due to adverse events	13	4219	Risk Ratio (IV, Random, 95% CI)	1.10 [0.83, 1.48]
1.15 Cancer	2	5581	Risk Ratio (IV, Random, 95% CI)	1.03 [0.82, 1.30]
1.16 Onset of diabetes	1	3267	Risk Ratio (IV, Random, 95% CI)	1.03 [0.71, 1.50]
1.17 Elevated creatine kinase	7	4514	Risk Ratio (IV, Random, 95% CI)	0.84 [0.20, 3.48]
1.18 Total cholesterol	27	2234	Mean Difference (IV, Random, 95% CI)	‐50.26 [‐64.34, ‐36.17]
1.19 LDL cholesterol	24	2183	Mean Difference (IV, Random, 95% CI)	‐43.84 [‐52.56, ‐35.12]
1.20 Triglycerides	20	1186	Mean Difference (IV, Random, 95% CI)	‐26.02 [‐40.99, ‐11.06]
1.21 HDL cholesterol	22	1374	Mean Difference (IV, Random, 95% CI)	2.92 [‐0.03, 5.88]
1.22 Subgroup analysis (cardiovascular disease): death	12	34857	Risk Ratio (IV, Random, 95% CI)	0.80 [0.73, 0.88]
1.22.1 No cardiovascular disease	4	13462	Risk Ratio (IV, Random, 95% CI)	0.70 [0.55, 0.90]
1.22.2 Cardiovascular disease	8	21395	Risk Ratio (IV, Random, 95% CI)	0.82 [0.76, 0.89]
1.23 Subgroup analysis (cardiovascular disease): major cardiovascular events	14	36156	Risk Ratio (IV, Random, 95% CI)	0.72 [0.66, 0.79]
1.23.1 No cardiovascular disease	5	13766	Risk Ratio (IV, Random, 95% CI)	0.60 [0.46, 0.79]
1.23.2 Cardiovascular disease	9	22390	Risk Ratio (IV, Random, 95% CI)	0.76 [0.71, 0.81]
1.24 Subgroup analysis (statin dose): major cardiovascular death	14	36156	Risk Ratio (IV, Random, 95% CI)	0.72 [0.66, 0.79]
1.24.1 < 20 mg/day simvastatin equivalent	4	3630	Risk Ratio (IV, Random, 95% CI)	0.49 [0.37, 0.64]
1.24.2 ≥ 20 mg/day simvastatin equivalent	10	32526	Risk Ratio (IV, Random, 95% CI)	0.77 [0.74, 0.81]
1.25 Subgroup analysis (statin dose): death	12	34857	Risk Ratio (IV, Random, 95% CI)	0.80 [0.73, 0.88]
1.25.1 < 20 mg/day simvastatin equivalent	4	9869	Risk Ratio (IV, Random, 95% CI)	0.78 [0.68, 0.89]
1.25.2 ≥ 20 mg/day simvastatin equivalent	8	24988	Risk Ratio (IV, Random, 95% CI)	0.81 [0.71, 0.92]
1.26 Subgroup analysis (statin dose): withdrawal due to adverse events	12	4189	Risk Ratio (IV, Random, 95% CI)	1.16 [0.82, 1.64]
1.26.1 < 20 mg/day simvastatin equivalent	5	250	Risk Ratio (IV, Random, 95% CI)	2.66 [0.61, 11.65]
1.26.2 ≥ 20 mg/day simvastatin equivalent	7	3939	Risk Ratio (IV, Random, 95% CI)	1.08 [0.77, 1.51]
1.27 Subgroup analysis (statin dose): total cholesterol	27	2234	Mean Difference (IV, Random, 95% CI)	‐50.26 [‐64.34, ‐36.17]
1.27.1 < 20 mg/day simvastatin equivalent	15	510	Mean Difference (IV, Random, 95% CI)	‐41.16 [‐51.24, ‐31.07]
1.27.2 ≥ 20 mg/day simvastatin equivalent	12	1724	Mean Difference (IV, Random, 95% CI)	‐60.28 [‐84.29, ‐36.27]
1.28 Subgroup analysis (statin dose): LDL cholesterol	24	2183	Mean Difference (IV, Random, 95% CI)	‐43.84 [‐52.56, ‐35.12]
1.28.1 < 20 mg/day simvastatin equivalent	12	433	Mean Difference (IV, Random, 95% CI)	‐39.42 [‐51.98, ‐26.87]
1.28.2 ≥ 20 mg/day simvastatin equivalent	12	1750	Mean Difference (IV, Random, 95% CI)	‐47.69 [‐59.55, ‐35.84]
1.29 Subgroup analysis (statin dose): HDL cholesterol	22	1374	Mean Difference (IV, Random, 95% CI)	2.92 [‐0.03, 5.88]
1.29.1 < 20 mg/day simvastatin equivalent	12	433	Mean Difference (IV, Random, 95% CI)	2.77 [1.18, 4.36]
1.29.2 ≥20 mg/dL simvastatin equivalent	10	941	Mean Difference (IV, Random, 95% CI)	3.33 [‐2.31, 8.97]
1.30 Subgroup analysis (statin dose): triglycerides	20	1186	Mean Difference (IV, Random, 95% CI)	‐26.02 [‐40.99, ‐11.06]
1.30.1 < 20 mg/day simvastatin equivalent	10	398	Mean Difference (IV, Random, 95% CI)	‐38.43 [‐66.72, ‐10.15]
1.30.2 ≥ 20 mg/day simvastatin equivalent	10	788	Mean Difference (IV, Random, 95% CI)	‐15.23 [‐29.18, ‐1.28]
1.31 Subgroup analysis (age): total cholesterol	27	2234	Mean Difference (IV, Random, 95% CI)	‐50.26 [‐64.34, ‐36.17]
1.31.1 < 55 years	14	1572	Mean Difference (IV, Random, 95% CI)	‐38.28 [‐45.93, ‐30.63]
1.31.2 ≥ 55 years	13	662	Mean Difference (IV, Random, 95% CI)	‐60.48 [‐84.81, ‐36.15]
1.32 Subgroup analysis (age): withdrawal due to adverse events	12	4189	Risk Ratio (IV, Random, 95% CI)	1.16 [0.82, 1.64]
1.32.1 < 55 years	6	1111	Risk Ratio (IV, Random, 95% CI)	1.19 [0.55, 2.58]
1.32.2 ≥ 55 years	6	3078	Risk Ratio (IV, Random, 95% CI)	1.25 [0.86, 1.80]
1.33 Subgroup analysis (age): LDL cholesterol	24	2183	Mean Difference (IV, Random, 95% CI)	‐43.84 [‐52.56, ‐35.12]
1.33.1 < 55 years	10	1203	Mean Difference (IV, Random, 95% CI)	‐39.06 [‐50.84, ‐27.28]
1.33.2 ≥ 55 years	14	980	Mean Difference (IV, Random, 95% CI)	‐46.80 [‐58.28, ‐35.33]
1.34 Subgroup analysis (age): HDL cholesterol	22	1374	Mean Difference (IV, Random, 95% CI)	2.92 [‐0.03, 5.88]
1.34.1 < 55 years	9	657	Mean Difference (IV, Random, 95% CI)	2.97 [1.49, 4.45]
1.34.2 ≥ 55 years	13	717	Mean Difference (IV, Random, 95% CI)	2.70 [‐2.60, 8.01]
1.35 Subgroup analysis (age): triglycerides	20	1186	Mean Difference (IV, Random, 95% CI)	‐26.02 [‐40.99, ‐11.06]
1.35.1 < 55 years	6	228	Mean Difference (IV, Random, 95% CI)	‐33.45 [‐44.75, ‐22.15]
1.35.2 ≥ 55 years	14	958	Mean Difference (IV, Random, 95% CI)	‐23.37 [‐43.72, ‐3.02]
1.36 Subgroup analysis (diabetes mellitus): withdrawal due to adverse events	13	4219	Risk Ratio (IV, Random, 95% CI)	1.16 [0.84, 1.60]
1.36.1 < 20% with DM	8	3541	Risk Ratio (IV, Random, 95% CI)	0.98 [0.72, 1.32]
1.36.2 ≥ 20% with DM	5	678	Risk Ratio (IV, Random, 95% CI)	1.47 [1.10, 1.98]
1.37 Subgroup analysis (diabetes mellitus): death	13	34980	Risk Ratio (IV, Random, 95% CI)	0.80 [0.73, 0.88]
1.37.1 < 20% with DM	7	26672	Risk Ratio (IV, Random, 95% CI)	0.73 [0.62, 0.86]
1.37.2 ≥ 20% with DM	6	8308	Risk Ratio (IV, Random, 95% CI)	0.86 [0.77, 0.96]
1.38 Subgroup analysis (diabetes mellitus): major cardiovascular death	14	36156	Risk Ratio (IV, Random, 95% CI)	0.72 [0.66, 0.79]
1.38.1 < 20% with DM	9	27014	Risk Ratio (IV, Random, 95% CI)	0.66 [0.56, 0.77]
1.38.2 ≥ 20% with DM	5	9142	Risk Ratio (IV, Random, 95% CI)	0.75 [0.69, 0.83]
1.39 Subgroup analysis (diabetes mellitus): total cholesterol	27	2234	Mean Difference (IV, Random, 95% CI)	‐50.26 [‐64.34, ‐36.17]
1.39.1 < 20% with DM or not reported	15	1759	Mean Difference (IV, Random, 95% CI)	‐55.16 [‐77.63, ‐32.68]
1.39.2 ≥ 20% with DM	12	475	Mean Difference (IV, Random, 95% CI)	‐43.89 [‐51.36, ‐36.43]
1.40 Subgroup analysis (diabetes mellitus): LDL cholesterol	24	2179	Mean Difference (IV, Random, 95% CI)	‐43.84 [‐52.56, ‐35.12]
1.40.1 < 20% with DM or not reported	14	1749	Mean Difference (IV, Random, 95% CI)	‐42.19 [‐55.12, ‐29.26]
1.40.2 ≥ 20% with DM	10	430	Mean Difference (IV, Random, 95% CI)	‐46.09 [‐53.60, ‐38.58]
1.41 Subgroup analysis (diabetes mellitus): HDL cholesterol	22	1374	Mean Difference (IV, Random, 95% CI)	2.92 [‐0.03, 5.88]
1.41.1 < 20% with DM or not reported	13	973	Mean Difference (IV, Random, 95% CI)	2.87 [‐1.19, 6.92]
1.41.2 ≥ 20% with DM	9	401	Mean Difference (IV, Random, 95% CI)	2.25 [‐0.43, 4.93]
1.42 Subgroup analysis (diabetes mellitus): triglycerides	20	1186	Mean Difference (IV, Random, 95% CI)	‐26.02 [‐40.99, ‐11.06]
1.42.1 < 20% with DM or not reported	11	769	Mean Difference (IV, Random, 95% CI)	‐25.71 [‐37.17, ‐14.24]
1.42.2 ≥ 20% with DM	9	417	Mean Difference (IV, Random, 95% CI)	‐26.53 [‐68.03, 14.97]
1.43 Subgroup analysis (baseline cholesterol): total cholesterol	27	2234	Mean Difference (IV, Random, 95% CI)	‐50.26 [‐64.34, ‐36.17]
1.43.1 < 230 mg/dL	16	1758	Mean Difference (IV, Random, 95% CI)	‐37.10 [‐43.11, ‐31.08]
1.43.2 ≥ 230 mg/dL	11	476	Mean Difference (IV, Random, 95% CI)	‐68.21 [‐96.42, ‐40.01]
1.44 Subgroup analysis (baseline cholesterol): LDL cholesterol	24	2183	Mean Difference (IV, Random, 95% CI)	‐43.84 [‐52.56, ‐35.12]
1.44.1 < 230 mg/dL	14	1735	Mean Difference (IV, Random, 95% CI)	‐34.01 [‐40.83, ‐27.19]
1.44.2 ≥ 230 mg/dL	10	448	Mean Difference (IV, Random, 95% CI)	‐58.87 [‐72.67, ‐45.07]
1.45 Subgroup analysis (baseline cholesterol): withdrawal due to adverse events	13	4219	Risk Ratio (IV, Random, 95% CI)	1.16 [0.84, 1.60]
1.45.1 < 230 mg/dL	7	1798	Risk Ratio (IV, Random, 95% CI)	1.27 [0.69, 2.32]
1.45.2 ≥ 230 mg/dL	6	2421	Risk Ratio (IV, Random, 95% CI)	1.02 [0.77, 1.37]
1.46 Subgroup analysis (baseline cholesterol): HDL cholesterol	22	1374	Mean Difference (IV, Random, 95% CI)	2.92 [‐0.03, 5.88]
1.46.1 < 230 mg/dL	12	926	Mean Difference (IV, Random, 95% CI)	2.41 [0.98, 3.84]
1.46.2 ≥ 230 mg/dL	10	448	Mean Difference (IV, Random, 95% CI)	4.01 [‐2.45, 10.46]
1.47 Subgroup analysis (baseline cholesterol): triglycerides	20	1186	Mean Difference (IV, Random, 95% CI)	‐26.02 [‐40.99, ‐11.06]
1.47.1 < 230 mg/dL	11	755	Mean Difference (IV, Random, 95% CI)	‐22.34 [‐31.33, ‐13.35]
1.47.2 ≥ 230 mg/dL	9	431	Mean Difference (IV, Random, 95% CI)	‐35.24 [‐64.04, ‐6.44]
1.48 Subgroup analysis (allocation concealment): death	13	34980	Risk Ratio (IV, Random, 95% CI)	0.80 [0.73, 0.88]
1.48.1 Low RoB	8	32142	Risk Ratio (IV, Random, 95% CI)	0.77 [0.70, 0.84]
1.48.2 High/Unclear RoB	5	2838	Risk Ratio (IV, Random, 95% CI)	0.98 [0.82, 1.16]
1.49 Subgroup analysis (allocation concealment): total cholesterol	27	2234	Mean Difference (IV, Random, 95% CI)	‐50.26 [‐64.30, ‐36.21]
1.49.1 Low RoB	5	1083	Mean Difference (IV, Random, 95% CI)	‐32.67 [‐39.88, ‐25.47]
1.49.2 High/Unclear RoB	22	1151	Mean Difference (IV, Random, 95% CI)	‐53.66 [‐70.93, ‐36.39]
1.50 Subgroup analysis (allocation concealment): major cardiovascular events	14	36156	Risk Ratio (IV, Random, 95% CI)	0.72 [0.66, 0.79]
1.50.1 Low RoB	9	31287	Risk Ratio (IV, Random, 95% CI)	0.75 [0.69, 0.81]
1.50.2 High/Unclear RoB	5	4869	Risk Ratio (IV, Random, 95% CI)	0.60 [0.45, 0.79]
1.51 Subgroup analysis (allocation concealment): triglycerides	20	1186	Mean Difference (IV, Random, 95% CI)	‐26.02 [‐40.99, ‐11.06]
1.51.1 Low RoB	4	345	Mean Difference (IV, Random, 95% CI)	‐30.22 [‐42.66, ‐17.78]
1.51.2 High/Unclear RoB	16	841	Mean Difference (IV, Random, 95% CI)	‐25.27 [‐44.38, ‐6.16]
1.52 Subgroup analysis (kidney function): end of treatment kidney function	17	4170	Mean Difference (IV, Random, 95% CI)	1.57 [0.25, 2.88]
1.52.1 < 55 mL/min	5	3207	Mean Difference (IV, Random, 95% CI)	1.56 [‐3.02, 6.15]
1.52.2 ≥ 55 mL/min	12	963	Mean Difference (IV, Random, 95% CI)	2.24 [0.30, 4.17]
1.53 Sensitivity analysis (excluding SHARP): major cardiovascular events	13	29909	Risk Ratio (IV, Random, 95% CI)	0.70 [0.63, 0.77]
1.54 Sensitivity analysis (excluding SHARP): death	12	28733	Risk Ratio (IV, Random, 95% CI)	0.80 [0.70, 0.90]
1.55 Sensitivity analysis (funding): major cardiovascular events	5	4126	Risk Ratio (IV, Random, 95% CI)	0.54 [0.40, 0.72]
1.55.1 Non‐industry funding/not reported	5	4126	Risk Ratio (IV, Random, 95% CI)	0.54 [0.40, 0.72]
1.56 Sensitivity analysis (funding): death	5	4249	Risk Ratio (IV, Random, 95% CI)	0.73 [0.49, 1.08]
1.56.1 Non industry funding/not reported	5	4249	Risk Ratio (IV, Random, 95% CI)	0.73 [0.49, 1.08]
1.57 Sensitivity analysis (funding): withdrawal due to adverse events	9	1267	Risk Ratio (IV, Random, 95% CI)	1.24 [0.71, 2.17]
1.57.1 Non industry funding/not reported	9	1267	Risk Ratio (IV, Random, 95% CI)	1.24 [0.71, 2.17]
1.58 Sensitvitiy analysis (funding): total cholesterol	22	1118	Mean Difference (IV, Random, 95% CI)	‐54.42 [‐71.98, ‐36.87]
1.58.1 Non‐industry funding/not reported	22	1118	Mean Difference (IV, Random, 95% CI)	‐54.42 [‐71.98, ‐36.87]
1.59 Sensitivity analysis (funding): LDL cholesterol	19	1071	Mean Difference (IV, Random, 95% CI)	‐47.85 [‐57.72, ‐37.98]
1.59.1 Non‐industry funding/not reported	19	1071	Mean Difference (IV, Random, 95% CI)	‐47.85 [‐57.72, ‐37.98]
1.60 Sensitivy analysis (funding): HDL cholesterol	19	1098	Mean Difference (IV, Random, 95% CI)	3.08 [‐0.29, 6.45]
1.60.1 Non‐industry funding/not reported	19	1098	Mean Difference (IV, Random, 95% CI)	3.08 [‐0.29, 6.45]
1.61 Sensitivity analysis (funding): triglycerides	17	845	Mean Difference (IV, Random, 95% CI)	‐27.28 [‐44.25, ‐10.31]
1.61.1 Non‐industry funding/not reported	17	845	Mean Difference (IV, Random, 95% CI)	‐27.28 [‐44.25, ‐10.31]

1.57. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 57: Sensitivity analysis (funding): withdrawal due to adverse events

1.58. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 58: Sensitvitiy analysis (funding): total cholesterol

1.59. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 59: Sensitivity analysis (funding): LDL cholesterol

1.60. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 60: Sensitivy analysis (funding): HDL cholesterol

1.61. Analysis.

Comparison 1: Statins versus placebo or no treatment, Outcome 61: Sensitivity analysis (funding): triglycerides

Comparison 2. High dose versus low dose statin.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Major cardiovascular events	2	3226	Risk Ratio (IV, Random, 95% CI)	1.17 [0.25, 5.55]
2.2 Death	3	3465	Risk Ratio (IV, Random, 95% CI)	1.05 [0.29, 3.83]
2.3 Stroke	1	3107	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.50, 0.89]
2.4 Hospitilisation due to heart failure	1	3107	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.39, 0.77]
2.5 Serious adverse events	2	358	Risk Ratio (IV, Random, 95% CI)	1.12 [0.73, 1.72]
2.6 Elevated liver enzyme	1	3107	Risk Ratio (M‐H, Random, 95% CI)	20.67 [2.79, 153.14]
2.7 eGFR [mL/min/1.73 m2]	1	105	Mean Difference (IV, Random, 95% CI)	‐11.00 [‐19.49, ‐2.51]

2.7. Analysis.

Comparison 2: High dose versus low dose statin, Outcome 7: eGFR [mL/min/1.73 m²]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

4S 1993.

