Cerivastatin for lowering lipids

Stephen P Adams; Nicholas Tiellet; Nima Alaeiilkhchi; James M Wright

doi:10.1002/14651858.CD012501.pub2

. 2020 Jan 25;2020(1):CD012501. doi: 10.1002/14651858.CD012501.pub2

Cerivastatin for lowering lipids

Stephen P Adams ^1,^✉, Nicholas Tiellet ¹, Nima Alaeiilkhchi ², James M Wright ¹

Editor: Cochrane Hypertension Group

PMCID: PMC6984625 PMID: 31981471

Abstract

Background

Cerivastatin was the most potent statin until it was withdrawn from the market due to a number of fatalities due to rhabdomyolysis, however, the dose‐related magnitude of effect of cerivastatin on blood lipids is not known.

Objectives

Primary objective

To quantify the effects of various doses of cerivastatin on the surrogate markers: LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides in children and adults with and without cardiovascular disease.

The aim of this review is to examine the pharmacology of cerivastatin by characterizing the dose‐related effect and variability of the effect of cerivastatin on surrogate markers.

Secondary objectives  To quantify the effect of various doses of cerivastatin compared to placebo on withdrawals due to adverse effects. To compare the relative potency of cerivastatin with respect to fluvastatin, atorvastatin and rosuvastatin for LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides.

Search methods

The Cochrane Hypertension Information Specialist searched the following databases for RCTs up to March 2019: CENTRAL (2019, Issue 3), Ovid MEDLINE, Ovid Embase, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov.We also searched the European Patent Office, FDA.gov, and ProQuest Dissertations & Theses, and contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions.

Selection criteria

RCTs and controlled before‐and‐after studies evaluating the dose response of different fixed doses of cerivastatin on blood lipids over a duration of three to 12 weeks in participants of any age with and without cardiovascular disease.

Data collection and analysis

Two review authors independently assessed eligibility criteria for trials to be included and extracted data. We entered data from RCTs and controlled before‐and‐after studies into Review Manager 5 as continuous and generic inverse variance data respectively. We collected information on withdrawals due to adverse effects from the RCTs. We assessed all trials using the 'Risk of bias' tool under the categories of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases.

Main results

Fifty trials (19 RCTs and 31 before‐and‐after studies) evaluated the dose‐related efficacy of cerivastatin in 12,877 participants who had their LDL cholesterol measured. The participants were of any age with and without cardiovascular disease and the trials studied cerivastatin effects within a treatment period of three to 12 weeks. Cerivastatin 0.025 mg/day to 0.8 mg/day caused LDL cholesterol decreases of 11.0% to 40.8%, total cholesterol decreases of 8.0% to 28.8% and triglyceride decreases of 9.0% to 21.4%. We judged the certainty of evidence for these effects to be high. Log dose‐response data over doses of 2.5 mg to 80 mg revealed strong linear dose‐related effects on LDL cholesterol, total cholesterol and triglycerides.

When compared to fluvastatin, atorvastatin and rosuvastatin, cerivastatin was about 250‐fold more potent than fluvastatin, 20‐fold more potent than atorvastatin and 5.5‐fold more potent than rosuvastatin at reducing LDL cholesterol; 233‐fold more potent than fluvastatin, 18‐fold more potent than atorvastatin and six‐fold more potent than rosuvastatin at reducing total cholesterol; and 125‐fold more potent than fluvastatin, 11‐fold more potent than atorvastatin and 13‐fold more potent than rosuvastatin at reducing triglycerides. There was no dose‐related effect of cerivastatin on HDL cholesterol, but overall cerivastatin increased HDL cholesterol by 5%. There was a high risk of bias for the outcome withdrawals due to adverse effects, but a low risk of bias for the lipid measurements. Withdrawals due to adverse effects were not different between cerivastatin and placebo in 11 of 19 of these short‐term trials (risk ratio 1.09, 95% confidence interval 0.68 to 1.74).

Authors' conclusions

The LDL cholesterol, total cholesterol, and triglyceride lowering effect of cerivastatin was linearly dependent on dose. Cerivastatin log dose‐response data were linear over the commonly prescribed dose range. Based on an informal comparison with fluvastatin, atorvastatin and rosuvastatin, cerivastatin was about 250‐fold more potent than fluvastatin, 20‐fold more potent than atorvastatin and 5.5‐fold more potent than rosuvastatin in reducing LDL cholesterol, and 233‐fold greater potency than fluvastatin, 18‐fold greater potency than atorvastatin and six‐fold greater potency than rosuvastatin at reducing total cholesterol. This review did not provide a good estimate of the incidence of harms associated with cerivastatin because of the short duration of the trials and the lack of reporting of adverse effects in 42% of the RCTs.

Plain language summary

Cerivastatin for lowering lipids

Review question

How different doses of cerivastatin affect fats in our blood.

Background

Cerivastatin is a very strong cholesterol‐lowering drug. We don't know how its dose size affects the amount of fats in our blood.

Search date

We looked at research up to March 2019.

Study characteristics

We looked for high quality randomised trials (RCTs) and before‐and‐after studies with cerivastatin in different dose sizes . The trials were between three and twelve weeks long. People of any age and gender, either with or without heart disease were in these trials.

Participants could be of any age and gender, with or without cardiovascular disease.

Key results

We found fifty trials with 13,018 participants who had their lipid levels measured. 12,877 participants had their LDL cholesterol measured.

People taking 0.025 to 0.8 mg of cerivastatin per day lowered their LDL cholesterol by 12% to 42%. The higher the dose, the lower the levels of three measures of cholesterol. HDL cholesterol increased by 5%.

For lowering LDL cholesterol, cerivastatin is 250‐times stronger than fluvastatin, 20‐times stronger than atorvastatin and 5.5 times stronger than rosuvastatin.

Only 11 of the 19 RCTs reported the number of people who dropped out of the studies because of adverse effects. The level of drop outs due to adverse effects were similar in the people who took cerivastatin and placebo.

Certainty of the evidence

There is a high level of trust around the results for total cholesterol and LDL cholesterol and very low to moderate for triglycerides. We have a low level of trust in the evidence around drop outs because many (8 out of 19 trials) did not report drop outs due to adverse effects.

Summary of findings

Background

Description of the condition

Cardiovascular disease is a major cause of death and disability in the developed world, accounting for more than one‐third of total deaths (Kreatsoulas 2010). In the USA, cardiovascular disease causes one in three reported deaths each year (CDC 2011; Roger 2011). Existing evidence shows a weak association between adverse cardiovascular events and blood concentrations of low‐density lipoprotein (LDL) cholesterol in adults (Grundy 2004). The current recommended treatment for secondary prevention of adverse cardiovascular events consists of diet and lifestyle changes plus drug therapy with the drug class widely known as ’statins’. In addition statins are commonly prescribed to lower cholesterol with the intent of reducing adverse cardiovascular events in primary prevention patients.

Description of the intervention

Cerivastatin is a synthetic statin and the most potent statin that has been marketed. However, it was withdrawn from the market in 2001, four years after its launch, due to a higher occurrence of rhabdomyolysis (breakdown of muscle fibres), including fatal cases (Furberg 2001), than other available statins. Before it was withdrawn, cerivastatin was prescribed to prevent adverse cardiovascular events and to lower total cholesterol and LDL cholesterol. Cerivastatin is rapidly absorbed, reaching peak plasma concentration within two to three hours and has a short half‐life, two to three hours. Cerivastatin is metabolised by cytochromes P‐450 2C8 and P‐450 3A4 to desmethylcerivastatin (M‐1) and its hydroxy metabolite (M‐23), which are also active (Muck 2000; Plosker 2000). Statins as a class have been shown in individual randomised controlled trials (RCTs) and systematic reviews of RCTs to reduce mortality and major vascular events in people with occlusive vascular disease (CTT 2005).

How the intervention might work

Cerivastatin acts in the liver by inhibiting an enzyme early in the pathway for cholesterol synthesis, 3‐hydroxy‐3‐methyl‐glutarylcoenzyme A reductase (HMG CoA reductase). This enzyme irreversibly converts HMG CoA to mevalonate (Moghadasian 1999). This reaction is the third step in a sequence of reactions resulting in the production of many compounds including cholesterol and its circulating blood derivatives, LDL cholesterol and very low‐density lipoprotein (VLDL) cholesterol (Gaw 2000). The prevailing hypothesis is that statins reduce mortality and morbidity in people with occlusive vascular disease by reducing liver production of cholesterol and thus causing a reduction in LDL cholesterol that increases the risk of atherogenesis. However, the HMG CoA reductase enzyme is also responsible for the production of ubiquinone (co‐enzyme Q10), heme A, vitamin D, steroid hormones and many other compounds. It remains possible that the beneficial effects of statins are due to actions other than the reduction of circulating cholesterol. These other actions have been referred to as the pleiotropic effects of statins (Liao 2005).

Why it is important to do this review

Statins are the most widely prescribed class of drugs in the world. Prescribing of statins is increasing, as are average prescribed doses. At the present time, clinicians have only an approximate sense of the different potency of the different statins. Previous systematic reviews have assessed the effect of statins on serum lipids (Bandolier 2004; Edwards 2003; Law 2003; Ward 2007). They have demonstrated that different statins have different potencies in terms of lipid lowering and that higher doses of statins cause greater lowering of serum lipids than lower doses (Kellick 1997; Schaefer 2004; Schectman 1996). However, a systematic assessment of the potency, dose‐response relationship, and variability of effect has only been published for atorvastatin (Adams 2015), rosuvastatin (Adams 2014) and fluvastatin (Adams 2018). These reviews showed that rosuvastatin is about three times more potent than atorvastatin and about 46‐fold more potent than fluvastatin in lowering LDL cholesterol. In addition, the slope of the dose‐response relationship was similar for those three statins. It is possible that, in addition to a difference in potency, the slope of the dose‐response or the variability of response is different for cerivastatin. Cerivastatin is not currently available as it was withdrawn from the market in 2001 but it is essential to determine the dose‐response relationship of cerivastatin as it may provide a clue as to why it was more toxic to muscle than the other statins (Psaty 2004). At the present time, the reason for cerivastatin’s increased toxicity is unknown. Statin‐induced myopathy, is common to all statins, and limits the use of statins in many people. Knowledge of the effects of statins on blood lipids can help us to use them more effectively. We will use the percentage reduction from baseline of the following surrogate markers to describe the dose‐response relationship of the effect of cerivastatin: total cholesterol, LDL cholesterol, high‐density lipoprotein (HDL) cholesterol, and triglycerides (Boekholdt 2012). We will use the results of this review to compare cerivastatin with rosuvastatin, atorvastatin and fluvastatin. Subsequent reviews of other drugs in the class (i.e. lovastatin, pravastatin, simvastatin, and pitavastatin) will also be done, in order to compare the results of all the statins.

Objectives

Primary objective

The aim of this review is to examine the pharmacology of cerivastatin by characterizing the dose‐related effect and variability of the effect of cerivastatin on surrogate markers.

Secondary objectives

To quantify the variability of the effect of various doses of cerivastatin on withdrawals due to adverse effects. To quantify the relative potency of cerivastatin with respect to fluvastatin, atorvastatin and rosuvastatin for LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised, placebo‐controlled trials (RCTs) and controlled before‐and‐after studies. We included before‐and‐after studies because it has been shown that there is no placebo effect of statins on lipid parameters. Therefore a placebo control is not essential (Tsang 2002). We included data from cross‐over trials if the trial authors reported data for the initial treatment period versus parallel treatment groups, followed by an adequate washout period before crossing over to the other active treatments, and if they reported data in a similar manner during all treatment periods.

Types of participants

Participants could be of any age, with and without cardiovascular disease. They could have normal lipid parameters or any type of hyperlipidaemia or dyslipidaemia. We included participants with various comorbid conditions, including type 2 diabetes mellitus, hypertension, metabolic syndrome, chronic renal failure or cardiovascular disease.

Types of interventions

Cerivastatin had to be administered at a constant daily dose defined as a single dose per day compared to placebo or alone defined as a single cerivastatin dose per day for a period of three to 12 weeks. We have chosen this administration time window to allow at least three weeks for a steady‐state effect of cerivastatin to occur and to keep it short enough to minimise participants dropping out.

We included trials where cerivastatin was administered at any time during the day. Trials required a washout baseline dietary stabilisation period of at least three weeks, where all previous lipid‐altering medication was withdrawn. This baseline phase ensured that participants followed a standard lipid‐regulating diet and helped to stabilise baseline lipid values prior to treatment. In trials where participants were not receiving lipid‐altering medications or dietary supplements before receiving the test drug, we did not require washout baseline dietary stabilisation periods.

Types of outcome measures

The doses of cerivastatin that we studied were 0.05 mg/day, 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day and 0.8 mg/day.

Lipid parameters: for the RCTs, we present the mean percentage change from baseline for different doses of cerivastatin minus the mean percentage change from baseline with placebo for LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides. For the before‐and‐after studies we present the mean percentage change from baseline of different doses of cerivastatin. We combined data from RCTs and before‐and‐after studies because it was shown that there was a lack of difference in the mean differences between the two types of trials (Tsang 2002). We used only data from RCTs for triglycerides because there was a difference in the mean differences between the two types of trials (Tsang 2002) and it was judged that RCT data provided a better efficacy estimate.

Primary outcomes

LDL cholesterol

Secondary outcomes

Total cholesterol
HDL cholesterol
Triglycerides
End‐of‐treatment variability (standard deviation (SD)) and coefficient of variation of LDL cholesterol measurements for each dose of cerivastatin. It is important to know whether cerivastatin has an effect on the variability of lipid measures and ultimately to compare this with the effect of other statins.
Withdrawals due to adverse effects limited to RCTs.

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Information Specialist searched the following databases without language, publication year or publication status restrictions:

the Cochrane Central Register of Controlled Trials (CENTRAL, 2019, Issue 2) via the Cochrane Register of Studies (CRS‐Web; searched 17 March 2019);
MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations (searched 17 March 2019);
Embase Ovid (from 1974 onwards; searched 17 March 2019);
ClinicalTrials.gov (www.clinicaltrials.gov; searched 17 March 2019);
World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch; searched 17 March 2019);
Epistemonikos (www.epistemonikos.org; searched 17 March 2019).

The Information Specialist modelled subject strategies for databases on the search strategy designed for MEDLINE. We present search strategies for major databases in Appendix 1.

Searching other resources

The Cochrane Hypertension Information Specialist searched the Cochrane Database of Systematic Reviews (CDSR) via Wiley and the Database of Abstracts of Reviews of Effects (DARE) via Wiley for related reviews so that we could scan their reference lists for additional trials.

We checked the bibliographies of included trials and any relevant systematic reviews identified for further references to relevant trials.

We contacted experts/organisations in the field to obtain additional information on relevant trials.

We contacted original authors for clarification and further data if trial reports were unclear.

We included grey literature by searching these other resources:

ProQuest Dissertations and Theses (search.proquest.com/pqdtft/)
US Food and Drug Administration (www.fda.gov/)
European Patent Office (worldwide.espacenet.com

We used the following keywords to search the grey literature resources: cerivastatin, baycol, lipobay, BAY w 6228, "BAY w 6228".