Study characteristics
Methods	Study design Double‐blinded placebo‐controlled RCT Time frame Recruitment: 1988 to 1989 Study duration: 1988 to 1994 Follow‐up period: 5.4 years
Participants	Study characteristics Country: Scandinavian countries Setting: multicentre (94 sites) Inclusion criteria: men and women aged 35 to 70 years; history of angina pectoris or AMI; eGFR < 75 mL/min/1.73 m² Exclusion criteria: premenopausal women of childbearing potential; secondary hypercholesterolaemia; unstable or Prinzmetal angina; tendon xanthomata; planned coronary artery surgery or angioplasty; MI during the preceding 6 months; antiarrhythmic therapy; CHF requiring treatment with digitalis; diuretics, or vasodilators; persistent atrial fibrillation; cardiomegaly; haemodynamically important valvular heart disease; history of completed stroke; impaired hepatic function; partial ileal bypass; history of drug or alcohol abuse; poor mental function; other serious disease; current treatment with another investigational drug; hypersensitivity to statins Baseline characteristics Number (randomised/analysed): intervention group (1143/1143); control group (1171/1171) Mean age ± SD (years): intervention group (60.6 ± 6.1); control group (60.3 ± 6.2) Sex (M/F): intervention group (846/297); control group (850/321) Mean eGFR ± SD (mL/min): intervention group (65.2 ± 7.4); control group (65.2 ± 7.1)
Interventions	Intervention group Simvastatin: 20 mg titrated to 40 mg if needed to decrease total cholesterol levels to < 200 mg/dL Control group Placebo
Outcomes	Reported outcomes Death Major coronary events, including coronary deaths, definite or probable hospital‐verified non‐fatal acute MI, resuscitated cardiac arrest, and definite silent MI verified by ECG Any coronary event, i.e. the secondary endpoint events plus myocardial revascularization procedures and hospital admission for acute CHD events without a diagnosis of MI (mainly prolonged chest pain) Death or any atherosclerotic event (coronary, cerebrovascular, and peripheral), i.e. death from any cause and events included under the first tertiary end‐point plus hospital‐verified non‐fatal coronary atherosclerotic events Incidence of myocardial revascularization procedures, either coronary artery bypass grafting or percutaneous transluminal coronary angioplasty Incidence of hospital admission for acute CHD events without MI diagnosis
Notes	Additional information Funding: supported by a grant from Merck Research Laboratories, Rahway, NJ
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Low risk	Randomisation by sequential assignment of allocation numbers for which the pre‐packaged test medication had been prepared according to the randomisation code. Patients who qualified for the study on the basis of a previous MI were assigned allocation numbers beginning with the lowest allocation number available for each respective centre; patients who qualified on the basis of angina only were assigned allocation numbers starting with the highest number available. Randomisation was made in separate blocks for each centre. The block size was unknown to the investigators
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The Scandinavian Simvastatin Survival Study (4S) was a multicentre, double‐blind (triple‐blind because patients, investigators and study administration were unaware of patients’ drug assignment), randomised, placebo‐controlled study with simvastatin
Blinding of outcome assessment (detection bias) All outcomes	Low risk	4S was a multicentre, double‐blind (triple‐blind because patients, investigators and study administration were unaware of patients’ drug assignment), randomised, placebo‐controlled study with simvastatin
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients accounted for in the analysis; all data analysed by intention‐to‐treat (ITT)
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	High risk	Funding: supported by a grant from Merck Research Laboratories, Rahway, NJ

Abe 2011c.

Study characteristics
Methods	Study design Open‐label, parallel RCT Time frame December 2009 and December 2010 Study duration and follow‐up: 6 months
Participants	Study characteristics Country: Japan Setting: unclear Inclusion criteria: type 2 DM in those who were not treated with statins within 6 months of the start of the trial; LDL‐cholesterol ≥120 mg/dL; stage 1‐2 CKD eGFR ≥ 60 mL/min/1.73 m2; albuminuria; UACR ≥30 mg/g (average of 2 consecutive measurements taken during a 4‐week period before the study); BP ＜140/90 mm Hg treated with RAS inhibitors including ACEi and/or ARBs for at least 8 weeks before the study Exclusion criteria: 1) age ＜20 years or ＞80 years; 2) eGFR ＜60 mL/min/1.73 m2; BP ≥ 140/90 mm Hg; history of heart failure, angina, myocardial infarction, or stroke within 6 months before the start of the trial; previous treatment with steroids or immunosuppressants; DM that led to hospitalisation because of diabetic ketoacidosis Baseline characteristics Number (randomised/analysed): intervention group (52/52); control group (52/52) Mean age ± SD (years): intervention group (64.5± 9.6); control group (64.9 ± 9.2) Sex (M/F): intervention group (30/22); control group (29/23) Mean eGFR ± SD (mL/min/1.73m2) intervention group (70.4 ± 11.9); control group (69.3 ± 9.5)
Interventions	Intervention group Rosuvastatin: 5 mg rosuvastatin once/day; dose was increased to 10 mg/day if target LDL‐cholesterol levels(< 100 mg/dL) were not reached after 4 weeks Duration: 6 months Control group Standard of care Cointerventions These subjects were already being administered RAS inhibitors and were controlled to ensure BP ＜140/90 mm Hg. The investigators subjectively adjusted the dose of antidiabetic agents such that the level of HbA1c, a glycaemic target, achieved ＜7.0% in both groups All patients were instructed on how to maintain their diet and exercise therapy; all patients received nutrition education from a dietitian according to the Impact of the Kidney Disease Outcomes Quality Initiative guideline
Outcomes	Reported outcomes LDL cholesterol HDL cholesterol Total cholesterol Triglyceride Non‐HDL cholesterol LDL/HDL ratio
Notes	Additional information Trial registration: UMIN000001778 Protocol registration/published: published Ethics: study was conducted in compliance with Declaration of Helsinki and the Ethical guidelines for Clinical Studies (issued by the Ministry of Health, Labour and Welfare of Japan) Declaration of interest/disclosures: no conflicts to declare Funding declared: AstraZeneca "No financial support was received for implementation of this study"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: A computer‐generated list was used for randomization.
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	Around 97% of enrolled participants completed the study and were analysed.
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement from publications
Other bias	Low risk	Study appears free of other biases

Abe 2015.

Study characteristics
Methods	Study design Open‐label, parallel RCT Time frame Study duration and follow‐up: 12 months
Participants	Study characteristics Country: Japan Setting: single centre Inclusion criteria: dyslipidaemia with LDL‐cholesterol > 100 mg/dL and concurrent CKD (eGFR < 60 mL/min/1.73m2 or UACR ≥ 30 mg/g or both) Exclusion criteria: < 20 years or > 80 years; LDL‐cholesterol ≤ 100 mg/dL, severe kidney disease with eGFR < 30 mL/min/1.73m2; fasting serum triglyceride ≥ 400 mg/dL; history of hypersensitivity to statins, use of oral statin medication within the past 3 months; uncontrolled hypertension, type 1 DM or uncontrolled type 2 DM; onset of MI or stroke within the past 3 months; severe heart failure (NYHA class III or IV); active liver disease; SCr kinase ≥ 500 IU/L; current use of steroid therapy or immunosuppressive therapy; current pregnancy, possible pregnancy, breastfeeding or desire to become pregnant during the study period; presence of malignancy or suspected malignancy; hypothyroidism; genetic muscle disease (e.g. muscular dystrophy) or history of drug‐induced myopathy; drug abuse or alcohol poisoning or any other condition that precluded participation in the study in the opinion of the investigator Baseline characteristics Number (randomised/analysed): intervention group 1 (68/68); intervention group 2 (66/66) Mean age ± SD (years): intervention group 1 (69.7 ± 10.5); intervention group 2 (69.7 ± 8.2) Gender (M/F): intervention group 1 (40/28); intervention group 2 (38/28) Mean eGFR ± SD (mL/min/1.73 m2): intervention group 1 (65.1 ± 20.8); intervention group 2 (66.3 ± 22.2)
Interventions	Intervention group 1 Rosuvastatin: started on 2.5 mg with the target LDL‐cholesterol < 100 mg/dL; dose could be increased up to 5 mg for poor responders Duration: 12 months Intervention group 2 Pitavastatin: started on 1 mg or 2 mg with the target LDL‐cholesterol level < 100 mg/dL; dose could be increased up to 2 mg for poor responders Cointerventions Not reported
Outcomes	Reported outcomes LDL‐cholesterol HDL‐cholesterol Total cholesterol Triglyceride MDA‐LDL Non‐HDL‐cholesterol SCr UACR eGFR Adverse events Onset of diabetes
Notes	Additonal information Trial registration: not reported Protocol registration/published: not reported Declaration of interest/disclosures: not reported Funding declared: "Grant from AstraZeneca (No financial support was received for implementation of this study)" Comment: unclear of the involvement of funder in study design etc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation was undertaken by an independent investigator. Unclear what methods, i.e.. random number tables were used.
Allocation concealment (selection bias)	Low risk	The details of the assignment were maintained by four independent investigators
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement from publications. Unclear if ITT was undertaken
Selective reporting (reporting bias)	Low risk	All outcomes in the registry are reported
Other bias	Unclear risk	Funding declared: "Grant from AstraZeneca (No financial support was received for implementation of this study)"

AFCAPS/TexCAPS 1997.

Study characteristics
Methods	Study design Double‐blind, placebo‐controlled RCT Time frame Study duration: not reported Follow‐up period: 5.1 years
Participants	Study characteristics Country: USA Setting: multicentre (2 sites) Inclusion criteria: men (45 to 73 years) and women (55 to 73 years) with normal to mildly elevated cholesterol and reduced HDL defined as total cholesterol 180 to 264 mg/dL, LDL 130 to 190 mg/dL, HDL < 45 mg/dL for men, and > 47 mg/dL for women, TG > 400 mg/dL Exclusion criteria: prior MI history; angina; claudication; CVA or TIA; those with secondary hyperlipoproteinaemia; nephrotic syndrome; uncontrolled or insulin‐dependent DM; or uncontrolled hypertension Baseline characteristics Number: intervention group (145); control group (159) Mean age ± SD (years): intervention group (62 ± 8.0); control group (62 ± 7.0) Sex (M/F): intervention group (119/26); control group (120/39) eGFR ± SD (mL/min/1.73 m2): intervention group (53 ± 6); control group (53 ± 6)
Interventions	Intervention group Lovastatin: 20 mg dose titrated to 40 mg if LDL > 110 mg/dL Control group Placebo
Outcomes	Outcomes reported Rate of first acute major coronary events (i.e. sudden cardiac death, fatal and non‐fatal MI, and unstable angina) Fatal and non‐fatal coronary revascularization procedures Unstable angina Fatal and non‐fatal MI Fatal and non‐fatal cardiovascular events Fatal and non‐fatal coronary events Cardiovascular mortality CHD mortality Total mortality Non‐cardiovascular mortality (with subset analyses for accidental/violent death and death from cancer) Fatal and non‐fatal cancer (excluding basal cell and squamous cell skin cancers) Discontinuation for adverse drug effects
Notes	Additional information Trial registration: not reported Protocol registration/published: not reported Declaration of interest/disclosures: not reported Funding declared: 'Mr Cook is an employee of Merck & Co Inc, which markets lovastatin'. 'This study was funded by an Amgen fellowship grant.'
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	AFCAPS/TexCAPS was a double blind, randomised, placebo‐controlled study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants, investigators, Steering Committee members, and those providing participant care, monitoring or managing data, or adjudicating end points were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Details of study withdrawals provided, all analyses were based on ITT basis
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	High risk	'Mr Cook is an employee of Merck & Co Inc, which markets lovastatin'. 'This study was funded by an Amgen fellowship grant.'

ALLIANCE 2000.

Study characteristics
Methods	Study design Open‐label RCT Time frame Study duration: 1995 to 2002 Follow‐up period: 54.3 months
Participants	Study characteristics Country: USA Setting: multicentre (16 sites) Inclusion criteria: Men or women aged ≥ 18 years with known CHD, defined as prior acute MI, percutaneous coronary intervention, CABG, or unstable angina Exclusion criteria: breastfeeding or pregnancy; women of childbearing age who planned to become pregnant during the study; women who did not practice birth control methods considered acceptable to the investigator; any significant abnormalities the investigator believed may compromise patient safety or successful completion of the study; any disease process likely to limit life to less than the duration of the study; all cancers (excluding basal cell and squamous cell skin cancers); NYHA class III or IV CHF; and known hypersensitivities to statins Baseline characteristics Number (randomised/analysed): intervention group (286/226); control group (293/238) Mean age ± SD (years): intervention group (65.6 ± 7.4); control group (64.8 ± 7.0) Sex (M/F): intervention group (217/69); control group (228/65) Mean eGFR ± SD (mL/min/1.73 m2): intervention group (51.3 ± 7.8); control group (51.1 ± 8.5)
Interventions	Intervention group Atorvastatin: started at 10 mg/day and doubled every 4 weeks until patients achieved LDL cholesterol level goal < 80 mg/dL or were receiving a maximum dose of 80 mg/day Control group Usual care patients were maintained on the lipid‐lowering program to which they were already prescribed
Outcomes	Outcomes reported Time from randomisation to first occurrence of a primary cardiovascular event, including cardiac death, non‐fatal MI, resuscitated cardiac arrest, cardiac revascularization, and unstable angina requiring hospitalisation Death (any cause) Peripheral revascularization Hospitalisation for CHF Stroke
Notes	Additional information Trial registration: not reported Protocol registration/published: not reported Declaration of interest/disclosures: Dr Koren has received research support from Pfizer Inc, Merck, AstraZeneca, Novartis, and Merck/Schering‐Plough and consulting fees from Pfizer Inc. Dr Davidson has received research support from Pfizer Inc, Merck, AstraZeneca, and Merck/Schering‐Plough and consulting fees from Merck, AstraZeneca, and Merck/Schering‐Plough and has served on speaker bureaus for Pfizer Inc, Merck, AstraZeneca, and Novartis. Drs Wilson, Fayyad, Zuckerman, and Reed are employees of Pfizer Inc. Pfizer Inc is the manufacturer of Lipitor, a proprietary version of atorvastatin Funding declared: This study was sponsored initially by Parke‐Davis and later by Pfizer Inc. Editorial support was provided by Mr Steve Dobson and Dr Shirley Smith at Envision Pharma Ltd and funded by Pfizer Inc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficent information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficent information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	Lost to follow‐up details reported, ITT analysis performed for all randomised patients
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	High risk	Support: This study was sponsored initially by Parke‐Davis and later by Pfizer Inc. Editorial support was provided by Mr Steve Dobson and Dr Shirley Smith at Envision Pharma Ltd and funded by Pfizer Inc.

Aranda Arcas 1994.

Study characteristics
Methods	Study design Open‐label RCT Time frame Study duration: not reported Follow‐up period: not reported
Participants	Study characteristics Country: Spain Setting: single centre Inclusion criteria: proteinuria > 2 g/day, CrCl > 30 mL/min, LDL > 190 mg/dL Exclusion criteria: not reported Baseline characteristics Number: intervention group (8); control group (8) Mean age ± SD (years): intervention group (57 ± 6); control group (47 ± 6) Sex (M/F): not reported eGFR (mL/min/1.73 m2): not reported
Interventions	Treatment group Hypolipaemic diet Pravastatin: 20 to 40 mg Control group Placebo
Outcomes	Reported outcomes CrCl proteinuria Lipid parameters (TC, LDL, HDL, triglycerides)
Notes	Additional information Trial registration: not reported Protocol registration/published: not reported Declaration of interest/disclosures: not reported Financial disclosure: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Funding: insufficient information to permit judgement

ASCOT‐LLA 2003.