Data collection and analysis

Selection of studies

Initial selection of RCTs and before‐and‐after studies involved retrieving and reading the titles and abstracts of each paper found from the electronic search databases or bibliographic citations (see Figure 1 for PRISMA flow diagram (Moher 2009)). Two review authors (SA and NT) analysed the full‐text papers independently, to decide on the trials to be included. We resolved disagreements by recourse to a third review author (JMW). Two review authors (SA and NT) independently extracted the appropriate data from each of the included trials.

Data extraction and management

We extracted the mean percentage change directly from the data, or we calculated it from the baseline and endpoint values using the calculation found in Appendix 2. We added the calculated data to the 'Data and analyses' section of the review. If the calculated data differed from the given data by more than 10%, we did not include the data in the review. We extracted standard deviations (SDs) and standard errors (SEs) from the report or calculated them when possible using the calculation in Appendix 3. We entered data from RCTs and controlled before‐and‐after studies into Review Manager 5 (Review Manager 2014) as continuous and generic inverse variance data, respectively.

Assessment of risk of bias in included studies

We assessed all RCTs and before‐and‐after studies using the Cochrane 'Risk of bias' tool under the categories of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other potential biases. We produced 'Risk of bias' tables' as outlined in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 8 (Higgins 2011). Controlled before‐and‐after studies should be scored “High risk” and “Low grading” compared to RCTs. Having only one trial group makes this feature at high risk of bias, as the risk of bias for random sequence generation and allocation concealment were high for the before‐and‐after studies but other features in this trial design might be at lower risk, there may be unidentified differences between the intervention and control groups that may affect changes in the outcome measure. We appreciate that blinding of participants and personnel and blinding of outcome assessment are inappropriate for before‐and‐after studies and that this is a limitation. However, because the lipid parameter measurements are unlikely to be influenced by lack of blinding and were measured in a remote laboratory, we considered them unlikely to be affected by the trial design. We were able to use the Cochrane 'Risk of bias' tool for the controlled before‐and‐after studies because there was a lack of difference in the mean differences between the two type of trials (Tsang 2002).

Measures of treatment effect

We analysed the treatment effects as mean difference for each dose in the RCTs and generic inverse variance for each dose in the before‐and‐after controlled studies separately. In the event that the mean effects from the two trial designs were not statistically different, we re‐analysed all efficacy trial data using the generic inverse variance to determine the overall weighted treatment effects and their 95% confidence intervals (CIs) for LDL cholesterol, total cholesterol, HDL cholesterol, and triglycerides.

Unit of analysis issues

The unit of analysis is the mean values for the people completing the trial. We expect follow‐up to be reasonably high for these short‐term trials. The data however represent treatment efficacy and not real world effectiveness of cerivastatin on these lipid parameters.

Dealing with missing data

When data were missing, we requested them from the trial authors. The most common type of value that was not reported was the SD of the change.

In the case of a missing SD for the change in lipid parameters, we imputed the SD using the following hierarchy (listed from high to low preference).

SD calculated either from the T statistics corresponding to the exact P value reported or from the 95% CI of the mean difference between treatment groups.
Average weighted standard deviation of the change from other trials in the review (Furukawa 2006).

Because it is common for the SD to be miscalculated and in order not to overweight trials where it is inaccurately calculated and lower than expected, when SD values were less than 40% of the average weighted SDs, we used the imputed value by the method of Furukawa (Furukawa 2006).

Assessment of heterogeneity

The Chi² test to identify heterogeneity was not appropriate because it has low power when there are few trials but has excessive power to detect clinically unimportant heterogeneity when there are many trials (Higgins 2002). The I² is a better statistic. I² calculates between‐trial variance/(between trial variance + within trial variance). This measures the proportion of total variation in the estimate of the treatment effect that is due to heterogeneity between trials. This statistic is also independent of the number of trials in the analysis (Higgins 2002).

We assessed the I² statistic as moderate heterogeneity when it was 30% to 50% and high heterogeneity when greater than 50%.

Assessment of reporting biases

We assessed for publication bias using funnel plots, as outlined in chapter 13 of the Cochrane Handbook for Systematic Reviews of Interventions (Page 2019), when there were ten trials or more examining the same outcome (dose).

Data synthesis

We entered all RCTs into Review Manager 5 (Review Manager 2014), as mean difference using a fixed‐effect model to determine the weighted treatment effect and 95% CIs for LDL cholesterol, total cholesterol, HDL cholesterol, and triglycerides. We entered all controlled before‐and‐after studies as generic inverse variance fixed‐effect model data to determine the weighted treatment effect. If the effect in the RCTs was not statistically significantly different from the before‐and‐after studies, we entered all trials for each dose as fixed‐effect model generic inverse variance to determine the best overall weighted treatment effect for each dose.

We recorded data of each trial and dose in GraphPad Prism 4, to yield a weighted, least squares analysis, based on the inverse of the square of the SE for each lipid parameter, to generate weighted log dose‐response curves. We entered the number of participants in RCTs, who prematurely withdrew due to at least one adverse effect in Review Manager 5 (Review Manager 2014), as dichotomous data for each dose and all combined doses of cerivastatin.

We determined the relative potency of cerivastatin with respect to fluvastatin, atorvastatin and rosuvastatin as the ratio of the milligram (mg) amount of cerivastatin to the mg amount of fluvastatin or atorvastatin or rosuvastatin needed to produce the same specified effect. We calculated these values from the log dose‐response curves of cerivastatin, fluvastatin, atorvastatin and rosuvastatin for LDL cholesterol, total cholesterol, and triglycerides. We estimated the relative potencies from these dose ratios.

Subgroup analysis and investigation of heterogeneity

The main subgroup analyses were the different doses of cerivastatin. We assessed heterogeneity using I² statistic (Higgins 2002). If the I² statistic value was 50% or higher, we attempted to identify possible causes for this by carrying out a number of planned sensitivity analyses, provided there were sufficient numbers of trials (see below).

We analysed subgroups based on the following factors.

RCTs versus before‐and‐after studies (described above)
Men versus women
Morning administration time versus evening administration time as defined by the cut offs 6:00 am to noon and 6:00 pm to midnight
Bayer‐funded versus non‐Bayer‐funded trials

Sensitivity analysis

We conducted sensitivity analyses to assess the effect of different comorbidities, such as familial hyperlipidaemia, on the treatment effect. We compared the treatment effects as generic inverse variance between trials whose participants were reported to have type IIa or familial hypercholesterolaemia versus trials whose participants were not reported to have genetic hypercholesterolaemia. We excluded trials from this analysis if the participants in a trial included both familial and non‐familial hypercholesterolaemia. We conducted sensitivity analyses to assess the effect of different methods of dosing, such as twice daily versus single dose, on the treatment effect.

We analysed RCTs and before‐and‐after studies separately in the data and analysis section.

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach to assess the certainty of the supporting evidence behind each estimate of treatment effect (Schünemann 2019a; Schünemann 2019b). We presented key findings of the review, including a summary of the amount of data, the magnitude of the effect size and the overall certainty of the evidence, in Table 1, Table 2, Table 3 and Table 4. We did not summarize the findings on HDL cholesterol in a summary of findings table because cerivastatin doses ranging from 0.025 mg/day to 0.8 mg/day had no dose‐related effect on HDL cholesterol.

Summary of findings for the main comparison. Low‐density lipoprotein (LDL) cholesterol‐lowering efficacy of cerivastatin.

Low‐density lipoprotein (LDL) cholesterol lowering efficacy of cerivastatin
Patient or population: participants with normal or abnormal lipid profiles Settings: clinics or hospitals Intervention: different fixed doses of cerivastatin Comparison: placebo or baseline
Cerivastatin dose	Anticipated absolute effects mmol/L (95%CI)		Percentage change from baseline  (95% CI)	№ of participants  (trials)	Certainty of the evidence  (GRADE)	Comments
Cerivastatin dose	LDL‐cholesterol before exposure to cerivastatin^a	LDL‐cholesterol after exposure to cerivastatin	Percentage change from baseline  (95% CI)	№ of participants  (trials)	Certainty of the evidence  (GRADE)	Comments
0.05 mg/d	5.08 (4.75 to 5.41)	4.27 (4.21 to 4.33)	‐16.0 (‐17.2 to ‐14.7)	1811  (5)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −16.9%. Randomised and before‐and‐after design not different P = 0.46
0.1 mg/d	5.01 (4.72 to 5.31)	3.85 (3.81 to 3.90)	‐23.1 (‐24.0 to ‐22.2)	2327  (11)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −22.9%. Randomised and before‐and‐after design not different P = 0.13
0.2 mg/d	5.09 (4.72 to 5.45)	3.68 (3.64 to 3.73)	‐27.6 (‐28.5 to ‐26.6)	2498  (15)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −28.8%. Randomised and before‐and‐after design not different P = 0.07
0.3 mg/d	5.09 (4.74 to 5.43)	3.50 3.46 to 3.54)	‐31.2 (‐32.0 to ‐30.5)	3020  (19)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −32.3%. Randomised and before‐and‐after design not different P = 0.73
0.4 mg/d	5.00 (4.69 to 5.32)	3.28 (3.24 to 3.32)	‐34.5 (‐35.3 to ‐33.7)	3080  (13)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −34.8%. Randomised and before‐and‐after design not different P = 0.84
0.8 mg/d	4.91 (4.55 to 5.27)	2.84 (2.80 to 2.88)	‐42.2 (‐43.1 to ‐41.3)	2560  (6)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −40.8%. Randomised and before‐and‐after design not different P = 0.31
CI: confidence interval; LDL: low‐density lipoprotein
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.

Total cholesterol lowering efficacy of cerivastatin
Patient or population: participants with normal or abnormal lipid profiles Settings: clinics or hospitals Intervention: different fixed doses of cerivastatin Comparison: placebo or baseline
Cerivastatin dose	Anticipated absolute effects mmol/L (95%CI)		Percentage change from baseline  (95% CI)	№ of participants  (trials)	Certainty of the evidence  (GRADE)	Comments
Cerivastatin dose	Total cholesterol before exposure to cerivastatin^a	Total cholesterol after exposure to cerivastatin	Percentage change from baseline  (95% CI)	№ of participants  (trials)	Certainty of the evidence  (GRADE)	Comments
0.05 mg/d	7.14 (6.80 to 7.49)	6.32 (6.22 to 6.43)	‐11.5 (‐12.9 to ‐10.0)	569  (3)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −12.2%. Randomised and before‐and‐after design not different P = 0.87
0.1 mg/d	7.10 (6.80 to 7.39)	5.91 (5.86 to 5.96)	‐16.8 (‐17.5 to ‐16.1)	2114  (10)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −16.3%. Randomised and before‐and‐after design not different P = 0.90
0.2 mg/d	7.16 (6.80 to 7.52)	5.73 (5.68 to 5.78)	‐20.0 (‐20.7 to ‐19.3)	1953 (14)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −20.5%. Randomised and before‐and‐after design was different P = 0.002
0.3 mg/d	7.19 (6.85 to 7.54)	5.58 (5.54 to 5.62)	‐22.4 (‐23.0 to ‐21.8)	2567 (17)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −22.9%. Randomised and before‐and‐after design not different P = 0.055
0.4 mg/d	7.16 (6.88 to 7.44)	5.41 (5.36 to 5.46)	‐24.5 (‐25.2 to ‐23.8)	2715 (10)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −24.7%. Randomised and before‐and‐after design was different P = 0.03
0.8 mg/d	7.01 (6.66 to 7.36)	4.91 (4.84 to 4.98)	‐29.95 (‐31.0 to ‐28.9)	1938 (5)	⊕⊕⊕⊕  High	Effect predicted from log dose‐response equation is −28.8%. Randomised and before‐and‐after design not different P = 0.40
CI: confidence interval
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.

Triglyceride‐lowering efficacy of cerivastatin
Patient or population: participants with normal or abnormal lipid profiles Settings: clinics or hospitals Intervention: different fixed doses of cerivastatin Comparison: placebo
Cerivastatin dose	Anticipated absolute effects mmol/L (95%CI)		Mean difference from placebo  (95% CI)	№ of participants  (trials)	Certainty of the evidence  (GRADE)	Comments
Cerivastatin dose	Triglycerides before exposure to cerivastatin^a	Triglycerides after exposure to cerivastatin	Mean difference from placebo  (95% CI)	№ of participants  (trials)	Certainty of the evidence  (GRADE)	Comments
0.05 mg/d	1.85 (1.70 to 1.99)	1.62 (1.53 to 1.71)	‐12.5 (‐17.4 to ‐7.6)	504 (2)	⊕⊝⊝⊝  Very low^b,c	Effect predicted from log dose‐response equation is −11.5%
0.1 mg/d	1.85 (1.73 to 1.98)	1.55 (1.47 to 1.63)	‐16.1 (‐20.4 to ‐11.9)	731 (4)	⊕⊕⊕⊝  Moderate^c	Effect predicted from log dose‐response equation is −14.0%
0.2 mg/d	1.81 (1.68 to 1.94)	1.52 (1.44 to 1.59)	‐16.2 (‐20.3 to ‐12.0)	780 (5)	⊕⊕⊕⊝  Moderate^c	Effect predicted from log dose‐response equation is −16.4%
0.3 mg/d	1.85 (1.73 to 1.97)	1.49 (1.42 to 1.55)	‐19.6 (‐23.2 to ‐16.0)	1303 (8)	⊕⊕⊕⊝  Moderate^c	Effect predicted from log dose‐response equation is −17.9%
0.4 mg/d	1.88 (1.76 to 2.00)	1.55 (1.50 to 1.60)	‐17.6 (‐20.4 to ‐14.9)	1969 (6)	⊕⊕⊕⊝  Moderate^c	Effect predicted from log dose‐response equation is −18.9%
0.8 mg/d	1.90 (1.77 to 2.04)	1.50 (1.43 to 1.56)	‐21.2 (‐24.5 to ‐18.0)	1880 (4)	⊕⊕⊕⊝  Moderate^c	Effect predicted from log dose‐response equation is −20.0%
CI: confidence interval
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.

Withdrawals due to adverse events due to cerivastatin
Patient or population: participants with normal or abnormal lipid profiles  Setting: clinics or hospitals  Intervention: all doses of cerivastatin  Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (trials)	Certainty of the evidence  (GRADE)	Comments
	Risk with placebo	Risk with all doses of cerivastatin
Withdrawals due to adverse events  Follow‐up: range 3 weeks to 12 weeks	Trial population		RR 1.09  (0.68 to 1.74)	6570  (11 RCTs)	⊕⊝⊝⊝  Very low^a,b,c
	16 per 1000	17 per 1000  (11 to 28)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: risk ratio
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.