Study characteristics
Methods	Study design Double‐blind RCT Time frame Study duration: not reported Follow‐up period: 3.2 years
Participants	Study characteristics Country: UK, Ireland and Nordic countries Setting: multi‐centre Inclusion criteria: men and women aged 40 to 79 years; either untreated hypertension, defined as SBP ≥ 160 mm Hg and DBP ≥ 100 mm Hg, or both, or treated hypertension with SBP ≥ 140 mm Hg and DBP ≥ 90 mm Hg, or both; eligible for BP‐lowering arm, have TC concentrations ≤ 6.5 mmol/L; not currently be taking a statin or a fibrate Exclusion criteria: previous MI; currently treated angina; a cerebrovascular event within the previous 3 months; fasting triglycerides > 4.5 mmol/L; heart failure; uncontrolled arrhythmias or any clinically important haematological or biochemical abnormality on routine screening Baseline characteristics Number (total/CKD): 10,305/2022 Mean age ± SD (years): not reported Sex (M/F): not reported eGFR: not reported
Interventions	Intervention group Atorvastatin: 10 mg/day Control group Placebo
Outcomes	Reported outcomes Death (any cause) CV death Stroke Coronary events (MI, revascularization) Lipid profile (TC, LDL, HDL, triglycerides)
Notes	Additional information Trial registration: not reported Protocol registration/published: not reported Declaration of interest/disclosures: not reported Financial disclosure: not reported CKD subgroup data was only available abstracts and could not be meta‐analysed
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Investigators submitted all information relevant to any potential endpoints to the coordinating centre for central review of endpoints by the endpoint committee, who were unaware of treatment assignment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Funding: insufficient information to permit judgement

ASUCA 2013.

Study characteristics
Methods	Study design Parallel, open‐label RCT Time frame Study dates: April 2009 and March 2011 Study duration and follow‐up: 24 months
Participants	Study characteristics Country: Japan Setting: multicentre (number of sites not reported) Inclusion criteria: 40 to 75 years; not treated with statins; positive proteinuria and eGFR ≥ 60 mL/min/1.73 m2 3 months before enrolment or eGFR < 60 mL/min/1.73 m2 at enrolment; LDL ≥ 140 mg/dL in subjects not taking any dyslipidaemia treating agents or LDL ≥ 100 mg/dL in those taking dyslipidaemia‐treating agents other than statins Exclusion criteria: eGFR < 30 mL/min/1.73 m2; SBP ≥ 180 mm Hg or DBP ≥ 110 mm Hg; HbA1c ≥ 8.5%; familial hypercholesterolaemia; secondary hypercholesterolaemia including nephrotic syndrome; liver dysfunction including acute hepatitis, chronic active hepatitis, liver cirrhosis, and hepatoma; past history of severe side effects of atorvastatin; pregnancy, possibility of pregnancy, or breast‐feeding woman Baseline characteristics Number (randomised/analysed): intervention group (176/168); control group (173/166) Mean age ± SD (years): intervention group (63.2 ± 7.9); control group (63.1 ± 8.3) Sex (M/F): intervention group (105/63); control group (108/58) Mean eGFR ± SD (mL/min/1.73 m2): intervention group (56.0 ± 11.6); control group (54.0 ± 11.6)
Interventions	Intervention group Pravastatin: 10 mg/day then adjusted to 5 to 20 mg/day for 24 months Additional anti‐dyslipidaemia drugs except statins and fibrates were allowed to be used if target LDL (< 100 mg/dL) not met Control group No statin: 5 mg/day for 24 months Target LDL: < 100 mg/dL Cointerventions No changes in medications (doses of ACEi/ARB and steroids) and food intake
Outcomes	Outcomes reported Changes in eGFR eGFR CV events Death ESKD Stroke MI
Notes	Additional information Trial registration: UMIN000001778 Protocol registration/published: Published Ethics: approved by the Ethics Committee at the Kyoto University Graduate School of Medicine (C‐271). The trial was conducted in accordance with the Declaration of Helsinki Principles Declaration of interest/disclosures: Honoraria: Genjiro Kimura (Takeda, Daiichi‐Sankyo, Novartis and Taisho‐Toyama companies), Masato Ksahara (Pfizer, Daiichi‐Sankyo, Fuji companies), Kenji Ueshima (Pfizer company). Grants received: Genjiro Kimura (Japan Labour Health and Welfare Organization). Funding declared: Department of EBM Research Institute of Advancement of Clinical and Translational Science Kyoto University Hospital with an unrestricted grant from Pfizer Japan
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis undertaken has been reported but only < 80% included in the primary outcome analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcomes in the protocol are reported
Other bias	Low risk	Declaration of interest/disclosures: No conflict of interest Funding: Department of EBM Research Institute of Advancement of Clinical and Translational Science Kyoto University Hospital with an unrestricted grant from Pfizer Japan.

Bianchi 2003.

Study characteristics
Methods	Study design Parallel, open‐label RCT Time frame Study duration: not reported Follow‐up period: 12 months
Participants	Study characteristics Country: Italy, USA Setting: international, multicentre (2) Inclusion criteria: hypercholesterolaemia; mild‐to‐moderate CKD and proteinuria (idiopathic chronic GN) Exclusion criteria: DM; renovascular or malignant hypertension; secondary glomerular disease; malignancies; MI or CVA in the 6 months preceding the study; CHF; hepatic dysfunction; neuromuscular disorders; history of allergy to ACEi, ARB and statins Baseline characteristics Number: intervention group (28); control group (28) Mean age ± SD (years): intervention group (56.5 ± 1.5); control group (56.8 ± 1.5) Sex (M/F): intervention group (19/9); control group (19/9) Mean CrCl ± SD (mL/min): intervention group (50.8 ± 1.8); control group (50.0 ± 1.9)
Interventions	Intervention group Atorvastatin: maximum dose 40 mg/day (target LDL < 120 mg/dL or 40% reduction compared with baseline values) Control group Placebo
Outcomes	Outcomes reported Proteinuria Lipid profile (TC, LDL, HDL, triglycerides) Kidney function (CrCl)
Notes	Additional information Dedicated CKD study Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Controlled, prospective, open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Funding: Insufficient information to permit judgement

Buemi 2000.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 6 months
Participants	Study characteristics Country: Italy Setting: single centre Inclusion criteria: IgA nephropathy with TC < 6.73 mmol/L and no cholesterol‐lowering therapy in the previous year Exclusion criteria: DM; severe hypertension; kidney failure (SCr > 1.8 mg/dL); tobacco smoking; alcoholism Baseline characteristics Number: intervention group (13); control group (8) Mean age, range (years): intervention group (36, 35 to 41); control group (38, 30 to 45) Sex (M/F): intervention group (8/5); control group (5/3) Median CrCl, IQR (mL/min): intervention group (90,70 to 130); control group (90, 54 to 108)
Interventions	Intervention group Fluvastatin: 40 mg/day Control group Placebo
Outcomes	Outcomes reported Proteinuria and albuminuria Lipid profile Kidney function (CrCl)
Notes	Additional information Dedicated CKD study Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Funding: Insufficient information to permit judgement

CARDS 2003.

Study characteristics
Methods	Study design Placebo‐controlled RCT Time frame Study duration: November 1997 to June 2003 Follow‐up period: 4 years
Participants	Study characteristics Country: UK, Ireland Setting: multicentre (132 sites) Inclusion criteria: DM and at least 1 of the following risk factors: history of hypertension, retinopathy (i.e. any retinopathy, maculopathy, or prior photocoagulation), microalbuminuria or macroalbuminuria, current smoking Exclusion criteria: history of MI, angina, coronary vascular surgery, CVA, or severe peripheral vascular disease (defined as warranting surgery); SCr > 1.7 mg/dL; HbA1c > 12% Baseline characteristics Number: intervention group (482); control group (488) Mean age ± SD (years): intervention group (65.0 ± 6.7); control group (65.0 ± 6.7) Sex (M/F): intervention group (233/249); control group (232/256) Mean eGFR ± SD (mL/min/1.73 m2): intervention group (64.3 ± 10.3); control group (64.1 ± 10.3)
Interventions	Intervention group Atorvastatin: 10 mg Control group Placebo
Outcomes	Outcomes reported Acute CHD event (MI including silent infarction, unstable angina, acute CHD death, resuscitated cardiac arrest), coronary revascularization procedures, or stroke) Death (any cause) Any acute, hospital‐verified CV endpoint
Notes	Addtional information "The trial was terminated early in June 2003 on the recommendation of the data and safety monitoring board because a highly significant effect on CVD was apparent at the second interim analysis" Funding: this study was funded in part by the UK Department of Health and Diabetes UK
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Within every centre, the local investigator sequentially randomly assigned eligible patients to study treatment (either placebo or atorvastatin 10 mg daily) from a block of drugs that had been prepackaged for every centre by Pfizer, according to a computer‐generated randomisation code
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind placebo‐controlled
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Investigators, pharmacists, study administrators, and patients were unaware of the randomisation code throughout the study
Incomplete outcome data (attrition bias) All outcomes	Low risk	Lost to follow‐up was minimal, all analyses were ITT
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Funding: this study was funded in part by the UK Department of Health and Diabetes UK

Cha 2015.

Study characteristics
Methods	Study design Parallel RCT Time frame Study dates: not reported Study duration and follow‐up: 12 months
Participants	Study characteristics Country: South Korea Setting: multicentre Inclusion criteria: diabetic patients with CKD (stages 2 to 4) Exclusion criteria: not reported Baseline characteristics Number: total (75); numbers per group not reported Mean age ± SD (years): not reported Sex (M/F): not reported Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Intervention group Fluvastatin: 20 mg/day for 6 months Control group Standard of care Cointerventions All patients basically received fluvastatin 20mg for 6 months prior to randomisation
Outcomes	Outcomes reported GFR LDL‐cholesterol
Notes	Additional information Abstract‐only publication Trial registration: not reported Protocol registration/published: not reported Ethics: not reported Declaration of interest/disclosures: not reported Funding declared: Novatis Pharmaceuticals
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Norvatis role is unclear in the design, analysis and decision to present these findings

Di Lullo 2005.

Study characteristics
Methods	Study design Open‐label, parallel RCT Time frame Study duration: June 2002 to June 2004 Follow‐up period: 8 months
Participants	Study characteristics Country: Italy Setting: single centre Inclusion: Men and women 18 to 80 years; mild to moderate CKD (according to KDOQI guidelines) for at least 5 years: CrCl 45 to 55 mL/min (24‐hour collection); CRP 3 to 14 mg/dL; TC 250 to 350 mg/dL; HDL 50 to 70 mg/dL; LDL 100 to 190 mg/dL; triglycerides 160 to 450 mg/dL Exclusion criteria: current diagnosis of severe heart failure (NYHA Class II‐IV); familial hypercholesterolaemia; hypertriglyceridaemia; CrCl < 15 mL/min who were in dialysis Baseline characteristics Number: intervention group (80); control group (50) Mean age (years): intervention group (59.4); control group (58.7) Sex (M/F): 70/60 CrCl range (mL/min): 45 to 55 mL/min
Interventions	Intervention group Fluvastatin XL: 80 mg once/day Control group Placebo
Outcomes	Outcomes reported CrCl Lipid profile (TC, LDL, HDL, TG) Adverse events: liver function and myotoxicity indices (ALT, AST, gamma glutamyltransferase, lactic dehydrogenase, and creatine phosphokinase)
Notes	Additional information Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Funding: insufficient information to permit judgement

Dummer 2008.

Study characteristics
Methods	Study design Cross‐over RCT Time frame Study duration: March 2004 to 2006 Follow‐up period: 8 weeks
Participants	Study characteristics Country: Brazil Setting: single centre Inclusion criteria: ≥ 18 years with stage 3 or 4 CKD classified according to KDOQI criteria Exclusion criteria: acute or chronic inflammatory or infectious disease; any CV or cerebrovascular event in the last 3 months; need for KRT before or during the study period; receiving statins for secondary prevention of CV events; not sign the informed consent form Baseline characteristics Number (randomised/analysed): 68/66; intervention group (33); control group (33) Mean age (mean ± SD): intervention group (55.8 ± 15.3); control group (52.4 ± 15.7) Sex (M/F): intervention group (15/18); control group (17/16) Mean eGFR ± SD (mL/min/1.73 m2): intervention group (31.6 ± 9.7); control group (32.4 ± 11)
Interventions	Intervention group Simvastatin: 20 mg/day for 8 weeks Washout period: 4 weeks Control group Placebo for 8 weeks
Outcomes	Outcomes reported GFR‐MDRD formulae, proteinuria Lipid profile (TC, LDL, HDL, triglycerides) Adverse events: liver function (ALT, AST, gamma glutamyltransferase) and myotoxicity indices (creatine phosphokinase)
Notes	Additional information Funding: financial support was received from the research Promotion Fund of the Hospital de Clinicas de Porto Alegre (FIPE‐HCPA). The BIOLAB Pharma Laboratory provide the blinded simvastatin and placebo tablets
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Randomised, placebo‐controlled, double‐blind, cross‐over clinical study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients accounted for; 2 lost to follow‐up during 1st washout period
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Funding: financial support was received from the research Promotion Fund of the Hospital de Clinicas de Porto Alegre (FIPE‐HCPA) The BIOLAB Pharma Laboratory provide the blinded simvastatin and placebo tablets

ESPLANADE 2010.

Study characteristics
Methods	Study design Parallel, open‐label RCT Time frame Study duration Screening: July 2003 to July 20207 Follow‐up period: 6 months
Participants	Study characteristics Country: Italy Setting: multicentre (16 sites) Inclusion criteria: > 16 years; SBP/DBP > 140/90 mm Hg, or had concomitant antihypertensive therapy, and 24‐hour proteinuria persistently 1 g (subsequently amended to 0.5 g to avoid unnecessary exclusion of a proportion of patients expected to have residual proteinuria 0.25 g despite dual RAS blockade) after 2‐month washout from previous treatment with RAS inhibitors or statins, with variation in CrCl 30% over the last 3 months without evidence of UTI or heart failure Exclusion criteria: CrCl ≤ 20 mL/min/1.73 m²; LDL > 190 mg/dL despite low cholesterol diet; on chronic treatment with corticosteroids, NSAIDs, or immunosuppressive drugs; AMI or CVA in the 6 months preceding the study; SBP/DBP 220/115 mm Hg; renovascular disease; obstructive uropathy; DM type 1; vasculitis; cancer; serum AST concentrations 3 x ULN; chronic cough; history of poor tolerance or allergy to ACEi, ARB, or statins; drug or alcohol abuse; legal incapacity; pregnancy; breastfeeding; ineffective contraception Baseline characteristics Number (randomised/analysed): intervention group (92/83); control group (94/88) Mean age ± SD (years): intervention group (51.4 ± 13.9); control group (51.4 ± 13.9) Sex (M/F): 113/73 Mean eGFR ± SD (mL/min/1.73 m2): intervention group (67.7 ± 45.2); control group (59.4 ± 34)
Interventions	Intervention group Fluvastatin: up‐titrated to 80 mg/day in all patients ACEi and ARB Control group ACEi and ARB
Outcomes	Outcomes reported Lipid profile (TC, LDL, HDL, triglycerides) Adverse events: rhabdomyolysis, elevated liver enzymes
Notes	Additional information Funding: supported by a grant from Regione Lombardia, Direzione Generale Sanita`, Milan (Italy) and Novartis Farma S.p.A., Varese (Italy). Novartis Pharma also supplied the benazepril (Cibacen), valsartan (Tareg), and fluvastatin (Lescol) tablets required for study conduction. Novartis Pharma had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	175/186 (94%) completed study; ITT not reported
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Funding: supported by a grant from Regione Lombardia, Direzione Generale Sanita`, Milan (Italy) and Novartis Farma S.p.A., Varese (Italy). Novartis Pharma also supplied the benazepril (Cibacen), valsartan (Tareg), and fluvastatin (Lescol) tablets required for study conduction. Novartis Pharma had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Fassett 2010.

Study characteristics
Methods	Study design Parallel, open‐label RCT Time frame Study duration: not reported Follow‐up period: 2 years
Participants	Study characteristics Country: Australia Setting: multicentre (number of sites not reported) Inclusion criteria: confirmed ADPKD based on kidney ultrasound examination; positive family history and at all levels of kidney function and serum cholesterol levels Exclusion criteria: women of childbearing age and those participating in another investigational within 30 days Baseline characteristics Number (randomised/analysed): 60/49; intervention group (29); control group (20) Mean age ± SD (years): intervention group (53 ± 15); control group (49 ± 12) Sex (M/F): intervention group (12/17); control group (7/13) Mean eGFR ± SD (mL/min/1.73 m2): intervention group (58.5 ± 18.2); control group (49.9 ± 23.2)
Interventions	Intervention group Simvastatin: 10 mg/day Control group Placebo
Outcomes	Outcomes reported Kidney function measured by MDRD formula 24‐hour CrCl and proteinuria
Notes	Additional information Funding: supported by a grant from the Clifford Craig Medical Research Trust
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random number list
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study
Incomplete outcome data (attrition bias) All outcomes	High risk	49/60 (82%) completed study; ITT not conducted
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Funding: supported by a grant from the Clifford Craig Medical Research Trust

Fried 2001.