Cerivastatin dose  (mg/d)	0.025	0.05	0.1	0.15]	0.2	0.3	0.4	0.8
Mean percentage change from control of LDL‐C (95%CI)	‐12.2 (‐13.6 to ‐10.8)	‐16.0 (‐17.2 to ‐14.7)	‐23.1 (‐24.0 to ‐22.2)	‐28.5 (‐29.6 to ‐27.4)	‐27.55 (‐28.5 to ‐26.6)	‐31.2 (‐32.0 to ‐30.5)	‐34.5 (‐35.3 to ‐33.7)	‐42.2 (‐43.1 to ‐41.3)
Mean percentage change from control of total cholesterol (95%CI)	‐8.4 (‐10.1 to ‐6.6)	‐11.5 (‐12.9 to ‐10.0)	‐16.8 (‐17.5 to ‐16.1)	‐19.5 (‐20.3 to ‐18.7)	‐20.0 (‐20.7 to ‐19.3)	‐22.4 (‐23.0 to ‐21.8)	‐24.5 (‐25.2 to ‐23.8)	‐29.95 (‐31.0 to ‐28.9)
Mean difference from placebo of triglycerides (95%CI)	‐10.2 (‐12.5 to ‐8.0)	‐9.8 (‐14.1 to −5.5)	‐10.4 (‐13.0 to −7.75)	‐5.4 (‐11.8 to ‐1.05)	‐12.2 (‐14.6 to ‐9.7)	‐12.9 (‐14.6 to ‐11.2)	‐14.5 (‐16.5 to ‐12.6)	‐21.2 (‐24.5 to ‐18.0)
CI: confidence interval; LDL‐C: low‐density lipoprotein cholesterol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol RCTs	3	1100	Mean Difference (IV, Fixed, 95% CI)	‐12.65 [‐14.32, ‐10.97]
2 Total cholesterol RCTs	2	510	Mean Difference (IV, Fixed, 95% CI)	‐8.37 [‐10.13, ‐6.62]
3 HDL‐cholesterol RCTs	2	510	Mean Difference (IV, Fixed, 95% CI)	0.89 [‐1.49, 3.27]
4 Triglycerides RCTs	2	510	Mean Difference (IV, Fixed, 95% CI)	‐6.34 [‐11.27, ‐1.40]
5 WDAEs	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.42, 5.06]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol RCTs	4	1750	Mean Difference (IV, Fixed, 95% CI)	‐15.76 [‐17.12, ‐14.41]
2 Total cholesterol RCTs	2	504	Mean Difference (IV, Fixed, 95% CI)	‐11.56 [‐13.32, ‐9.80]
3 HDL‐cholesterol RCTs	2	504	Mean Difference (IV, Fixed, 95% CI)	3.21 [0.73, 5.69]
4 Triglycerides RCTs	2	504	Mean Difference (IV, Fixed, 95% CI)	‐12.52 [‐17.45, ‐7.59]
5 LDL‐cholesterol non‐RCTs	1	61	Mean Difference (Fixed, 95% CI)	‐17.1 [‐20.36, ‐13.84]
6 Total cholesterol non‐RCTs	1	65	Mean Difference (Fixed, 95% CI)	‐11.3 [‐13.85, ‐8.75]
7 HDL‐cholesterol non‐RCTs	1	65	Mean Difference (Fixed, 95% CI)	2.2 [‐1.69, 6.09]
8 Triglycerides non‐RCTs	1	63	Mean Difference (Fixed, 95% CI)	‐0.5 [‐9.56, 8.56]
9 WDAEs	2	558	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.34, 4.47]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol RCTs	7	1908	Mean Difference (IV, Fixed, 95% CI)	‐22.40 [‐23.71, ‐21.10]
2 Total cholesterol RCTs	6	1677	Mean Difference (IV, Fixed, 95% CI)	‐16.72 [‐17.76, ‐15.68]
3 HDL‐cholesterol RCTs	6	1675	Mean Difference (IV, Fixed, 95% CI)	4.49 [3.04, 5.94]
4 Triglycerides RCTs	4	731	Mean Difference (IV, Fixed, 95% CI)	‐16.17 [‐20.46, ‐11.89]
5 LDL‐cholesterol non‐RCTs	4	419	Mean Difference (Fixed, 95% CI)	‐23.84 [‐25.14, ‐22.54]
6 Total cholesterol non‐RCTs	4	437	Mean Difference (Fixed, 95% CI)	‐16.81 [‐17.74, ‐15.87]
7 HDL‐cholesterol non‐RCTs	4	437	Mean Difference (Fixed, 95% CI)	3.20 [1.85, 4.56]
8 Triglycerides non‐RCTs	4	426	Mean Difference (Fixed, 95% CI)	‐6.87 [‐10.18, ‐3.56]
9 WDAEs	4	942	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.40, 2.76]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol RCTs	1	60	Mean Difference (IV, Fixed, 95% CI)	‐23.05 [‐30.64, ‐15.46]
2 Total cholesterol RCTs	1	60	Mean Difference (IV, Fixed, 95% CI)	‐19.1 [‐25.17, ‐13.03]
3 HDL‐cholesterol RCTs	1	60	Mean Difference (IV, Fixed, 95% CI)	37.2 [29.10, 45.30]
4 Triglycerides RCTs	1	60	Mean Difference (IV, Fixed, 95% CI)	‐17.9 [‐33.84, ‐1.96]
5 LDL‐cholesterol non‐RCTs	10	483	Mean Difference (Fixed, 95% CI)	‐28.63 [‐29.74, ‐27.51]
6 Total cholesterol non‐RCTs	11	555	Mean Difference (Fixed, 95% CI)	‐19.51 [‐20.36, ‐18.66]
7 HDL‐cholesterol non‐RCTs	3	94	Mean Difference (Fixed, 95% CI)	1.03 [‐2.20, 4.26]
8 Triglycerides non‐RCTs	3	92	Mean Difference (Fixed, 95% CI)	‐2.82 [‐9.86, 4.23]
9 WDAEs	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol RCTs	7	2140	Mean Difference (IV, Fixed, 95% CI)	‐28.37 [‐29.66, ‐27.07]
2 Total cholesterol RCTs	6	1589	Mean Difference (IV, Fixed, 95% CI)	‐21.17 [‐22.24, ‐20.11]
3 HDL‐cholesterol RCTs	6	1584	Mean Difference (IV, Fixed, 95% CI)	4.69 [3.21, 6.18]
4 Triglycerides RCTs	5	780	Mean Difference (IV, Fixed, 95% CI)	‐16.21 [‐20.39, ‐12.02]
5 LDL‐cholesterol non‐RCTs	8	358	Mean Difference (Fixed, 95% CI)	‐26.65 [‐28.01, ‐25.29]
6 Total cholesterol non‐RCTs	8	364	Mean Difference (Fixed, 95% CI)	‐18.91 [‐19.86, ‐17.96]
7 HDL‐cholesterol non‐RCTs	7	349	Mean Difference (Fixed, 95% CI)	6.14 [4.71, 7.58]
8 Triglycerides non‐RCTs	6	328	Mean Difference (Fixed, 95% CI)	‐10.43 [‐13.70, ‐7.15]
9 WDAEs	4	1102	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.31, 2.37]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol RCTs	10	2327	Mean Difference (IV, Fixed, 95% CI)	‐31.33 [‐32.55, ‐30.12]
2 Total cholesterol RCTs	8	1874	Mean Difference (IV, Fixed, 95% CI)	‐23.25 [‐24.30, ‐22.19]
3 HDL‐cholesterol RCTs	8	1931	Mean Difference (IV, Fixed, 95% CI)	6.39 [4.96, 7.81]
4 Triglycerides RCTs	8	1303	Mean Difference (IV, Fixed, 95% CI)	‐19.59 [‐23.15, ‐16.04]
5 LDL‐cholesterol non‐RCTs	9	693	Mean Difference (Fixed, 95% CI)	‐31.06 [‐32.03, ‐30.08]
6 Total cholesterol non‐RCTs	9	693	Mean Difference (Fixed, 95% CI)	‐21.98 [‐22.74, ‐21.23]
7 HDL‐cholesterol non‐RCTs	7	632	Mean Difference (Fixed, 95% CI)	4.59 [3.55, 5.62]
8 Triglycerides non‐RCTs	6	592	Mean Difference (Fixed, 95% CI)	‐10.86 [‐12.82, ‐8.89]
9 WDAEs	5	665	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.38, 4.52]