Study characteristics
Methods	Study design Parallel, placebo‐controlled RCT Time frame Study duration: not reported Follow‐up period: 24 months
Participants	Study characteristics Country: USA Setting: single centre Inclusion criteria: diabetic patients without overt nephropathy with TC 100 to 160 mg/dL and no cholesterol‐lowering therapy in the previous year Exclusion criteria: prior CVD Baseline characteristics Number: intervention group (19); control group (20) Mean age ± SD (years): intervention group (33 ± 9.1); control group (31 ± 6.7) Sex (M/F): intervention group (11/8); control group (11/9) Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Intervention group Simvastatin: 10 mg/day Control group Placebo
Outcomes	Outcomes reported Albuminuria Lipid profile Adverse events
Notes	Additional information Dedicated CKD study Funding: supported by a grant from Merck
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation by an unblinded pharmacist using a randomly generated list
Allocation concealment (selection bias)	Unclear risk	Insufficent information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficent information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	Significant drop‐outs at 1 year and 2 year follow‐up; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	High risk	Funding: supported by a grant from Merck

Gheith 2002.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: 1996 to 1998 Follow‐up period: 12 months
Participants	Study characteristics Country: Egypt Setting: single centre Inclusion criteria: nephrotic syndrome (steroid‐resistant, dependent, or frequently relapsing); hypercholesterolaemia; while off all lipid‐lowering drugs and adhering to an appropriate diet for at least 4 weeks; SCr < 2 mg/dL; recent renal biopsy showing FSGS or MPGN and written consent Exclusion criteria: lesion other than GSFS and MPGN; hepatic disease; muscle disease; history of familial dyslipidaemia; DM; patients with normal cholesterol; SCr > 2 mg/dL; concurrent use of lipid‐lowering agents Baseline characteristics Number: intervention group (21); control group (22) Mean age ± SD (years): intervention group (23.0 ± 13.3); control group (22.2 ± 9.5) Sex (M/F): intervention group (9/12); control group (9/13) Mean CrCl ± SD (mL/min): intervention group (98.8 ± 37); control group (115 ± 47)
Interventions	Treatment group Fluvastatin: 20 mg/day Control group No therapy
Outcomes	Outcomes reported Lipid profile Proteinuria Serum albumin‐CrCl (mL/dL/min) changes
Notes	Additional information Dedicated CKD study Funding: financially supported by the research unit of the Mansoura University
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Funding: financially supported by the research unit of the Mansoura University

Goicoechea 2006.

Study characteristics
Methods	Study design Parallel RCT (2:1 randomisation) Time frame Study duration: not reported Follow‐up period: 6 months
Participants	Study characteristics Country: Spain Setting: single centre Inclusion criteria: CKD with eGFR < 90 mL/min and > 15 mL/min Exclusion criteria: fasting serum LDL < 100 mg/dL and > 200 mg/dL; existence of liver, CV, infectious, or systemic disease unrelated to ESKD; history of vascular intervention, CHF, or MI within 3 months preceding enrolment Baseline characteristics Number (randomised/analysed): intervention group (44/44); control group (22/19) Mean age ± SD (years): intervention group (66.2 ± 13.6); control group (70.0 ± 14.3) Sex (M/F): intervention group (27/17); control group (13/6) GFR (mL/min/1.73m2): intervention group (42.8 ± 24.9); control group (44.2 ± 25.9)
Interventions	Intervention group Atorvastatin: 20 mg/day for 6 months Control group Placebo
Outcomes	Outcomes reported eGFR Lipid profile (TC, LDL, HDL, triglycerides)
Notes	Additional information Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	Three patients in the control group were lost to follow‐up
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Funding: not reported

Hommel 1992.

Study characteristics
Methods	Study design Parallel, placebo‐controlled RCT Time frame Study duration: not reported Follow‐up period: 12 weeks
Participants	Study characteristics Country: Denmark Setting: single centre Inclusion criteria: diabetic nephropathy; TC > 5.5 mmol/L; 18 to 50 years; SCr ≤ 200 µmol/L Exclusion criteria: TC ≤ 5.5 mmol/L; kidney transplantation; SCr ≥ 200 µmol/L; enrolment in other studies Baseline characteristics Number (randomised/analysed): intervention group (12/10); control group (9/6) Mean age ± SD (years): intervention group (41 ± 9); control group (35 ± 4) Sex (M/F): intervention group (6/6); control group (6/3) Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Treatment group Simvastatin: 10 to 20 mg/day Control group Placebo
Outcomes	Outcomes reported Lipid profile Urine albumin excretion Kidney function (GFR)
Notes	Additional information Funding: tablets supplied by Merck Sharpe and Dohme
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	5/21 patients were withdrawn from the study; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Funding: tablets supplied by Merck Sharpe and Dohme

HPS 2002.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: 1994 to 1997 Follow‐up period: 60 months
Participants	Study characteristics Country: UK Setting: multicentre Inclusion criteria: diabetic nephropathy; TC > 5.5 mmol/L; 18 to 50 years; SCr ≤ 200 µmol/L Exclusion criteria: not reported Baseline characteristics Number: 1329 Mean age ± SD (years): not reported Sex (M/F): Not reported Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Intervention group Simvastatin 40 mg/day Control group Placebo
Outcomes	Outcomes reported Death Lipid profile Coronary events, stroke, revascularization, major vascular events Kidney function Adverse events: rhabdomyolysis; elevated liver enzymes
Notes	Subgroup analysis of larger study conducted in general population Funding: funded by the UK Medical Research Council, the British Heart Foundation, Merck & Co (manufacturers of simvastatin), and Roche Vitamins Ltd (manufacturers of the vitamins).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A central randomisation service was telephoned which enabled the coordinating centre to conduct a final check of eligibility prior to randomisation, and to balance the randomisation with respect to important patient characteristics (in particular, eligibility criteria and other major prognostic factors) using a minimisation algorithm
Allocation concealment (selection bias)	Low risk	A central randomisation service was telephoned which enabled the coordinating centre to conduct a final check of eligibility prior to randomisation, and to balance the randomisation with respect to important patient characteristics (in particular, eligibility criteria and other major prognostic factors) using a minimisation algorithm
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blinded study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Yes ‐ outcome assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Funding: funded by the UK Medical Research Council, the British Heart Foundation, Merck & Co (manufacturers of simvastatin), and Roche Vitamins Ltd (manufacturers of the vitamins).

IDEAL 2004.

Study characteristics
Methods	Study design Parallel, open‐label RCT (PROBE design) Time frame Study duration: 1999 to 2005 Follow‐up period: 4.8 years
Participants	Study characteristics Countries: Denmark, Finland, Iceland, the Netherlands, Norway, Sweden Setting: multicentre (190 sites) Inclusion criteria: men and women ≤ 80 years with history of definite MI and who qualified for statin therapy according to national guidelines at the time of recruitment Exclusion criteria: any known contraindications to statin therapy; previous intolerance to statins in low or high doses; liver enzyme levels > 2 x ULN; pregnancy or breastfeeding; nephrotic syndrome; uncontrolled DM; uncontrolled hypothyroidism; plasma triglycerides > 600 mg/dL (6.8 mmol/L); CHF (NYHA classification IIIb or IV); haemodynamically important valvular heart disease; GI conditions affecting absorption of drugs; treatment with other drugs that seriously affect statins pharmacokinetics; treatment with other lipid‐lowering drugs Baseline characteristics Number: intervention group 1 (4439); intervention group 2 (4449) Number with CKD: intervention group 1 (1162); intervention group 2 (1159) Mean age ± SD (years): intervention group 1 (61.8 ± 9.5); intervention group 2 (61.6 ± 9.5) Sex (M/F): intervention group 1 (3590/849); intervention group 2 (3597/852) Mean eGFR ± SD (mL/min/1.73 m2): intervention group 1 (52 ± 6.6); intervention group 2 (52.3 ± 6.5)
Interventions	Intervention group 1 Atorvastatin: 80 mg/day Intervention group 2 Simvastatin: 20 mg/day
Outcomes	Outcomes reported Time to first occurrence of a major coronary event, defined as coronary death, hospitalisation for non‐fatal acute MI, or cardiac arrest with resuscitation Major CV events (any primary event plus stroke; diagnosis of stroke required evidence of a neurological deficit, usually localised, lasting 24 hours or until death, usually confirmed by diagnostic imaging) Any CHD event (any primary event, any coronary revascularization procedure, or hospitalisation for unstable angina) Any cardiovascular event (any of the former plus hospitalisation with a primary diagnosis of CHF and peripheral arterial disease, defined as a new clinical diagnosis or hospitalisation for such disease)
Notes	Additional information Funding: Drs Lindahl and Fayyad are Pfizer employees. All other authors except Dr Holdaas have received Honoraria from Pfizer Inc. as steering committee members of IDEAL. This study was sponsored by Pfizer Inc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Study medication assigned via a central interactive voice response system (ClinPhone, Nottingham, England)
Allocation concealment (selection bias)	Low risk	Allocation numbers assigned in blocks of 24. Allocation was balanced by centre; no other stratification was used
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	An end‐point classification committee blindly reviewed reports on potential end‐points and adjudicated outcomes at regular meetings. All reports were first screened by an independent centre (Inveresk, Raleigh, NC) for blinding of treatment allocation
Incomplete outcome data (attrition bias) All outcomes	Low risk	Number of randomised and analysed not reported but all analyses based on the ITT principle including all randomised patients
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	High risk	Funding: Drs Lindahl and Fayyad are Pfizer employees. All other authors except Dr Holdaas have received Honoraria from Pfizer Inc. as steering committee members of IDEAL. This study was sponsored by Pfizer Inc.

Ikeda 2012.

Study characteristics
Methods	Study design Cross‐over RCT Time frame Study dates: not reported Study duration and follow‐up: 12 months with 4‐8 weeks washout
Participants	Study characteristics Country: Japan Setting: Not reported Inclusion criteria: stable chronic GN patients with proteinuria (urinary protein excretion > 0.2g/g Cr) and hypercholesterolaemia (LDL >120 mg/dL) Exclusion criteria: not reported Baseline characteristics Number: 17 Mean age ± SD (years): not reported Sex (M/F): not reported Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Intervention group 1 Pravastatin: 5 mg/day for 6 months Intervention group 2 Rosuvastatin: 5 mg/day for 6 months Cointerventions No changes in medications (doses of ACEi/ARB and steroids) and food intake
Outcomes	Outcomes reported LDL MDA‐LDL Urinary protein excretion
Notes	Additional information Abstract‐only publication Trial registration: not reported Protocol registration/published: not reported Ethics: not reported Declaration of interest/disclosures: not reported Funding declared: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	100% of the randomised patients were analysed as part of the intention‐to‐treat population
Selective reporting (reporting bias)	High risk	No registry or protocol reported; no full‐text study published (2023)
Other bias	Unclear risk	Declaration of interest/disclosures: Not reported. Funding declared: Not reported."

Imai 1999.

Study characteristics
Methods	Study design Parallel, open‐label RCT Time frame Study duration: not reported Follow‐up period: 6 months
Participants	Study characteristics Country: Japan Setting: multicentre (number of sites not reported) Inclusion criteria: hypertensive patients with mild kidney dysfunction (SCr ≥ 1.2 mg/dL and < 2.5 mg/dL by Jaffe method or ≥ 0.9 mg/dL and < 2.2 mg/dL by enzymatic method) Exclusion criteria: nephrotic syndrome; familial hypercholesterolaemia; CHD; cerebrovascular disease; CKD due to collagen disease; pregnant women; nursing women; allergy to statin Baseline characteristics Number: intervention group (32); control group (25) Mean age ± SD (years): intervention group (58.5 ± 9.2); control group (49.5 ± 11.4) Sex (M/F): intervention group (19/13); control group (13/12) Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Intervention group Pravastatin: 3 patients received 5 mg/day; 29 patients received 10 mg/day Control group Placebo
Outcomes	Outcomes reported Lipid profile Kidney function (CrCl, SCr) 24‐hour albuminuria
Notes	Additional information Dedicated CKD study Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	A total of 62 participants were registered for the study. Five participants who did not conform to the criteria were excluded from the study after the study was completed. There were 57 patients entered into the analysis; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Funding: Insufficient information to permit judgement

Inukai 2011.

Study characteristics
Methods	Study design Parallel RCT Time frame Study dates: not reported Study duration and follow‐up: 6 months
Participants	Study characteristics Country: Japan Setting: single centre Inclusion criteria: type 2 DM on telmisartan 40 mg/day with positive urinary microalbumin and stage 2 to 3a diabetic nephropathy s table chronic GN patients with proteinuria (urinary protein excretion > 0.2g/g Cr) and hypercholesterolaemia (LDL> 120 mg/dL) Exclusion: liver dysfunction (AST/ALT > 40 U/L), kidney dysfunction (SCr > 1.5 mg/dL); already on medications for dyslipidaemia Baseline characteristics Number: intervention group (20); control group (20) Mean age ± SD (years): intervention group (58.9 ± 2.7); control group (59.7 ± 2.9) Sex(M/F): intervention group (8/12; control group (12/8) eGFR (mL/min/1.73 m2): intervention group (65.7 ± 4); control group (70.1 ± 6.2)
Interventions	Intervention group Atorvastatin: 10 mg/day for 6 months Control group Diet: usual nutritional guidance for diabetic patients, the usual diet guidance given to patients with high LDL cholesterol was provided twice in total for 6 months Cointerventions All participants received 40 mg of telmisartan. During this test period, drugs that are thought to affect glucose metabolism, lipid metabolism, or BP, and dosages were not altered
Outcomes	Outcomes reported LDL HDL Triglycerides eGFR SCr UACR
Notes	Additional information Trial registration: not reported Protocol registration/published: not reported Ethics: not reported Declaration of interest/disclosures: not reported Funding declared: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 100% of the randomised patients were analysed as part of the ITT population
Selective reporting (reporting bias)	Unclear risk	Comment: no registry or protocol reported
Other bias	Unclear risk	Insufficient information to permit judgement

JUPITER 2007.

Study characteristics
Methods	Study design Parallel, placebo‐controlled RCT Time frame Study duration: 2003 to 2008 Follow‐up period: median 1.9 years
Participants	Study characteristics Country: 26 countries Setting: international, multicentre Inclusion criteria: men ≥ 50 years and women ≥ 60 years; did not have CVD history, and LDL < 130 mg/dL (3.4 mmol/L) and a high‐sensitivity CRP ≥ 2.0 mg/L Exclusion criteria: previous or current use of lipid‐lowering therapy; current use of postmenopausal HRT; evidence of hepatic dysfunction (AST level > 2 x ULN); creatine kinase level > 3 x ULN; creatinine level > 2.0 mg/dL (176.8 μmol/L); DM; uncontrolled hypertension (SBP >190 mm Hg or DBP >100 mm Hg); cancer within 5 years before enrolment (exception basal cell or squamous cell carcinomas of the skin); uncontrolled hypothyroidism (TSH level > 1.5 x ULN); recent history of alcohol or drug abuse or another medical condition that might compromise safety or the successful completion of the study; inflammatory conditions such as severe arthritis, lupus, or inflammatory bowel disease; taking immunosuppressant agents such as cyclosporin, tacrolimus, azathioprine, or long‐term oral glucocorticoids Baseline characteristics Number: intervention group (8901); control group (8901) Number with CKD: 3267 Mean age (range): 70 years (65.0 to 75.0) Sex (M/F): 1138/2129 Median eGFR, IQR (mL/min/1.73 m2): intervention group (56, 51 to 58); control group (77, 69 to 89)
Interventions	Intervention group Rosuvastatin: 20 mg/day Control group Placebo
Outcomes	Reported outcomes Occurrence of a first major cardiovascular event, defined as non‐fatal MI, non‐fatal stroke, hospitalisation for unstable angina, arterial revascularization procedure, or confirmed death from cardiovascular causes Components of the primary end‐point considered individually Arterial revascularization or hospitalisation for unstable angina, MI, stroke, death from cardiovascular causes Death (any cause)
Notes	Additional information Funding: the JUPITER trial was supported by Astra‐Zeneca; Dr. Cressman is an employee of AstraZeneca
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation performed using an interactive voice‐response system and stratified according to centre
Allocation concealment (selection bias)	Low risk	Randomisation performed using an interactive voice‐response system and stratified according to centre
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Randomised, double‐blind, placebo‐controlled, multi‐centre study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All reported primary end‐points that occurred to 30 March 2008 were adjudicated on the basis of standardised criteria by an independent end‐point committee unaware of randomised treatment assignments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Lost to follow‐up was minimal, all primary analyses performed on ITT basis
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	High risk	Funding: the JUPITER trial was supported by Astra‐Zeneca; Dr. Cressman is an employee of AstraZeneca

Kimura 2012.

Study characteristics
Methods	Study design Parallel, placebo‐controlled RCT Time frame Study dates: September 2008 to April 2009 Study duration and follow‐up: 12 months
Participants	Study characteristics Country: Japan Setting: multicentre (10 sites) Inclusion criteria: type 2 diabetic patients with diabetic nephropathy with a history of diabetes for > 5 years and with diabetic retinopathy; UACR 30 to 600 mg/g (in 2 consecutive laboratory tests before the study period); diagnosed as hypercholesterolemia Exclusion criteria: kidney dysfunction (SCr ≥ 1.5 mg/dL); uncontrolled diabetes (HbA1c >10.4%) Baseline characteristics Number: intervention group 1 (44); intervention group 2 (39) Number with CKD: 28 Mean age ± SD (years): intervention group 1 (57 ± 10); intervention group 2 (60.6 ± 3.4) Sex (M/F): intervention group 1 (26/18); intervention group 2 (21/18) eGFR (mL/min/1.73m2): intervention group 1 (74.2 ± 22.7); intervention group 2 (73.6 ± 22)
Interventions	Intervention group 1 Pitavastatin: 2 mg/day for 12 months Intervention group 2 Pravastatin: 10 mg/day for 12 months Cointerventions Not reported
Outcomes	Outcomes reported TC LDL HDL Triglycerides eGFR AspAT
Notes	Additional information Trial registration: UMIN000001324 Protocol registration/published: not reported Ethics: protocol was approved by the ethic committees of all institutions Declaration of interest/disclosures: R. T. and T. I. were the guarantors of this study. S. K., T. I. and H. Y. wrote the manuscript. S. K. and T. I. contributed to the data analysis. S. K., T. I., H. Y., M. Y. and S. N. collected the data. The authors declare no conflict of interest Funding declared: unrestricted research grant from Kowa Pharmaceutical Co Ltd
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	Around 88% of enrolled participants completed the study and were analysed. Participants were lost to follow‐up because of study exclusions
Selective reporting (reporting bias)	Low risk	All outcomes are reported
Other bias	Low risk	Funding: unrestricted research grant from Kowa Pharmaceutical Co Ltd.

Lam 1995.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 24 months
Participants	Study characteristics Country: Hong Kong Setting: multicentre (2 sites) Inclusion criteria: mild to moderate hypercholesterolaemia (TC > 5.2 and < 7.8 mmol/L) and proteinuria > 0.15 g/day Exclusion criteria: not reported Baseline characteristics Number (randomised/analysed): intervention group (18/16); control group (18/18) Mean age ± SEM (years): intervention group (58.9 ± 2.3); control group (53.9 ± 2.5) Sex (M/F): intervention group (8/8); control group (11/7) Mean eGFR ± SEM (mL/min/1.73 m2): intervention group (83.1 ± 9.5); control group (84.3 ± 5.1)
Interventions	Intervention group Lovastatin: 20 mg/day Control group Placebo
Outcomes	Outcomes reported Lipid profile Kidney function (GFR, SCr) Proteinuria
Notes	Additional information Dedicated CKD study Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Single blinded study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Single blinded study
Incomplete outcome data (attrition bias) All outcomes	High risk	All subjects accounted for in the main analysis; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

Lee 2002.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 12 months
Participants	Study characteristics Country: Taiwan Setting: single centre Inclusion criteria: stable, well‐controlled hypertension with seated DBP < 90 mm Hg and SBP 140 mm Hg at 3 months screening period Exclusion criteria: DM; secondary hypertension; kidney disease (SCr > 1.5 mg/dL or 133 µmol/L) proteinuria (> 3 g/day); hyperlipidaemia (plasma TC > 240 mg/dL); treatment with corticosteroids or NSAIDs Baseline characteristics Number: intervention group (42); control group (40) Mean age ± SD (years): intervention group (50 ± 9); control group (48 ± 8) Sex (M/F): intervention group (29/13); control group (27/13) Mean eGFR ± SD (mL/min/1.73 m2): intervention group 85 ± 16; control group 90 ± 19
Interventions	Intervention group Pravastatin: 10 mg/day Control group Placebo
Outcomes	Outcomes reported Lipid profile Kidney function (SCr, CrCl) Proteinuria‐urinary excretion of markers for glomerular size
Notes	Additional information Funding: Pravastatin was in part a generous gift from Sankyo Company, Limited, Tokyo, Japan. This work was supported by the grant of Chi‐Mei Medical Center (CMFHT 9201, CMFHR9303, CMFHR9307, and CMTMU9305) and the grant of National Science Council, Republic of China (NSC 91‐2314‐B‐384‐008, NSC 91‐2314‐B‐384‐009, NSC92‐2314‐B‐384‐007, and NSC 92‐2314‐B‐384‐011)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blinded study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	3/63 (%) patients excluded; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Study appears free of other biases

Lintott 1995.

Study characteristics
Methods	Study design Parallel, placebo‐controlled RCT Time frame Study duration: not reported Follow‐up period: 12 weeks
Participants	Study characteristics Country: New Zealand Setting: single centre Inclusion criteria: hyperlipidaemic patients with plasma TC levels > 6.2 mmol/L and HDL < 0.90 mmol/L Exclusion criteria: active cardiac, GI, hepatic, or kidney disease (active kidney disease defined as > 10% decline in kidney function in the preceding 3 months); hypothyroidism, unless treated or stable; secondary hyperlipidaemia; MI or coronary bypass surgery within the previous 3 months; unstable angina Baseline characteristics Number: intervention group (32); control group (10) Mean age ± SD (years): intervention group (57 ± 11); control group (63 ± 9) Sex (M/F): intervention group (23/9); control group (8/2) Mean eGFR ± SD (mL/min/1.73 m2): mot reported
Interventions	Intervention group Fluvastatin: 40 mg/day Control group Placebo
Outcomes	Outcomes reported Lipid parameters (TC, LDL, HDL, triglycerides)
Notes	Additional information Funding: Dr. Tony Cutten of Sandoz Pharma (New Zealand) for his support of this study
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Funding: Dr. Tony Cutten of Sandoz Pharma (New Zealand) for his support of this study

LIPS 2001.

Study characteristics
Methods	Study design Parallel, placebo‐controlled RCT Time frame Study duration: April 1996 to October 1998 Follow‐up period: 3 to 4 years
Participants	Study characteristics Country: International Setting: multicentre (number of sites not reported) Inclusion criteria: one or more of the following: TC 135 to 270 mg/dL with fasting triglycerides < 400 mg/dL; TC < 212 mg/dL for patients whose lipids levels were measured 24 hours to 4 weeks after MI episode; TC < 232 mg/dL for patients with DM Exclusion criteria: baseline SCr > 1.8 mg/dL Baseline characteristics Number (kidney impairment): intervention group (150); control group (160) Mean age ± SD (years): 69 ± 7 Sex (M/F): 208/102 Mean CrCl ± SD (mL/min): 47 ± 7
Interventions	Intervention group Fluvastatin: 20 mg/day Control group Placebo
Outcomes	Outcomes reported Cardiac death, non‐fatal MI, coronary re‐interventions not related to stenosis Lipid profile Kidney function
Notes	Additional information Dedicated CKD study Funding: this study was supported by an industry grant (Novartis)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Low risk	Patients were allocated to treatment in the order in which they were enrolled into the study at each centre according to medication pack numbers using block randomisation.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	Not reported; ITT performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	High risk	Funding: this study was supported by an industry grant (Novartis)

LORD 2006.

Study characteristics
Methods	Study design Parallel, placebo‐controlled RCT Time frame Study duration: 2002 to 2008 Follow‐up period: 2.5 years
Participants	Study characteristics Country: Australia Setting: single centre Inclusion criteria: 8 to 85 years; SCr > 120 μmol/L at screening visit; history of CKD Exclusion criteria: use of lipid‐lowering medication; females of childbearing age, able to conceive and not using contraception; acute liver disease or unexplained persistent elevations of serum transaminases, or a history of alcoholism; history seizure within a year of study entry; hypersensitivity to atorvastatin or one of its components; participating in, or propose to participate in, another clinical investigational drug study within 30 days prior to study entry Baseline characteristics Number (randomised/commenced/completed): intervention group (64/58/47); control group (68/65/48) Mean age ± SD (years): intervention group (60.0 ± 15.0); control group (60.3 ± 15.2) Sex (M/F): intervention group (36/22); control group (44/21) Mean eGFR ± SD (mL/min/1.73 m2): intervention (31.9 ± 11); control group (29.1 ± 12.8)
Interventions	Intervention group Atorvastatin: 10 mg/day Control group Placebo
Outcomes	Outcomes reported Kidney function: eGFR (mL/min/1.73 m²/month) measured by MDRD and Cockcroft Gault equations, CrCl, SCr, proteinuria or albuminuria CV events and death Drug safety and tolerability Death (any cause) Stroke MI Heart failure Kidney failure
Notes	Additional information Funding: Clifford Craig Medical Research Trust funded the study. Pfizer Pharmaceuticals provided the atorvastatin and placebo
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random numbers
Allocation concealment (selection bias)	Low risk	A clinical research pharmacist independent of the trial used computer generated random numbers to conduct the randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blinded
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	3/37 patients were excluded; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Study appears free of other biases

Masajtis‐Zagajewska 2018.

Study characteristics
Methods	Study design Cross‐over placebo‐controlled RCT Time frame Study dates: Not reported Study duration and follow‐up: 15 months (6 months cross‐over + 3 months washout)
Participants	Study characteristics Country: Poland Setting: single centre Inclusion criteria: stable kidney function (± 5%) for at least 6 months prior to the study and were not expected to start KRT within the next 6 months; ESAs naive, with adequate iron stores (ferritin level > 150 ng/mL and TSAT > 20%), with a constant dose of oral iron administered for at least the last 6 months; not receiving any blood transfusion or IV iron for 3 months before the study Exclusion criteria: Hb < 10 g/dL; uncontrolled or treatment‐resistant hypertension; persistent urine protein excretion >1 g/24 hours; chronic steroid therapy with a dose of prednisone > 5 mg/24 hours; chronic heart failure NYHA stage 3 or higher; malignancy; administration of any lipid‐lowering medication for 6 months prior to the study; administration of oral phosphate binders Baseline characteristics Number: 36 Mean age ± SD (years): 56 ± 11 Sex (M/F): 17/19 Mean eGFR ± SD (mL/min/1.73 m2): 22.7 ± 9.4
Interventions	Intervention group Atorvastatin: 20 mg in a single evening dose for 6 months Washout period 3 months Control group Placebo for 6 months Cointerventions Not reported
Outcomes	Outcomes reported TC LDL HDL Triglycerides eGFR Hb AST ALT
Notes	Additional information Trial registration: not reported Protocol registration/published: not reported Ethics: obtained permission to perform this study from the Local Ethics Committee and followed the guidelines of the Helsinki Declaration Declaration of interest/disclosures: "No potential conflict of interest was reported by the authors" Funding declared: Medical University of Lodzresearch Grant No. 503/1‐151‐02/503‐01
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	100% of the randomised patients were analysed as part of the ITT population
Selective reporting (reporting bias)	Unclear risk	Comment: No registry or protocol reported
Other bias	Low risk	Study appears free of other biases

MEGA 2004.

Study characteristics
Methods	Study design Parallel, open‐label RCT Time frame Study duration: 1994 to 2004 Follow‐up period: 5.3 years
Participants	Study characteristics Country: Japan Setting: not reported Inclusion criteria: men and postmenopausal women, 40 to 70 years; bodyweight ≥ 40 kg; hypercholesterolaemia (TC concentration 5.69 to 6.98 mmol/L) Exclusion criteria: familial hypercholesterolemia; CHD or stroke history Baseline characteristics Number (overall moderate CKD group): 2978 Mean age: 60 years Sex (M/F): 745/2233 Mean eGFR ± SD (mL/min/1.73 m2): intervention group (52.6 ± 5.7); control group (52.5 ± 5.6)
Interventions	Intervention group Pravastatin: 10 to 20 mg/day Control group Placebo
Outcomes	Outcomes reported First occurrence of CHD, which included fatal and non‐fatal MI, angina, cardiac and sudden death, and coronary revascularization procedure Stroke CHD plus cerebral infarction All CV events Death (any cause) Cancer
Notes	Additional information Funding: none Post‐hoc analysis
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Eligible patients were randomly assigned either diet or diet plus pravastatin by computerised randomisation by the permuted‐block method
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All endpoints were reviewed strictly by the endpoint committee, without knowledge of treatment allocations, and additional information obtained from the physician as needed
Incomplete outcome data (attrition bias) All outcomes	High risk	102 participants lost to follow‐up; statistical analyses done by ITT
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Study appears free of other biases

Mori 1992.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 12 months
Participants	Study characteristics Country: Japan Setting: single centre Inclusion criteria: hyper‐ and normocholesterolaemic patients with non‐insulin‐dependent DM Exclusion criteria: not reported Baseline characteristics Number: intervention group (18); control group (15) Mean age ± SD (years): intervention group (62.0 ± 13.0); control group (64.1 ± 9.1) Sex (M/F): intervention group (6/12); control group (6/9) Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Intervention group Pravastatin: 10 mg/day Control group Placebo
Outcomes	Outcomes reported UACR
Notes	Additional information Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

Nakamura 2002.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 6 months
Participants	Study characteristics Country: Japan Setting: not reported Inclusion criteria: chronic GN and hypercholesterolemia Exclusion criteria: heart disease; collagen disease; DM Baseline characteristics Number: intervention group (20); control group (20) Mean age ± SD (years): 40.8 ± 14.4 Sex (M/F): 24/16 Mean CrCl ± SD (mL/min): intervention group(104 ± 10); control group (102 ± 12)
Interventions	Intervention group Cerivastatin: 0.15 mg/day Control group Placebo
Outcomes	Outcomes reported Lipid profile Kidney function (SCr, CrCl) Proteinuria urinary podocyte number
Notes	Addtional information Dedicated CKD study Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

Nakamura 2005.

Study characteristics
Methods	Study design Parallel, placebo‐controlled RCT Time frame Study duration: not reported Follow‐up period: 12 months
Participants	Study characteristics Country: Japan Setting: single centre Inclusion criteria: diabetes and microalbuminuria Exclusion criteria: not reported Baseline characteristics Number: intervention group (10); control group (10) Median age, range (years): intervention group (51, 42 to 60); control group (49, 44 to 58) Sex (M/F): intervention group (6/4); control group (6/4) eGFR (mL/min/1.73m2): not reported
Interventions	Intervention group Pitvastatin: 1 mg/day Control group Placebo
Outcomes	Outcomes reported Urinary albumin excretion TC
Notes	Additional information Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Low risk	Sealed envelope method
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

Nakamura 2006.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 6 months
Participants	Study characteristics Country: Japan Setting: single centre Inclusion criteria: patients with mild CKD Exclusion criteria: hypertension (> 140/90 mm Hg) and kidney dysfunction (SCr > 1.5 mg/dL or 24‐hour CrCl > 80 mL/min) Baseline characteristics Number: intervention group (15); control group (15) Mean age ± SD (years): intervention group (39.5 ± 10.0); control group (40.5 ± 11.0) Sex (M/F): intervention group (9/6); control group (9/6) Mean CrCl ± SD (mL/min): intervention group (103 ± 7); control group (105 ± 9)
Interventions	Intervention group Pitavastatin: 1 mg/day Control group Placebo
Outcomes	Outcomes reported Urinary albumin excretion TC, triglycerides
Notes	Additional information Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Low risk	Sealed envelope method
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

Nielsen 1993.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 36 weeks
Participants	Study characteristics Country: not reported Setting: not reported Inclusion criteria: persistent microalbuminuria; fasting cholesterol > 5.5 mmol/L; triglycerides < 4.5 mmol/L; HbA1c < 10%; fasting serum C‐peptide > 0.49 mmol/L; BP < 160/95 mm Hg Exclusion criteria: primary kidney, hepatic or insufficiently‐treated cardiac disease Baseline characteristics Number: intervention group (8); control group (10) Mean age ± SD (years): intervention group (65 ± 2); control group (65 ± 1) Sex (M/F): intervention group (6/2); control group (6/4) Mean eGFR ± SD (mL/min/1.73 m2): intervention group (96.6 ± 8); control group (97.1 ± 6.7)
Interventions	Intervention group Simvastatin: 10 to 20 mg/day Control group Placebo
Outcomes	Outcomes reported Lipid profile Kidney function (GFR) Urinary albumin excretion Glycaemic control
Notes	Additional information Dedicated CKD study Funding: this study was supported by Novo Nordisk Research Foundation, the Danish Medical Research Council, and Merck Sharp & Dohme
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	Not all patients accounted for in the analysis; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	High risk	Funding: this study was supported by Novo Nordisk Research Foundation, the Danish Medical Research Council, and Merck Sharp & Dohme

Ohsawa 2015.

Study characteristics
Methods	Study design Open‐label, parallel RCT Time frame Study dates: September 2009 to January 2011 Study duration and follow‐up: 12 months
Participants	Study characteristics Country: Japan Setting: Single‐centre Inclusion criteria: CKD patients with dyslipidemia who had no history of treatment with lipid‐lowering agents; ≥ 20 years; LDL ≥ 100 mg/dL; albuminuria categories A2 or A3 (UACR ≥ 30 mg/g) Exclusion criteria: CKD patients of G5 category (eGFR < 15 mL/min/1.73 m2) or on dialysis; uncontrolled type 1 or type 2 diabetes; hypothyroidism; a history of CVD; hypersensitivity to pitavastatin Baseline characteristics Number: intervention group (14); control group (14) Age (mean ± SD) years: intervention group (60.6 ± 3.4); control group (63.9 ± 3.3) Sex (M/F): intervention group (72%/28%); control group (72%/28%) Mean eGFR ± SD (mL/min/1.73 m2): intervention group (48.6 ± 4.7); control group (50.1 ± 4.9)
Interventions	Intervention group Pitavastatin: initially given 1 mg once/ day, and the dose was titrated up to 4 mg/day as needed for 12 months Target LDL: < 100 mg/dL Control group Placebo Co‐interventions Diet counselling used in both groups Restrict the energy intake according to their pathological conditions and needs (25–30 kcal/kg‐standard body weight/day), and take a diet including 25% of energy from fat, < 300 mg cholesterol daily and < 25 g alcohol daily
Outcomes	Outcomes reported TC LDL HDL Triglycerides eGFR UACR Liver enzyme (AST, ALT) Glucose HbA1c
Notes	Additional information Trial registration: UMIN000002526 Protocol registration/published: Not reported Ethics: Ethical principles of the Declaration of Helsinki and was approved by the ethics committees of Yokohama City University Hospital Declaration of interest/disclosures: K.T. received research grants from Takeda, Daiichi Sankyo, Kyowa‐hakko Kirin, Dainippon‐Sumitomo, Mochida, MSD, Pfizer and Novartis, and honoraria from Mochida, Dainippon‐Sumitomo, Nippon Boehringer Ingelheim, Kyowa‐hakko Kirin and Daiichi Sankyo. S.U. received research grants from Shionogi, Astellas, Nippon Boehringer Ingelheim, MSD, Pfizer, Daiichi Sankyo, Novartis, AstraZeneka and Dainippon‐Sumitomo, and honoraria from Daiichi Sankyo, Takeda, MSD, Shionogi and Kyowa‐hakko Kirin Funding declared: Health and Labor Sciences Research Grant, by Grants‐in‐Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS), and by grants from SENSHIN Medical Research Foundation, Banyu Life Science Foundation International, and Salt Science Research Foundation (No. 1428)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	100% of the randomised patients were analysed as part of the intention‐to‐treat population
Selective reporting (reporting bias)	High risk	Some outcomes listed in the registry have not been reported (hs‐CRP, L‐FABP, Ambulatory BP monitoring, PWV, central blood pressure)
Other bias	Low risk	Study appears free of other biases

PANDA 2011.