Methods	4‐week run‐in period 12‐week RCT
Participants	58 men and women with type 2 diabetes aged 35‐75 years old LDL‐C 100 mg/dL (2.57 mmol/L)‐190 mg/dL (4.91 mmol/L) Exclusion criteria: patients under therapy with heparin, known thrombophilia, neoplasia, unstable angina, known intolerance or hypersensitivity to statins, major organ system failure, transplantation, organic brain syndrome, clinically manifest hypothyroidism, pregnancy or lactation period, women of childbearing potential not using adequate methods of contraception, myopathy (CK > 3 times ULN), impaired hepatic function (SGOT or SGPT > 2 times ULN), SCr > 2 mg/dL, intake of drugs influencing endothelial function if a dose change (inc. start or withdrawal) occurred within the last 12 weeks prior to the screening visit, intake of statins within the last 8 weeks prior to the screening visit, drug or alcohol abuse, reversal of a normal sleep/wake cycle (e.g. patients on nightshift) Placebo baseline TC: 6.0 mmol/L (232.1 mg/dL)  Placebo baseline LDL‐C: 3.9 mmol/L (150.8 mg/dL)  Placebo baseline HDL‐C: 1.1 mmol/L (42.5 mg/dL) Placebo baseline TG: 2.3 mmol/L (203.7 mg/dL) Cerivastatin 0.2 mg/d baseline TC: 5.9 mmol/L (228.2 mg/dL)  Cerivastatin 0.2 mg/d baseline LDL‐C: 3.8 mmol/L (146.9 mg/dL)  Cerivastatin 0.2 mg/d baseline HDL‐C: 1.3 mmol/L (50.3 mg/dL) Cerivastatin 0.2 mg/d baseline TG: 2.0 mmol/L (177.1 mg/dL) Cerivastatin 0.8 mg/d baseline TC: 5.4 mmol/L (208.8 mg/dL)  Cerivastatin 0.8 mg/d baseline LDL‐C: 3.5 mmol/L (135.3 mg/dL)  Cerivastatin 0.8 mg/d baseline HDL‐C: 1.2 mmol/L (46.4 mg/dL) Cerivastatin 0.8 mg/d baseline TG: 1.8 mmol/L (159.4 mg/dL)
Interventions	Placebo Cerivastatin 0.2 mg/d Cerivastatin 0.8 mg/d
Outcomes	Percentage change from baseline at 12 weeks of plasma TC, LDL‐C, HDL‐C, TG and WDAEs
Source of funding	Unknown
Notes	SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of sufficient blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	LDL‐C was measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	Unclear risk	Blinding method was not described
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding not reported

Methods	10‐week run‐in washout period 6‐week RCT
Participants	55 men and women with heterozygous FH aged 21‐75 years LDL‐C > 5.0 mmol/L (193 mg/dL), TG ≤ 4.02 mmol/L (356 mg/dL), hypertensive patients on a stable dose of beta‐blockers or diuretics and patients on thyroid replacement therapy TSH was ≤ 7.5mu/L with T4 within normal range, postmenopausal women on HRT Exclusion criteria: homozygous FH, MI, stroke, PTCA or coronary bypass surgery within the previous 6 months, congestive heart failure grade 3 or 4, significant cardiac arrhythmias, uncontrolled diabetes mellitus, endocrine disease, significant renal disease, respiratory disease, hepatic dysfunction, significant eye disease, neuromuscular disease, infections that may interfere with the trial, cancer within 5 years, women of child bearing potential, drug or alcohol abuse, night shift workers, mental disorders, HIV positive, pancreatitis, use of immunosuppressants, corticosteroids, androgens, erythromycin, niacin, psyllium, fish oil and excess bran and therapy with any other investigational drug within 30 d prior to the screening visit Placebo baseline TC: 9.00 mmol/L (348 mg/dL)  Placebo baseline LDL‐C: 7.24 mmol/L (280 mg/dL)  Placebo baseline HDL‐C: 1.19 mmol/L (46 mg/dL) Placebo baseline TG: 1.24 mmol/L (110 mg/dL) Cerivastatin 0.2 mg/d baseline TC: 9.08 mmol/L (351 mg/dL)  Cerivastatin 0.2 mg/d baseline LDL‐C: 7.27 mmol/L (281 mg/dL)  Cerivastatin 0.2 mg/d baseline HDL‐C: 1.16 mmol/L (45 mg/dL) Cerivastatin 0.2 mg/d baseline TG: 1.39 mmol/L (123 mg/dL) Cerivastatin 0.3 mg/d baseline TC: 9.59 mmol/L (371 mg/dL)  Cerivastatin 0.3 mg/d baseline LDL‐C: 7.63 mmol/L (295 mg/dL)  Cerivastatin 0.3 mg/d baseline HDL‐C: 1.19 mmol/L (46 mg/dL) Cerivastatin 0.3 mg/d baseline TG: 1.68 mmol/L (149 mg/dL)
Interventions	Placebo evening dosing Cerivastatin 0.2 mg/d evening dosing Cerivastatin 0.3 mg/d evening dosing
Outcomes	Percentage change from baseline at 6 weeks of plasma TC, LDL‐C, HDL‐C, TG and WDAEs
Source of funding	Bayer
Notes	SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind fashion lipid parameter measurements unlikely influenced by lack of sufficient blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	Low risk	No participants withdrew due to adverse events
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Bayer funded the trial, data may support bias for cerivastatin

Methods	10‐week baseline washout period 6 months for probucol 24‐week RCT
Participants	908 men and women aged 18‐75 with documented primary hypercholesterolaemia Exclusion criteria: weight > 140% ideal body weight, homozygous FH, cancer except squamous or basal cell skin cancer or psychosis, women of childbearing potential, night shift workers, drug or alcohol abuse, MI, stroke, TIA, unstable angina, CABG and PTCA within 6 months of trial, uncontrolled hypertension within 3 months of trial, patients with hypertension who had a change in diuretic or beta blocker therapy within 3 months of trial, diabetes mellitus or other endocrine disorders, significant eye disease, active hepatic disease, GI disorders that could affect drug absorption, HMG CoA reductase inhibitor hypersensitivity, renal dysfunction, current use of corticosteroids, erythromycin, all macrolide antibiotics, rifampin, androgens, immunosuppressants, ketoconazole and itraconazole, treatment with cerivastatin within 6 months of trial and therapy with another investigational product within 30 d Placebo baseline TC: 7.10 mmol/L (275 mg/dL)  Placebo baseline LDL‐C: 4.94 mmol/L (191 mg/dL)  Placebo baseline HDL‐C: 1.25 mmol/L (48 mg/dL) Placebo baseline TG: 1.99 mmol/L (176 mg/dL) Cerivastatin 0.3 mg/d baseline TC: 7.15 mmol/L (276 mg/dL)  Cerivastatin 0.3 mg/d baseline LDL‐C: 4.96 mmol/L (192 mg/dL)  Cerivastatin 0.3 mg/d baseline HDL‐C: 1.26 mmol/L (49 mg/dL) Cerivastatin 0.3 mg/d baseline TG: 2.11 mmol/L (187 mg/dL) Cerivastatin 0.4 mg/d baseline TC: 7.05 mmol/L (273 mg/dL)  Cerivastatin 0.4 mg/d baseline LDL‐C: 4.84 mmol/L (187 mg/dL)  Cerivastatin 0.4 mg/d baseline HDL‐C: 1.27 mmol/L (49 mg/dL) Cerivastatin 0.4 mg/d baseline TG: 2.08 mmol/L (184 mg/dL)
Interventions	Placebo Cerivastatin 0.3 mg/d Cerivastatin 0.4 mg/d
Outcomes	Percentage change from baseline at 8 weeks of blood TC, LDL‐C, HDL‐C and TG
Source of funding	Bayer
Notes	SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind lipid parameter measurements unlikely influenced by lack of adequate blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No WDAE data for the 8‐week period
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Bayer funded the trial, data may support bias for cerivastatin

Methods	10‐week run‐in period 12‐week RCT
Participants	978 men and women aged 21‐75 years with uncomplicated primary hypercholesterolaemia LDL‐C ≥ 160 mg/dL (4.12 mmol/L) and TG ≤ 350 mg/dL (4.02 mmol/L) Exclusion criteria: homozygous FH, MI, stroke or bypass surgery within the last 6 months, diabetes mellitus, significant renal hepatic muscular or neuromuscular or eye abnormalities Placebo baseline TC: 7.75 mmol/L (300 mg/dL)  Placebo baseline LDL‐C: 5.64 mmol/L (218 mg/dL)  Placebo baseline HDL‐C: 1.39 mmol/L (54 mg/dL) Placebo baseline TG: 1.57 mmol/L (139 mg/dL) Cerivastatin 0.025 mg/d baseline TC: 7.71 mmol/L (298 mg/dL)  Cerivastatin 0.025 mg/d baseline LDL‐C: 5.63 mmol/L (218 mg/dL)  Cerivastatin 0.025 mg/d baseline HDL‐C: 1.35 mmol/L (52 mg/dL) Cerivastatin 0.025 mg/d baseline TG: 1.59 mmol/L (141 mg/dL) Cerivastatin 0.05 mg/d baseline TC: 7.62 mmol/L (295 mg/dL)  Cerivastatin 0.05 mg/d baseline LDL‐C: 5.55 mmol/L (215 mg/dL)  Cerivastatin 0.05 mg/d baseline HDL‐C: 1.38 mmol/L (53 mg/dL) Cerivastatin 0.05 mg/d baseline TG: 1.53 mmol/L (136 mg/dL) Cerivastatin 0.1 mg/d baseline TC: 7.56 mmol/L (292 mg/dL)  Cerivastatin 0.1 mg/d baseline LDL‐C: 5.49 mmol/L (212 mg/dL)  Cerivastatin 0.1 mg/d baseline HDL‐C: 1.33 mmol/L (51 mg/dL) Cerivastatin 0.1 mg/d baseline TG: 1.61 mmol/L (143 mg/dL) Cerivastatin 0.2 mg/d baseline TC: 7.64 mmol/L (295 mg/dL)  Cerivastatin 0.2 mg/d baseline LDL‐C: 5.58 mmol/L (216 mg/dL)  Cerivastatin 0.2 mg/d baseline HDL‐C: 1.34 mmol/L (52 mg/dL) Cerivastatin 0.2 mg/d baseline TG: 1.58 mmol/L (140 mg/dL)
Interventions	Placebo evening dosing Cerivastatin 0.025 mg/d evening dosing Cerivastatin 0.05 mg/d evening dosing Cerivastatin 0.1 mg/d evening dosing Cerivastatin 0.2 mg/d evening dosing Simvastatin 20 mg/d evening dosing
Outcomes	Percentage change from baseline at 12 weeks of plasma TC, LDL‐C, HDL‐C, TG and WDAEs
Source of funding	Bayer AG
Notes	Simvastatin 20 mg/d group was not analysed
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind cerivastatin and placebo tablets were all identical in appearance
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	Unclear risk	Blinding method was not described
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Bayer AG funded the trial, data may support bias for cerivastatin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol RCTs	8	2531	Mean Difference (IV, Fixed, 95% CI)	‐34.61 [‐35.76, ‐33.46]
2 Total cholesterol RCTs	7	2344	Mean Difference (IV, Fixed, 95% CI)	‐25.29 [‐26.26, ‐24.31]
3 HDL‐cholesterol RCTs	8	2551	Mean Difference (IV, Fixed, 95% CI)	4.85 [3.65, 6.04]
4 Triglycerides RCTs	6	1969	Mean Difference (IV, Fixed, 95% CI)	‐17.63 [‐20.39, ‐14.87]
5 LDL‐cholesterol non‐RCTs	5	549	Mean Difference (Fixed, 95% CI)	‐34.45 [‐35.54, ‐33.35]
6 Total cholesterol non‐RCTs	3	371	Mean Difference (Fixed, 95% CI)	‐23.73 [‐24.69, ‐22.77]
7 HDL‐cholesterol non‐RCTs	4	533	Mean Difference (Fixed, 95% CI)	6.31 [5.35, 7.26]
8 Triglycerides non‐RCTs	1	244	Mean Difference (Fixed, 95% CI)	‐11.4 [‐14.15, ‐8.65]
9 WDAEs	2	603	Risk Ratio (M‐H, Fixed, 95% CI)	1.95 [0.55, 6.87]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol RCTs	4	1879	Mean Difference (IV, Fixed, 95% CI)	‐41.55 [‐43.05, ‐40.06]
2 Total cholesterol RCTs	4	1880	Mean Difference (IV, Fixed, 95% CI)	‐30.17 [‐31.33, ‐29.01]
3 HDL‐cholesterol RCTs	4	1880	Mean Difference (IV, Fixed, 95% CI)	5.67 [4.23, 7.10]
4 Triglycerides RCTs	4	1880	Mean Difference (IV, Fixed, 95% CI)	‐21.23 [‐24.46, ‐18.01]
5 LDL‐cholesterol non‐RCTs	2	681	Mean Difference (Fixed, 95% CI)	‐42.52 [‐43.63, ‐41.42]
6 Total cholesterol non‐RCTs	1	58	Mean Difference (Fixed, 95% CI)	‐29.1 [‐31.34, ‐26.86]
7 HDL‐cholesterol non‐RCTs	2	681	Mean Difference (Fixed, 95% CI)	8.49 [7.33, 9.65]
8 WDAEs	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	2.04 [0.52, 8.05]

Methods	4‐week placebo run‐in period 12‐week before‐and‐after study
Participants	11 men and women with type IIa and IIb hyperlipidaemia and type 2 diabetes mellitus age > 20 years old TC ≥ 220 mg/dL (5.69 mmol/L) Exclusion criteria: secondary hypercholesterolaemia, FH, statin hypersensitivity, difficulty evaluating drug efficacy, Cerivastatin 0.15 mg/d baseline TC: 5.88 mmol/L (227 mg/dL)  Cerivastatin 0.15 mg/d baseline LDL‐C: 3.54 mmol/L (137 mg/dL)
Interventions	Cerivastatin 0.15 mg/d evening dosing
Outcomes	Percentage change from baseline at 4‐12 weeks of blood TC and LDL‐C
Source of funding	Unknown
Notes	HDL‐C and TG were not included in the efficacy analysis because the given values and the calculated values differed by > 10%
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before‐and‐after design
Allocation concealment (selection bias)	High risk	Controlled before‐and‐after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No comparison possible
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	High risk	Not included in the efficacy analysis because the given values and the calculated values differed by > 10%
Incomplete outcome data (attrition bias)   Triglycerides	High risk	Not included in the efficacy analysis because the given values and the calculated values differed by > 10%
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding not reported