Study characteristics
Methods	Study design Parallel, placebo‐controlled RCT Time frame Study duration: January 2005 to January 2009 Follow‐up period: 36 months
Participants	Study characteristics Country: UK Setting: Four hospital‐based diabetic clinics Inclusion criteria: > 40 years; DM type 2 (WHO criteria); UACR > 5 mg/mmol on 2 occasions Exclusion criteria: pregnancy or potential pregnancy; urinary protein excretion > 2 g daily; SCr > 200 µmol ⁄ L; BP > 160 ⁄ 90 mm Hg at randomisation; serum cholesterol > 7 mmol/L; fasting triglycerides > 6 mmol/L; hepatic transaminase > 2 x ULN; alkaline phosphatase > 1.5 ULN; HbA1c > 10% (86 mmol/mol); untreated hypothyroidism; intolerance of ARBs or statins; taking atorvastatin > 10 mg daily (or the equivalent effective dose of another statin) or use of any other lipid‐lowering medication; other illness likely to influence the study Baseline characteristics Number: intervention group 1 (60); intervention group 2 (59) Mean age ± SD (years): intervention group 1 (63.5 ± 9.5); intervention group 2 (64.5 ± 10.1) Sex (M/F): intervention group 1 (51/9); intervention group 2 (48/11) Mean eGFR ± SD (mL/min/1.73 m2): intervention group 1 (66 ± 23); intervention group 2 (74 ± 22)
Interventions	Intervention group 1 (high dose) Atorvastatin: 80 mg/day Intervention group 2 (low dose) Atorvastatin: 10 mg/day
Outcomes	Outcomes reported MDRD eGFR and UAE rate Lipid profile CHD death Non‐fatal AMI Hospital admission for unstable angina Coronary revascularization Lower limb revascularization or amputation or ischaemic stroke Adverse events
Notes	Additional information Funding: We acknowledge support from the Manchester NIHR Biomedical Research Centre and Manchester Academic Health Sciences Centre (MAHSC). The study was funded by an unrestricted grant from Pfizer UK which markets atorvastatin. The sponsors were allowed to comment on the manuscript but they had no right of veto over any of its contents.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All adverse events and outcomes were assessed by an investigator who was blind to patient status
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	111/119 (93%) included in analysis of kidney function; ITT not conducted
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Study appears free of other biases

Panichi 2006a.

Study characteristics
Methods	Study design Parallel, placebo‐controlled RCT Time frame Study duration: January to June 2004 Follow‐up period: 6 months
Participants	Study characteristics Country: Italy Setting: single centre Inclusion criteria: CKD and hypercholesterolaemia defined as LDL > 100 mg/dL Exclusion criteria: > 75 years; presence of nephrotic syndrome; DM; malignant diseases; treatment with immunosuppressant agents; connective tissue disease; any CV event in the previous 6 months; any acute disease; hypersensitivity to statins Baseline characteristics Number: intervention group (28); control group (27) Mean age ± SD (years): intervention group (60 ± 10); control group (55 ± 13) Sex (M/F): intervention group (23/5); control group (21/6) Mean eGFR ± SD (mL/min/m2): intervention group (40 ± 12); control group (32 ± 13)
Interventions	Intervention group Simvastatin: 40 mg/day Control group Placebo
Outcomes	Outcomes reported Carotid intimal thickness Echo parameters Lipid profile (TC, LDL, HDL, triglycerides) Kidney function Adverse events (creatine phosphokinase, ALT, AST)
Notes	Additional information Funding: none received
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficent information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficent information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Data analysers were blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	Significant drop‐outs, treatment group (8/28), control group (12/27); ITT not reported
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Study appears free of other biases

PLANET I 2006.

Study characteristics
Methods	Study design Parallel RCT Time frame Study dates: 8 February 2006 to 3 March 2009 Study duration and follow‐up: 12 months
Participants	Study characteristics Countries: Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, USA Setting: multicentre (147 sites) Inclusion criteria: >18 years; LDL > 90.1 mg/dL with diabetes Exclusion criteria: HbA1c > 11%, statin intolerance; presence of familial hypercholesterolaemia or known type 3 hyperlipoproteinaemia; severe renal impairment (eGFR < 40 mL/min/1.73 m2 1 week before randomisation); active liver disease; use of immunosuppressive drugs for the treatment of proteinuria or kidney disease or both within 3 months of the first screening visit Baseline characteristics Number: intervention group 1 (107); intervention group 2 (116); intervention group 3 (102) Mean age ± SD (years): intervention group 1 (58.5 ± 11.7); intervention group 2 (58.5 ± 11.7); intervention group (57.9 ± 11.4) Sex (M/F): intervention group 1 (66/41); intervention group 2 (89/27); intervention group 3 (73/29) Mean eGFR ± SD (mL/min/1.73 m2): intervention group 1 (68.8 ± 24.1) intervention group 2 (72.6 ± 25.8); intervention group 3 (72.1 ± 24.9)
Interventions	Intervention group 1 Low‐dose rosuvastatin: 10 mg/day; half‐dose to assess tolerability for the 1st 4 weeks, then titrated to the full dose for the remaining 48 weeks Intervention group 2 High‐dose rosuvastatin: 40 mg/day; half‐dose to assess tolerability for the 1st 4 weeks, then titrated to the full dose for the remaining 48 weeks Intervention group 3 Atorvastatin: 80 mg/day; half‐dose to assess tolerability for the 1st 4 weeks, then titrated to the full dose for the remaining 48 weeks Co‐interventions or additional treatments During an 8‐week lead‐in period, patients with diabetes and proteinuria were given dietary advice and underwent optimisation of existing hypertension treatment and stopped taking statins (if applicable)
Outcomes	Outcomes reported Change in UPCR eGFR Death (any cause) Adverse events Serious adverse events TC LDL HDl Triglycerides AKI Doubling SCr
Notes	Additional information Trial registration: NCT00296400 Protocol registration/published: published Ethics: Declaration of Helsinki and Good Clinical Practice guidelines. Ethics committees and institutional review boards approved the research protocol. All patients gave written informed consent before starting. Declaration of interest/disclosures: N.M.A.I. and M.J.P. report no conflicts of interest. D.d.Z. is consultant for and received honoraria (to employer) from AbbVie, Astellas, Eli‐Lilly, Chemocentryx, Fresenius and Janssen. H.‐H.P. is consultant for and received honoraria from AbbVie, Novartis and Astra Zeneca. H.J.L.H. is consultant for AbbVie, Astellas, Astra Zeneca, Boehringer Ingelheim, Fresenius, Janssen and Merck and has a policy that all honoraria are paid to his employer. The manuscript or portions thereof are not under consideration by another journal or electronic publication and have not been previously published. Funding declared: Pfizer
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation sequence was produced with Global Randomisation System software (AstraZeneca)
Allocation concealment (selection bias)	Low risk	Quote: "All study drugs were in identical capsules, and supplied in identical bottles labelled appropriately so as to maintain the allocation masking"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All study personnel were blinded to the allocation."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: About 92% of the randomised patients were analysed as part of the intention‐to‐treat population
Selective reporting (reporting bias)	Low risk	Comment: All outcomes listed in the trial registry are reported in the study.
Other bias	High risk	Funding: Provided by AstraZenca The management strategy while important may not be sufficient to avoid bias. Quote: "The study was overseen by a steering committee, including non‐voting members from the sponsor. The steering committee oversaw the design of the study, the conduct of the trial, and the management and analysis of all data. The sponsor was involved in the design of the study, in the collection and analysis of data, and in writing the report." Conflicts: authors being employees or having stock options in the company

PLANET II 2006.

Study characteristics
Methods	Study design Parallel group RCT Time frame Study dates: not reported Study duration and follow‐up: 12 months
Participants	Study characteristics Countries: Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, USA Setting: multicentre (147 sites) Inclusion criteria: >18 years; LDL > 90.1 mg/dL without diabetes Exclusion criteria: HbA1c > 11%; statin intolerance; presence of familial hypercholesterolaemia or known type 3 hyperlipoproteinaemia; severe kidney impairment eGFR < 40 mL/min/1.73 m2 1 week before randomisation); active liver disease; use of immunosuppressive drugs for treatment of proteinuria or kidney disease or both within 3 months of the first screening visit; diabetic patients with moderate proteinuria Baseline characteristics Number: intervention group 1 (65); intervention group 2 (80); intervention group 3 (75) Mean age ± SD (years): intervention group 1 (48.0 ± 12.8); intervention group 2 (49.5 ± 13.0); intervention group 3 (48.0 ± 14.1) Sex (M/F) (%): intervention group 1 (40/25); intervention group 2 (49/31); intervention group 3 (47/28) Mean eGFR ± SD (mL/min/1.73 m2): intervention group 1 (78.3 ± 28.1); intervention group 2 (80.9 ± 8.3); intervention group 3 (81.8 ± 9.5)
Interventions	Intervention group 1 Low‐dose rosuvastatin: 10 mg/day; half‐dose to assess tolerability for the 1st 4 weeks, then titrated to the full dose for the remaining 48 weeks Intervention group 2 High‐dose rosuvastatin: 40 mg/day; half‐dose to assess tolerability for the 1st 4 weeks, then titrated to the full dose for the remaining 48 weeks Intervention group 3 Atorvastatin: 80 mg/day; half‐dose to assess tolerability for the 1st 4 weeks, then titrated to the full dose for the remaining 48 weeks Co‐interventions or additional treatments During an 8‐week lead‐in period, patients with diabetes and proteinuria were given dietary advice and underwent optimisation of existing hypertension treatment and stopped taking statins (if applicable)
Outcomes	Outcomes reported Change in UPCR eGFR
Notes	Trial registration: NCT00296400 Protocol registration/published: published Ethics: Declaration of Helsinki and Good Clinical Practice guidelines. Ethics committees and institutional review boards approved the research protocol. All patients gave written informed consent before starting. Declaration of interest/disclosures: N.M.A.I. and M.J.P. report no conflicts of interest. D.d.Z. is consultant for and received honoraria (to employer) from AbbVie, Astellas, Eli‐Lilly, Chemocentryx, Fresenius and Janssen. H.‐H.P. is consultant for and received honoraria from AbbVie, Novartis and Astra Zeneca. H.J.L.H. is consultant for AbbVie, Astellas, Astra Zeneca, Boehringer Ingelheim, Fresenius, Janssen and Merck and has a policy that all honoraria are paid to his employer. The manuscript or portions thereof are not under consideration by another journal or electronic publication and have not been previously published. Funding declared: Pfizer
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: The randomisation sequence was produced with Global Randomisation System software (AstraZeneca)
Allocation concealment (selection bias)	Low risk	Quote: "All study drugs were in identical capsules, and supplied in identical bottles labelled appropriately so as to maintain the allocation masking"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "All study personnel were blinded to the allocation."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: Insufficient information to permit judgement from publications
Selective reporting (reporting bias)	High risk	Comment: Secondary outcomes of the PLANET II trial are not reported in the publications
Other bias	High risk	Funding: Provided by AstraZenca The management strategy while important may not be sufficient to avoid bias. Quote: "The study was overseen by a steering committee, including non‐voting members from the sponsor. The steering committee oversaw the design of the study, the conduct of the trial, and the management and analysis of all data. The sponsor was involved in the design of the study, in the collection and analysis of data, and in writing the report." Conflicts: authors being employees or having stock options in the company

PPP 1992.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: 12 June 1990 to 18 December 1992 Follow‐up period: 5 years
Participants	Study characteristics Countries: Australia and New Zealand Setting: multicentre (87 sites) Inclusion criteria: 3 studies (CARE, LIPID, WOSCOPS); mild to moderate CKD (30 to 89.9 mL/min/1/.73 m²); acute MI; hospital‐discharge diagnosis of unstable angina in previous 3 to 36 months Exclusion criteria: clinically significant medical or surgical event within three months before study entry; cardiac failure; kidney or hepatic disease; current use of any cholesterol‐lowering agents Baseline characteristics Number: 16,824 Mean age range: 57.5 to 63.5 years Sex (M/F): 14,484/1761 Mean eGFR ± SD (mL/min/1.73 m2) mild kidney disease (74.1 ± 8.1); moderate kidney disease (51.8 ± 6.3)
Interventions	Intervention group Pravastatin: 40 mg/day Control group Placebo
Outcomes	Outcomes reported Death (any cause) Cardiovascular death Non‐fatal MI, coronary revascularization, non‐fatal stroke Lipid profile Kidney function (GFR)
Notes	Additional information This is a combined analysis of three different studies conducted in the general population. Funding: The CARE, LIPID, and WOSCOPS studies and this substudy on kidney disease are investigator‐initiated studies funded by Bristol‐Myers Squibb. Statistical analyses were performed at Wake Forest University, Winston‐Salem, NC, independently of the sponsor. The authors had unlimited access to the data used in this analysis. The sponsor is entitled to comment on manuscripts before submission, and the authors may consider these comments, but the rights to publication reside contractually with the investigators. The sponsor maintained information on adverse events and other trial data, as required by federal regulation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Low risk	Computer‐generated allocation numbers
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT performed; analyses in this article were not prespecified in the original Pravastatin Pooling Project (PPP) protocol but were specified before examining information on kidney function and were undertaken on ITT basis
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Funding: The CARE, LIPID, and WOSCOPS studies and this substudy on kidney disease are investigator‐initiated studies funded by Bristol‐Myers Squibb. Statistical analyses were performed at Wake Forest University, Winston‐Salem, NC, independently of the sponsor. The authors had unlimited access to the data used in this analysis. The sponsor is entitled to comment on manuscripts before submission, and the authors may consider these comments, but the rights to publication reside contractually with the investigators. The sponsor maintained information on adverse events and other trial data, as required by federal regulation

PREVEND IT 2000.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration (screening period): 1997 to 1998 Follow‐up period: 46 months
Participants	Study characteristics Country: Netherlands Setting: community‐based Inclusion criteria: persistent microalbuminuria with lipid levels from 5 to 8 mmol/L with or without prior CVD Exclusion criteria: CrCl < 60% of the normal age‐adjusted value; use of ACEi or ARB Baseline characteristics Number: intervention group (433); control group (431) Mean age ± SD (years): intervention group (52.1 ± 11.9); control group (50.5 ± 11.7) Mean eGFR ± SD (mL/min/1.73 m2): not reported Sex (M/F): intervention group (290/141); control group (267/164)
Interventions	Intervention group Pravastatin: 40 mg/day Control group Placebo
Outcomes	Outcomes reported Cardiovascular death Non‐fatal MI, coronary revascularization, non‐fatal stroke Cardiovascular hospitalisation Lipid profile Albuminuria BP
Notes	Additional information Subgroup analysis of larger study conducted in general population Funding: "This study was financially supported by grant E.013 of the Dutch Kidney Foundation, grant NHS 99.103 and NHS 2002‐B202 of the Netherlands Heart Foundation, and an unrestricted grant of Bristol‐Myers Squibb. Dr Asselbergs is a research fellow of the Netherlands Heart Foundation (2003T010)"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation performed in blocks of 20 based on computer‐generated randomisation list
Allocation concealment (selection bias)	Low risk	Subjects meeting the randomisation criteria were allocated to a treatment number in the order in which they entered the randomised study period
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	An independent endpoint committee reviewed all end points. Committee members had no knowledge of the subject’s treatment assignment
Incomplete outcome data (attrition bias) All outcomes	Low risk	> 10% withdrawals in treatment and control arms; all analyses were performed on ITT basis
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Study appears free of other biases

Rayner 1996.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 24 months
Participants	Study characteristics Country: South Africa Setting: single centre Inclusion criteria: hypertension; GFR 22 to 55 mL/min; on ACEi; fasting cholesterol > 240 mg/dL Exclusion criteria: evidence of cataracts; received any lipid‐lowering agents prior to entry; fasting serum triglycerides > 4.5 mmol/L; underlying liver disease; pregnant or not on reliable contraceptives Baseline characteristics Number: intervention group (9); control group (8) Mean age (years): intervention group (42); control group (45 Sex (M/F): not reported Mean eGFR ± SEM (mL/min/1.73 m2): intervention group (84.3 ± 10.5); control group (73.5 ± 11)
Interventions	Intervention group Simvastatin: 10 to 40 mg/day Diet Control group Diet
Outcomes	Outcomes reported Lipid profile Albuminuria Kidney function (GFR)
Notes	Additional information Dedicated CKD study Funding: supported by Logos Pharmaceuticals, South Africa
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Low risk	Patients were alternatively allocated to treatment and control groups
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	9/17 terminated study and were not included in analyses; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	High risk	This study was supported by Logos Pharntaceuticals, South Africa

Renke 2010a.

Study characteristics
Methods	Study design Cross‐over, placebo‐controlled RCT Time frame Study duration: not reported Follow‐up period: 12 weeks
Participants	Study characteristics Country: Poland Setting: single centre Inclusion criteria: 18 to 65 years; chronic non‐diabetic proteinuric nephropathy without dyslipidemia; normal or slightly impaired stable kidney function (eGFR > 45 mL/min); stable proteinuria (> 300 mg/24 hours); no steroids or other immunosuppressive treatment for a minimum of 6 months before the study Exclusion criteria: nephrotic syndrome; DM; CVD; potassium serum level > 5.1 mmol/L; history of malignancy including leukaemia and lymphoma; fertile women who were not taking oral contraceptives; pregnant or lactating women; patients with active liver disease, i.e. AST or ALT values > 3 x ULN; known or suspected contraindications to study medications, including history of adverse reactions to statins, ACEI or ARB Baseline characteristics Number: 14 Mean age ± SD: 4.2 ± 6.9 years Sex (M/F): 7/7 Mean eGFR ± SD (mL/min/1.73 m2): 104.7± 33.3
Interventions	Intervention group Atorvastatin: 40 mg/day Control group Placebo
Outcomes	Outcomes reported Lipid profile 24‐hour protein excretion eGFR BP Adverse events: AST, ALT, CKD levels
Notes	Additional information Funding: supported by grant from the Committee for Scientific Research through the Medical University of Gdansk (ST‐4 and W‐80). The authors thank Pfizer Polska and Adamed for providing drugs. The drug providers and sponsors had no involvement in the study design, patient recruitment, analysis, interpretation of data, writing of the report, or the decision to submit the report for publication
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random list
Allocation concealment (selection bias)	Unclear risk	Not adequately described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	12/14 (86%) completed protocol; ITT not conducted
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Funding: supported by grant from the Committee for Scientific Research through the Medical University of Gdansk (ST‐4 and W‐80). The authors thank Pfizer Polska and Adamed for providing drugs. The drug providers and sponsors had no involvement in the study design, patient recruitment, analysis, interpretation of data, writing of the report, or the decision to submit the report for publication

SAGE 2004.

Study characteristics
Methods	Study design Parallel RCT Time frame Study dates: not reported Study duration and follow‐up: 12 months
Participants	Study characteristics Country: 16 countries (Australia, Canada, Denmark, Egypt, Finland, France, Germany, Israel, the Netherlands, Norway, Poland, Spain, Sweden, Turkey, UK, USA) Setting: multicentre (192 sites) Inclusion criteria: 65 to 85 years; documented history of CAD, baseline LDL 100 mg/dL (2.6 mmol/L) and 250 mg/dL (6.5 mmol/L), 1 episode of myocardial ischaemia with a total duration of 3 minutes during 48‐hour ambulatory ECG monitoring at the screening visit Exclusion criteria: recent acute coronary event o clinical instability of medical condition following such an event; atrial fibrillation or atrial flutter; recent or anticipated angioplasty, other catheter‐based procedures, cardiac catheterization, coronary bypass surgery or cardiac transplantation; moderate or more severe congestive heart failure(NYHA Class III o rIV); clinically significant valvular heart disease likely to require surgical repair/replacement during the course of the study; uncontrolled hypertension; triglyceride > 600 mg/dL; artificial pacemaker or expected to require a pacemaker during the course of the study; history of sustained ventricular tachyarrhythmias; baseline AECG changes that preclude accurate ambulatory monitoring for ischemia; known hypersensitivity to statins; Any medical condition that renders the patient unable to complete the study or will limit study participation; history of malignancy within the 5 years prior to screening; alcohol or drug abuse; inability or unwillingness to adhere to a lipid‐lowering diet; participation in any investigational drug or device study 30 days prior to study entry; use of excluded medications (lipid regulating agents, immunosuppressive agents, tricyclicantidepressants, amiodarone, digitalis glycosides, drugs that are known to affect lipid levels or that are associated with rhabdomyolysis in combination with a statin; abnormal laboratory findings Baseline characteristics (CKD sub‐study) Number: intervention group 1 (206); intervention group 2 (212) Mean age ± SD (years): intervention group 1 (73.2 ± 5.1); intervention group 2 (73.0 ± 5.3) Sex (M/F): intervention group 1 (114/92); intervention group 2 (116/96) Mean eGFR ± SD (mL/min/1.73 m2): intervention group 1 (51.6 ± 6.5); intervention group 2 (52.0 ± 6.5)
Interventions	Intervention group 1 Atorvastatin: 80 mg/day for 12 months Intervention group 2 Pravastatin: 40 mg/day for 12 months Co‐interventions or additional treatments Not reported
Outcomes	Outcomes reported Absolute change in the total duration of myocardial ischaemia on 48‐hour Holter monitor Kidney failure Adverse events GFR TC LDL HDL Triglycerides AKI
Notes	Additional information CKD sub‐study ‐ KDOQI criteria for GFR (had baseline eGFR and 12‐month eGFR measurements) Trial registration: not reported Protocol registration/published: published Ethics: Declaration of Helsinki (Revised South Africa, 1996) and in compliance with the institutional review board/independent ethics committee, informed consent regulations, and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines Declaration of interest/disclosures: PCD has received research grants and consulting fees/other remuneration from Pfizer, Amgen, and Sanofi/Regeneron PHS has received research grants from Boston Scientific and AstraZeneca. RSF and REL are employees of Pfizer. DJW was an employee of Pfizer at the time the study was conducted Funding declared: Pfizer
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All Holter tests were analysed in a blinded fashion by an experienced physician at Covance Central Diagnostics (Reno, Nev)."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 96% of participants in main trial had eGFR readings, with 48% having CKD
Selective reporting (reporting bias)	High risk	Comment: the primary outcome has not been reported in the CKD substudy
Other bias	High risk	Funding: Pzifer Conflicts: Authors employees of Pzifer at the time of publication Other: posthoc analysis of larger trial (no test for subgroup differences undertaken)

Samuelsson 2002.

Study characteristics
Methods	Study design Cross‐over, placebo‐controlled RCT Time frame Study duration: not reported Follow‐up period: 8 weeks
Participants	Study characteristics Country: Sweden Setting: multicentre (2 sites) Inclusion criteria: Non‐nephrotic patients with primary CKD and moderate to advanced renal insufficiency Exclusion criteria: secondary kidney disease (such as DM); ongoing immunosuppressive treatment; heavy proteinuria combined with hypoalbuminaemia and oedema; ongoing oestrogen therapy; ongoing lipid‐lowering therapy Baseline characteristics Number (randomised/completed): 48/45 Mean age ± SD: 56.4 ± 11 years Sex (M/F): 28/17 Mean eGFR ± SD (mL/min/1.73 m2): 27.5 ± 10.5
Interventions	Intervention group Fluvastatin: 40 mg Control group Placebo
Outcomes	Outcomes reported Lipid profile Lipoprotein profile EDTA GFR
Notes	Additional information Funding: supported in part by a research grant from AstraZeneca, Molndal, Sweden, and resources of the Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blind study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	High risk	Funding: supported in part by a research grant from AstraZeneca, Molndal, Sweden, and resources of the Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

Sawara 2008.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period:12 months
Participants	Study characteristics Country: Japan Setting: single centre Inclusion criteria: CKD with eGFR < 90 mL/min and > 15 mL/min Exclusion criteria: LDL < 100 mg/dL or > 200 mg/dL; existence of liver, cardiovascular, infectious or systemic diseases Baseline characteristics Number: intervention group (22); control group (16) Mean age ± SD (years): intervention group (63.8 ± 9.1); control group (67.0 ± 7.9) Sex (M/F): intervention group (11/11); control group (9/7) Mean eGFR ± SD (mL/min/1.73 m2): intervention group (50.7 ± 18.7); control group (57.3 ± 16.2)
Interventions	Intervention group Rosuvastatin: 2.5 mg/day Control group No lipid‐lowering drug
Outcomes	Outcomes reported Lipid profile (TC, LDL, HDL, triglycerides) Inflammatory markers Carotid intimal thickness
Notes	Additional information Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	Significant number of drop‐outs; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

Scanferla 1991.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 24 months
Participants	Study characteristics Country: Italy Setting: university tertiary hospital Inclusion criteria: 34 to 73 years; biopsy‐proven IMN with SCr < 150 µmol/L; urine protein > 6.1 g/24 hours; fasting cholesterol > 6.1 mmol/L Exclusion criteria: cataracts; fasting serum triglycerides > 4.5 mmol/L; liver disease; previous lipid‐lowering therapy; pregnancy; contraceptives Baseline characteristics Number: intervention group (12); control group (12) Mean age ± SD (year): not reported Sex (M/F): 14/10 Mean eGFR ± SD (mL/min/1.73 m2): 41 ± 8
Interventions	Intervention group Simvastatin or pravastatin: 10 mg/day Diet Control group Previous therapy
Outcomes	Outcomes reported Lipid profile Kidney function (GFR)
Notes	Additional information Letter Dedicated CKD study Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

SHARP 2010.

Study characteristics
Methods	Study design Parallel, placebo‐controlled RCT Time frame Study duration: August 2003 to August 2010 Follow‐up period: 4.9 years
Participants	Study characteristics Country: International; 18 countries Setting: multicentre (380 sites) Inclusion criteria: men or women aged ≥ 40 years; predialysis (SCr ≥ 1.7 mg/dL (≥150 μmol/L) in men or ≥1.5 mg/dL (≥ 130 μmol/L) in women at both the most recent routine clinic visit and the study screening visit) or dialysis (haemodialysis or peritoneal dialysis) Exclusion criteria: definite history of MI or coronary revascularization procedure; functioning renal transplant or living donor kidney transplant planned; < 2 months since presentation as acute uraemic emergency; definite history of chronic liver disease or abnormal liver function (i.e. ALT N1.5 x ULN or, if ALT unavailable, AST N1.5 x ULN) (patients with a history of hepatitis were eligible if these limits were not exceeded); evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis) or CK N3 x ULN; definite previous adverse reaction to a statin or to ezetimibe; concurrent treatment with a contraindicated drug: statins; ezetimibe; fibrates; nicotinic acid; cyclosporin; erythromycin, clarithromycin; imidazole or triazole antifungals such as itraconazole, ketoconazole; protease‐inhibitors such as antiretroviral drugs for HIV infection; nefazodone; child‐bearing potential (i.e. premenopausal women not using reliable method of contraception); known to be poorly compliant with clinic visits or prescribed medication; medical history that might limit the individual's ability to take the study treatments for the duration of the study (e.g. severe respiratory disease, history of cancer other than non‐melanoma skin cancer, or recent history of alcohol or substance misuse) Baseline characteristics Number (total/on dialysis): intervention group (4650/1533); control group (4620/1490) Mean age ± SD (years): intervention group (62 ± 12); control group (62 ± 12) Sex (M/F): intervention group (2915/1735); control group (2885/1735) Mean eGFR ± SD (mL/min/1.73 m2): treatment group (26.6 ± 12.9); control group (26.6 ± 13.1)
Interventions	Intervention group Simvastatin: 20 mg/day Ezetimibe: 10 mg/day Control group Placebo
Outcomes	Outcomes reported Major atherosclerotic events (defined as non‐fatal MI or coronary death, non‐haemorrhagic stroke, or arterial revascularization excluding dialysis access procedures) Lipid profile Kidney function: SCr Kidney failure Adverse events: CK, ALT or AST
Notes	Additional information Funding: funded by Merck/Schering‐Plough Pharmaceuticals (North Wales, PA, USA), with additional support from the Australian National Health Medical Research Council, the British Heart Foundation, and the UK Medical Research Council. SHARP was initiated, conducted, and interpreted independently of the principal study funder
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Allocated by local study laptop computer with minimised randomisation
Allocation concealment (selection bias)	Low risk	Local laptop computer that was synchronised regularly with central database and double‐dummy treatment to ensure blinding
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐dummy 2 x 2 factorial design
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Central adjudication by trained clinicians who were masked to study treatment allocation
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants included in analyses; ITT conducted
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Funding: funded by Merck/Schering‐Plough Pharmaceuticals (North Wales, PA, USA), with additional support from the Australian National Health Medical Research Council, the British Heart Foundation, and the UK Medical Research Council. SHARP was initiated, conducted, and interpreted independently of the principal study funder

Stegmayr 2005.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: from February 1998 Follow‐up period: 5 years
Participants	Study characteristics Country: Sweden Setting: multicentre Inclusion criteria: GFR < 30 mL/min Exclusion criteria: < 18 years; fertile women not taking oral contraceptives; pregnant or lactating women; active liver disease; history of adverse reactions to statins; patients with functioning kidney transplant not on dialysis; patients waiting for transplantation; those on a protein‐restricted diet < 40 g of protein/day; poor compliance to medication and follow‐up; history of a progressive malignancy and life expectance < 6 months Baseline characteristics Number: intervention group (70); control group (73) Mean age ± SD (years): intervention group (67.8 ± 12.4); control group (69.4 ± 10.2) Sex (M/F): intervention group (48/22); control group (51/22) Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Intervention group Atorvastatin: 10 mg/day Control group Placebo
Outcomes	Outcomes reported Death (any cause) Acute MI, need for PTCA, CABG Lipid profile
Notes	Additional information Dedicated CKD study Funding: Samverkansnamnden for the Region of Northern Sweden (Project VISARENORR), the University of Umea and the Department of Medicine, Umea University Hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Low risk	Randomisation was done by means of a telephone call to the study data centre where sealed envelopes were drawn
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients analysed; ITT performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Study appears free of other biases

Thomas 1993.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 24 weeks
Participants	Study characteristics Country: UK Setting: multicentre (3 sites) Inclusion criteria: proteinuria 1 to 3 g/day or nephrotic syndrome > 3.5 g/day; fasting cholesterol ≥ 6.5 mmol/L after diet therapy; 18 to 70 years Exclusion criteria: DM; hypertriglyceridaemia warranting drug therapy; ESKD; steroid‐responsive minimal change disease; uncontrolled hypertension; impaired liver function or history of hepatobiliary disease; recent MI; CABG or unstable angina; women who were pregnant, nursing, or not adequately protected against pregnancy; other lipid‐lowering or cyclosporin therapy; carcinoma; lymphoma or amyloidosis Baseline characteristics Number: intervention group (15); control group (15) Mean age (years): intervention group (52); control group (49) Sex (M/F): intervention group (7/8); control group (9/6) Mean eGFR ± SD (mL/min/1.73 m2): intervention group (76.5 ± 36.5); control group (75.4 ± 40.2)
Interventions	Intervention group Simvastatin: 40 mg/day Control group Placebo
Outcomes	Outcomes reported Lipid profile Proteinuria SCr
Notes	Additional information Dedicated CKD study Funding: supported by a grant from Merck Sharp & Dohme, UK
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	7/30 patients did not complete the study; ITT not reported
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Comment: Funders role in the study design, conduct and analysis is not clear.

TNT 2004.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: 1998 to 2005 Follow‐up period: 4.9 years
Participants	Study characteristics Country: multinational (14 countries) Setting: multicentre (number of sites not reported) Inclusion criteria: men and women aged 35 to 75 years with clinically evident CHD, defined as previous MI, previous or current angina with objective evidence of atherosclerotic CHD, or history of coronary revascularization Exclusion criteria: hypersensitivity to statins; active liver disease or hepatic dysfunction defined as ALT or AST > 1.5 x ULN; women who were pregnant or breastfeeding; nephrotic syndrome; uncontrolled DM; uncontrolled hypothyroidism; uncontrolled hypertension (as defined by the investigator) at the screening visit; MI, coronary revascularization procedure or severe/unstable angina within 1 month of screening; any planned surgical procedure for the treatment of atherosclerosis; ejection fraction < 30%; haemodynamically important valvular disease; GI disease limiting drug absorption or partial ileal bypass; any non skin malignancy, malignant melanoma or other survival‐limiting disease; unexplained creatine phosphokinase levels > 6 x ULN; concurrent therapy with long‐term immunosuppressants; concurrent therapy with lipid‐regulating drugs not specified as study treatment in the protocol; history of alcohol abuse; and participation in another clinical study concurrently or within 30 days before screening Baseline characteristics Number (total/CKD): intervention group 1 (4827/1602); intervention group 2 (4829/1505) Mean age ± SD (years): intervention group 1 (65.5 ± 7.1); intervention group 2 (65.6 ± 6.9) Sex (M/F): intervention group 1 (1110/590); intervention group 2 (992/513) Mean eGFR ± SD (mL/min/1.73 m2): intervention group 1 (52.8 ± 6.6); intervention group 2 (53 ± 6.4)
Interventions	Intervention group 1 Atorvastatin: 80 mg/day Intervention group 2 Atorvastatin: 10 mg/day
Outcomes	Outcomes reported Primary endpoint: occurrence of a major cardiovascular event, defined as death from CHD, non‐fatal non–procedure‐related MI, resuscitation after cardiac arrest, or fatal or non‐fatal stroke Secondary endpoint: major coronary event (defined as death from CHD, non‐fatal, non‐procedure‐related MI, or resuscitation after cardiac arrest), a cerebrovascular event, hospitalisation for CHF, peripheral‐artery disease, death from any cause, any cardiovascular event, and any coronary event
Notes	Additional information Funding: Pfizer Inc (New York, NY, USA)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated code
Allocation concealment (selection bias)	Low risk	Randomisation code was prepared by a central unit
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blind study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	An endpoint committee reviewed (blinded) all potential primary and secondary endpoints to adjudicate the endpoint designation. The committee members who performed patient endpoint review were not investigators or sub‐investigators in the study
Incomplete outcome data (attrition bias) All outcomes	Low risk	Lost to follow‐up details were presented in the primary publication and ITT analysis was conducted; interim analyses for the TNT study began after a median 3 year follow‐up
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	High risk	Funding: TNT trial (NCT00327691) was funded by Pfizer Inc (New York, NY, USA)

Tokunaga 2008.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: not reported
Participants	Study characteristics Country: Japan Setting: not reported Inclusion criteria: hypertension; albuminuria Exclusion criteria: not reported Baseline characteristics Number: intervention group (10); control group (10) Mean age ± SD (years): not reported Sex (M/F): not reported Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Intervention group Pitavastatin: 10 mg/day Control group Placebo
Outcomes	Outcomes reported Albuminuria Kidney function Lipid profile
Notes	Additional information Abstract only Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

Tonolo 1997.

Study characteristics
Methods	Study design Cross‐over RCT Time frame Study duration: not reported Follow‐up period: 24 months
Participants	Study characteristics Country: Italy Setting: single centre Inclusion criteria: normotensive type 2 DM patients in good metabolic control HbA1c < 7.5% at any time in the previous year Exclusion criteria: not reported Baseline characteristics Number: intervention group (10); control group (9) Mean age ± SD (years): intervention group (60 ± 3); control group (62 ± 7) Sex (M/F): intervention group (8/2); control group (6/3) Mean eGFR ± SD (mL/min/1.73 m2): intervention group (101 ± 8); control group (97 ± 7)
Interventions	Intervention group Simvastatin: 20 mg/day Control group Placebo
Outcomes	Outcomes reported Lipid profile Kidney function (CrCl) Albumin excretion rate
Notes	Additional information Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	Dropouts not reported; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

UK‐HARP‐I 2005.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: October 1999 to March 2001 Follow‐up period: 12 months
Participants	Study characteristics Country: UK Setting: Not reported Inclusion criteria: > 18 years; pre‐dialysis patients with SCr > 1.7 mg/dL; HD or PD patients; or kidney transplant (with any creatinine level) Exclusion criteria: recent history of acute uraemia; history of chronic liver disease; inflammatory muscle disease; creatine kinase > 3 x ULN; previous adverse reaction to a statin or history of aspirin hypersensitivity; concurrent treatment with a contraindicated drug; high immediate risk for bleeding; child‐bearing potential in the absence of a reliable method of contraception; a life‐threatening condition other than CKD or vascular disease; frequent non‐attendance at clinics or known non‐compliance with drug treatments; or alcohol or substance abuse Baseline characteristics Number: intervention group 1 (112); intervention group 2 (112); intervention group 3 (113); control group (111) Mean age ± SD (years): intervention group 1 (54 ± 14); intervention group 2 (52 ± 15); intervention group 3 (52 ± 16); control group (54 ± 15) Sex (M/F): intervention group 1 (78/34); intervention group 2 (79/33); intervention group 3 (81/32); control group (76/35) Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Intervention group 1 Simvastatin: 20 mg/day Aspirin: 100 mg/day Intervention group 2 Simvastatin: 20 mg/day Intervention group 3 Aspirin: 100 mg/day Control group Double placebo
Outcomes	Outcomes reported Death Lipid profile CrCl (mL/min) changes
Notes	Additional information Dedicated CKD study Funding: The HARP pilot studies and the Study of Heart and Renal Protection (SHARP) were funded by unrestricted grants from Merck & Co. Conflict of interests: CB, ML, JA, and RC each received reimbursement from Merck for travel expenses in connection with various speaking engagements, but as members of the Clinical Trial Service Unit, comply with the Unit’s policy of not accepting honoraria
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Minimised randomisation used to balance the treatment groups
Allocation concealment (selection bias)	Low risk	Randomisation by telephone to the Clinical Trial Service Unit
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Matching placebo
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	All events were coded centrally according to a standard protocol. Otherwise unclear
Incomplete outcome data (attrition bias) All outcomes	Low risk	442/448 patients completed follow up; ITT performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	Study appears free of other biases

Verma 2005.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 20 weeks
Participants	Study characteristics Country: Georgia Setting: multicentre (2 sites) Inclusion criteria: > 18 years; CKD defined by GFR < 60 mL/min/1.73 m² BSA; no clinical evidence of AKI; not undergoing HD; not recently hospitalised for any reason; no known recent acute illness or infection; not currently taking anti‐lipidaemic medications; no history of statin therapy discontinuation because of adverse events; no known contraindications to statin therapy; fasting LDL > 100 mg/dL; HDL < 40 mg/dL; triglycerides > 150 mg/dL Exclusion criteria: not reported Baseline characteristics Number: intervention group (48); control group (43) Mean age ± SD (years): intervention group (73 ± 10); control group (74 ± 19) Sex (M/F): intervention group (19/29); control group (13/30) eGFR (mL/min/1.73m2): intervention group (42.3 ± 11.1); control group (49.4 ± 11.9)
Interventions	Intervention group Rosuvastatin: 10 mg/day Control group No treatment
Outcomes	Outcomes reported Lipid profile Kidney function (CrCl, SCr)
Notes	Additional information Dedicated CKD study Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	7/91 were excluded; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

Yasuda 2004.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 48 weeks
Participants	Study characteristics Country: Japan Setting: single centre Inclusion criteria: non‐insulin‐dependent diabetic nephropathy and patients with GN Exclusion criteria: not reported Baseline characteristics Number (randomised/analysed): intervention group (43/39); control group (45/41) Mean age ± SD (years): intervention group (57 ± 2); control group (58 ± 2) Sex (M/F): intervention group (18/21); control group (19/22) Mean eGFR ± SD (mL/min/1.73 m2): intervention group (59 ± 5); control group (60 ± 4)
Interventions	Intervention group Fluvastatin: 20 mg/day Control group Diet
Outcomes	Outcomes reported Lipid profile Kidney function (CrCl, SCr)
Notes	Additional information Dedicated CKD study Funding: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	8/88 patients excluded from the study; ITT not performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

Yi 2014.

Study characteristics
Methods	Study design Parallel RCT Time frame Study dates: December 2010 to May 2012 Study duration and follow‐up: 2 months
Participants	Study characteristics Country: South Korea Setting: multicentre (7 sites) Inclusion criteria: 20 to 75 years; CKD stage 3, 4, or 5 (predialysis); LDL 100 and 220 mg/dL and serum triglyceride < 400 mg/dL Exclusion criteria: previous hypersensitivity to components of any statin; drug abuse and alcohol consumption of least 14 standard units/week; impaired liver function (AST or ALT 42 times ULN); uncontrolled diabetes (HbA1c < 9.0%); uncontrolled hypertension (SBP < 160 mm Hg or DBP < 100 mm Hg at screening); congestive heart failure with symptoms of NYHA III or IV symptoms, unstable angina, MI, history of percutaneous coronary intervention or bypass surgery; cerebral infarction or transient ischaemic accident and deep venous thrombosis in the past 6 months; active peptic ulcer disease; GI disease that might influence the absorption of the test drug; current therapy with an immunosuppressant; malignancy Baseline characteristics Number (randomised/analysed): intervention group (62/45); control group (60/47) Mean age ± SD (years): intervention group (56.9 ± 10.5); control group (57.0 ± 12.1) Sex (M/F): intervention group (28/31); control group (29/30) Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Intervention group Continuous‐release tablet in the morning: 20 mg/day for 8 weeks Control group Intermittent release in the evening: 20 mg/day for 8 weeks
Outcomes	Outcomes reported LDL Adverse events Creatinine Total cholesterol LDL HDL GI disorders Albuminuria
Notes	Additional information Trial registration: not reported Protocol registration/published: not reported Ethics: The institutional review boards of each hospital approved the study design, and the study was performed in accordance with the Declaration of Helsinki and its amendments Declaration of interest/disclosures: no conflicts declared Funding declared: Hanmi Pharmaceutical Company Ltd
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Fixed‐allocation (1:1) block‐randomization method. The size of each block was 4 patients." Comment: Not reported
Allocation concealment (selection bias)	Low risk	Quote: "Each placebo was prepared in the same color and shape as the corresponding drugs so that patients and physicians could not differentiate them" Comment: The study referral institutions completed the random assignment of patients. All clinicians and patients remained blinded until the end of the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: ITT analysis undertaken for outcomes. With 96% included in the analysis, but only 78% completing the study
Selective reporting (reporting bias)	Unclear risk	Comment: No registry or protocol reported
Other bias	Unclear risk	Comment: Unclear role of the sponsor Trial registration: Not reported. Protocol registration/published: Not reported. Declaration of interest/disclosures: Not reported. Funding declared: Not reported."

Zhang 1995.

Study characteristics
Methods	Study design Parallel RCT Time frame Study duration: not reported Follow‐up period: 24 weeks
Participants	Study characteristics Country: Belgium Setting: single centre Inclusion criteria: insulin‐dependent DM and persistent microalbuminuria (20 to 200 µg/min) Exclusion criteria: not reported Baseline characteristics Number: intervention group (10); control group (10) Median age (range): 43 years (299 to 61) Sex (M/F): 16/4 Mean eGFR ± SD (mL/min/1.73 m2): not reported
Interventions	Intervention group Pravastatin: 20 mg/day Control group Placebo
Outcomes	Outcomes reported Lipid profile Apo A1, Apo B Urinary albumin Metabolic control (blood glucose, HbA1c)
Notes	Additional information Dedicated CKD study Funding: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

ADPKD: autosomal dominant polycystic kidney disease; ACEi: angiotensin‐converting enzyme inhibitors; AKI: acute kidney injury; ALT: alanine aminotransferase; AMI: acute myocardial infarction; Apo: apolipoprotein; ARB: angiotensin receptor blockers; AST: aspartate aminotransferase; BP: blood pressure; BSA: body surface area; CABG: coronary artery bypass graft; CHD: congestive heart disease; CHF: congestive heart failure; CKD: chronic kidney disease; CrCl: creatinine clearance; CRP: C‐reactive protein; CV: cardiovascular; CVA: cardiovascular accident; DM: diabetes mellitus; ECG: electrocardiograph; eGFR: estimated glomerular filtration rate; ESA: Erythropoietin stimulating agent; GN: glomerulonephritis; DBP: diastolic blood pressure; ESKD: end‐stage kidney disease; FSGS: focal segmental glomerulosclerosis; GFR: glomerular filtration rate; GN: glomerulonephritis; Hb: haemoglobin; HbA1c: glycated haemoglobin; HDL: high‐density lipoprotein; HRY: hormone‐replacement therapy; IgA: immunoglobulin A; IMN: idiopathic membranous nephropathy; ITT: intention‐to‐treat; IV: intravenous; KRT: kidney replacement therapy; LDL: low‐density lipoprotein; MDA: malondialdehyde‐modified; MDRD: modification of diet in renal disease; MI: myocardial infarction; MPGN: membranoproliferative glomerulonephritis; NSAID: nonsteroidal anti‐inflammatory drug; NYHA: New York Heart Association; PTCA: percutaneous transluminal coronary angiography; SBP: systolic blood pressure; SCr: serum creatinine; TC: total cholesterol; TIA: transient ischaemic attack; TSAT: transferrin saturation; TSH: thyroid‐stimulating hormones; UACR: urinary albumin‐creatinine ratio; UAE: urinary albumin excretion; ULN: upper limit of normal; UPCR: urinary protein‐creatinine ratio; UTI: urinary tract infection

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Almquist 2012	Wrong intervention
Almukhtar 2021	Wrong population
Dogra 2005	Short duration
Dogra 2007	Short duration
ESTABLISH 2004	Wrong comparator: no control for participants with CKD
Fotso 2021	Wrong population
Golper 1987	Duration not reported
Golper 1989	Short duration
IMPROVE‐IT 2008	Wrong intervention
Ishimitsu 2014	Wrong intervention
Kouvelos 2013	Wrong intervention
Mackie 2008	Wrong population: children (< 18 years)
Mohammadi 2023	Wrong population
Mose 2014a	Wrong study design
Mose 2014b	Wrong study design
NCT03543774	Wrong intervention
Ott 2008	Short duration
PACTR202110707328144	Wrong population
Paulsen 2010	Short duration
Schmieder 2003	Short duration
Siddiqi 2011	Wrong study design
Suzuki 2013a	Wrong intervention
Torraca 2006	Short duration
UK‐HARP‐II 2006	Wrong intervention
Van Dijk 2001	Short duration
Vasin 2021	Wrong population
Watanabe 2022	Wrong population
Weinstein 2013	Wrong intervention
Yasmeen 2015	Wrong intervention
Yasuda 2010	Active intervention
Yen 2022	Wrong population
Zinellu 2012	Wrong intervention

CKD ‐ chronic kidney disease; RCT ‐ randomised controlled trial

Characteristics of studies awaiting classification [ordered by study ID]

NCT00768638.

Methods	Randomised, parallel‐group, double‐blind
Participants	Inclusion criteria Aged ≥ 18 years Stage 3 or 4 CKD (modified MDRD) Proteinuria > 1 g/day on ACEi or ARB or both, or proteinuria > 1 g/day with intolerance or contraindication to ACEi or ARB or both BP < 130/80 mm Hg or < 140/90 mm Hg in patients with ≥ 3 antihypertensive drugs Stable kidney function
Interventions	Intervention group 1 Atorvastatin: 40 mg Intervention group 2 Atorvastatin: 10 mg
Outcomes	Proteinuria at 6 months
Notes

NCT02863185.

Methods	Randomised, parallel‐group, open‐label controlled trial
Participants	Inclusion criteria CKD patients Written informed consent Not taking statin LDL cholesterol > 100 mg/dL and coronary vascular disease or equivalent risk LDL cholesterol > 130 mg/dL and two or more coronary vascular risk LDL cholesterol > 160 mg/dL in patients with CKD stage 1 to 5 without dialysis Exclusion criteria Acute illness History of active infection Coronary vascular disease AKI during the past 3 months History of malignancy or liver disease Using statin, omega‐3 fatty acid or sevelamer hydrochloride within 3 months Experienced side effects by statin treatment Pregnant or pregnancy expected Dyslipidaemia due to nephrotic syndrome Imaging study using contrast media during the past 14 days Albumin < 3.0 g/dL
Interventions	Intervention group 1 Pitavastatin: 2 or 4 mg Intervention group 2 Atorvastatin: 10 or 20 mg
Outcomes	Primary outcomes Mean difference and change of erythrocyte membrane fatty acid including oleic acid at 24 weeks Secondary outcome Mean difference and change of total cholesterol, triglyceride, LDL cholesterol, HDL cholesterol at 24 weeks Mean difference and change of adiponectin at 24 weeks Mean difference and change of glucose and HbA1c at 24 weeks Mean difference and change of proteinuria at 24 weeks
Notes	Follow‐up 24 months

ACEi: angiotensin‐converting enzyme inhibitor; AKI: acute kidney injury; ARB: angiotensin receptor blocker; BP: blood pressure; CKD: chronic kidne disease; HbA1c: glycolated haemoglobin; HDL: high‐density lipoprotein; LDL: low‐density lipoprotein; MDRD: Modification of Diet on Renal Disease

Characteristics of ongoing studies [ordered by study ID]

NCT05870007.

Study name	Atorvastatin and alkali therapy in patients with autosomal dominant polycystic kidney disease
Methods	Parallel, open‐label RCT
Participants	Country: Taiwan Inclusion criteria: ADPKD; ≥ 18 years
Interventions	Intervention group Atorvastatin: 20 mg Control group Sodium bicarbonate: 600 mg
Outcomes	Change in kidney function: SCr; eGFR; BUN; potassium Change in liver function: ALT; AST; total bilirubin; prothrombin time; creatine phosphokinase Changes in muscle injury marker Changes in muscle tenderness BP
Starting date	Estimated: May 2023
Contact information	Not available
Notes	Not yet recruiting

ADPKD: autosomal‐dominant polycystic kidney disease; ALT: alanine aminotransferase; BP: blood pressure; BUN: blood urea nitrogen; CRP: C‐reactive protein; eGFR: estimated glomerular filtration rate; RCT: randomised controlled trial; SCr: serum creatinine

Differences between protocol and review

We did not include studies with follow‐up < eight weeks duration (excluding data from Van Dijk 2001) in the 2014 review update. The updated review has included some outcomes, including a new primary outcome of rhabdomyolysis, and secondary outcomes of onset of diabetes, revascularization procedures, fatigue, life participation, and memory loss. Additionally, post hoc analyses were conducted on the impact of baseline kidney function on the following outcomes: kidney failure, doubling serum creatinine, end‐of‐treatment kidney function, and end‐of‐treatment proteinuria. These outcomes were identified as critical and important by the CARI Statins in CKD living guideline Work Group (www.cariguidelines.org).

This update includes some new methods relevant to living systematic reviews, which are described in the Methods and Appendix 3 (Living systematic review protocol).

Contributions of authors

• David J Tunnicliffe: Data extraction, analysis and interpretation, drafting the updated manuscript, final approval of version to be published

• Suetonia C Palmer: Analysis and interpretation, drafting the updated manuscript, final approval of version to be published

• Brydee A Cashmore: Data extraction, analysis and interpretation, writing the final manuscript, final approval of version to be published

• Valeria M Saglimbene: Analysis and interpretation, writing the final manuscript, final approval of version to be published

• Kelly Lambert: Analysis and interpretation, writing the final manuscript, final approval of version to be published

• Rathika Krishnasamy: Analysis and interpretation, writing the final manuscript, final approval of version to be published

• David W Johnson: Analysis and interpretation of data, writing the final manuscript, final approval of version to be published

• Jonathan Craig: Concept and design, analysis and interpretation of data, writing the final manuscript, final approval of version to be published

• Giovanni FM Strippoli: Concept and design of the review, data extraction, analysis and interpretation of data, writing the final manuscript, final approval of version to be published

Sources of support

Internal sources

• No sources of support provided

External sources

• No sources of support provided

Declarations of interest

• David Tunnicliffe: no relevant interests were disclosed

• Suetonia Palmer: no relevant interests were disclosed

• Brydee A Cashmore: no relevant interests were disclosed

• Varleria M Saglimbene: no relevant interests were disclosed

• Kelly Lambert: no relevant interests were disclosed

• Rathika Krishnasamy: Baxter Healthcare Corporation (Independent Contractor ‐ Other), BAXTER HEALTHCARE (Independent Contractor ‐ Other), Amgen (Travel), Baxter Healthcare Corporation (Grant / Contract)

• Jonathan Craig: no relevant interests were disclosed

• David Johnson: Boehringer Ingelheim (Independent Contractor ‐ Other), Amgen (Travel), Ono (Independent Contractor ‐ Consultant), Vifor Fresenius Medical Care Renal Pharma Ltd. (Independent Contractor ‐ Consultant), AWAK (Independent Contractor ‐ Consultant), BAXTER HEALTHCARE (Independent Contractor ‐ Consultant), AstraZeneca (Independent Contractor ‐ Consultant), Bayer (Independent Contractor ‐ Consultant), Baxter Healthcare Corporation (Independent Contractor ‐ Consultant)

• Giovanni Strippoli: no relevant interests were disclosed

Edited (no change to conclusions)