Methods	4‐week placebo washout period 12‐week before‐and‐after study
Participants	73 men and women with type IIa and IIb hyperlipidaemia aged 20‐64 years old, hypertension, mild diabetes, obesity, cholelithiasis TC ≥ 260 mg/dL (6.72 mmol/L) TG < 400 mg/dL (4.52 mmol/L) Exclusion criteria: secondary hyperlipidaemia, hypothyroidism, Cushings syndrome, obstructive gallbladder disease, SLE, nephrotic syndrome, poorly controlled diabetes, severe hypertension, alcohol abuse, drug‐induced hyperlipidaemia, dietary treatment for obesity, heart, brain, kidney, liver diseases, MI within 3 months, cerebrovascular disorder, statin hypersensitivity, pregnancy potential and lactation, those participants considered inappropriate by the investigator Cerivastatin 0.05 mg/d baseline TC: 7.30 mmol/L (282 mg/dL) Cerivastatin 0.15 mg/d baseline TC: 7.79 mmol/L (301 mg/dL)  Cerivastatin 0.15 mg/d baseline LDL‐C: 5.66 mmol/L (219 mg/dL) Cerivastatin 0.3 mg/d baseline TC: 7.98 mmol/L (309 mg/dL)  Cerivastatin 0.3 mg/d baseline LDL‐C: 5.76 mmol/L (223 mg/dL)
Interventions	Cerivastatin 0.15 mg/d evening dosing Cerivastatin 0.3 mg/d evening dosing
Outcomes	Percentage change from baseline at 4‐12 weeks of blood TC and LDL‐C
Source of funding	Unknown
Notes	HDL‐C and TG data were excluded because the given data and the calculated values differed by > 10%
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before‐and‐after design
Allocation concealment (selection bias)	High risk	Controlled before‐and‐after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No comparison possible
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis for the cerivastatin 0.15 mg/d group for TC [(40‐39)/40]*100 = 2.5% participants were not included in the efficacy analysis for the cerivastatin 0.3 mg/d group
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	[(33‐28)/33]100 = 15.2% participants were not included in the efficacy analysis for the cerivastatin 0.15 mg/d group [(40‐39)/40]100 = 2.5% participants were not included in the efficacy analysis for the cerivastatin 0.3 mg/d group [(73‐67)/73]*100 = 8.2% participants were not included in the efficacy analysis for combined doses
Incomplete outcome data (attrition bias)   HDL cholesterol	High risk	Not included in the efficacy analysis because the given values and the calculated values differed by > 10%
Incomplete outcome data (attrition bias)   Triglycerides	High risk	Not included in the efficacy analysis because the given values and the calculated values differed by > 10%
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding not reported

Methods	4‐week washout period 12‐week before‐and‐after study
Participants	58 men and women with type IIa and IIb hyperlipidaemia aged 20‐64 years old TC ≥ 260 mg/dL (6.72 mmol/L) TG ≤ 400 mg/dL (4.52 mmol/L), moderate hypertension, mild diabetes mellitus, obesity, cholelithiasis Exclusion criteria: secondary hyperlipidaemia Cerivastatin 0.15 mg/d baseline TC: 7.92 mmol/L (306 mg/dL)  Cerivastatin 0.15 mg/d baseline LDL‐C: 5.74 mmol/L (222 mg/dL)
Interventions	Cerivastatin 0.15 mg/d evening dosing
Outcomes	Percentage change from baseline at 12 weeks of blood TC and LDL‐C
Source of funding	Unknown
Notes	HDL‐C and TG data were excluded because the given data and the calculated values differed by > 10%
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before‐and‐after design
Allocation concealment (selection bias)	High risk	Controlled before‐and‐after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No comparison possible
Incomplete outcome data (attrition bias)   Total cholesterol	High risk	[(108‐56)/108]*100 = 48.1% participants were not included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	High risk	[(108‐53)/108]*100 = 50.9% participants were not included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	High risk	Not included in the efficacy analysis because the given values and the calculated values differed by > 10%
Incomplete outcome data (attrition bias)   Triglycerides	High risk	Not included in the efficacy analysis because the given values and the calculated values differed by > 10%
Selective reporting (reporting bias)	Low risk	LD‐C outcome was reported
Other bias	Unclear risk	Source of funding was not reported

Methods	4‐week run‐in period 4‐week before‐and‐after study
Participants	8 men and women with type 2 diabetes age 40‐70 years LDL‐C > 213 mg/dL (5.52 mmol/L), TG > 133 mg/dL (1.5 mmol/L) Exclusion criteria: evidence of hepatic or renal disease, unstable hypertension, proliferative retinopathy, unstable angina, or recent MI (within 3 months) or patients with FH or those using any lipid‐lowering agent in the previous 3 months Cerivastatin 0.3 mg/d baseline TC: 6.2 mmol/L (239.8 mg/dL)  Cerivastatin 0.3 mg/d baseline LDL‐C: 4.5 mmol/L (174 mg/dL)  Cerivastatin 0.3 mg/d baseline HDL‐C: 1.1 mmol/L (42.5 mg/dL) Cerivastatin 0.3 mg/d baseline TG: 2.4 mmol/L (212.6 mg/dL)
Interventions	Cerivastatin 0.3 mg/d
Outcomes	Percentage change from baseline at 4 weeks of plasma TC, LDL‐C, HDL‐C and TG
Source of funding	Bayer UK
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before‐and‐after design
Allocation concealment (selection bias)	High risk	Controlled before‐and‐after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	LDL‐C was measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No comparison possible
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Trial supported by Bayer UK, data may support bias for cerivastatin

Methods	No washout required because participants were not receiving any lipid‐lowering medications within 4 weeks of the trial; 6 months for probucol 1‐month, RCT
Participants	36 men and women with primary hypercholesterolaemia aged 18‐75 years LDL‐C ≥ 130 mg/dL (3.36 mmol/L) and TG ≤ 350 mg/dL (4.02 mmol/L) Exclusion criteria: homozygous FH, CVD or cerebrovascular disease, TIA, uncontrolled hypertension, diabetes mellitus, clinically significant eye disease, malignancy, psychosis, chronic liver disease, prior exposure to cerivastatin nor HMG CoA reductase inhibitor hypersensitivity, drug or alcohol abuse, child bearing potential, patients who had taken another investigational drug within 30 d of trial, concurrent use of corticosteroids, erythromycin, oral anticoagulants, hypoglycaemic agents, digoxin, androgens, immunosuppressants or cimetidine and significant laboratory abnormalities Placebo baseline TC: 6.90 mmol/L (267 mg/dL)  Placebo baseline LDL‐C: 4.84 mmol/L (187 mg/dL)  Placebo baseline HDL‐C: 1.22 mmol/L (47 mg/dL) Placebo baseline TG: 1.89 mmol/L (167 mg/dL) Cerivastatin 0.3 mg/d baseline TC: 6.90 mmol/L (267 mg/dL)  Cerivastatin 0.3 mg/d baseline LDL‐C: 4.68 mmol/L (181 mg/dL)  Cerivastatin 0.3 mg/d baseline HDL‐C: 1.29 mmol/L (50 mg/dL) Cerivastatin 0.3 mg/d baseline TG: 1.99 mmol/L (176 mg/dL)
Interventions	Placebo evening dosing Cerivastatin 0.3 mg/d evening dosing
Outcomes	Percentage change from baseline at 4 weeks of blood TC, LDL‐C, HDL‐C, TG, and WDAEs
Source of funding	Bayer
Notes	SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind: placebo and cerivastatin tablets were all identical in appearance
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	Unclear risk	Method of blinding for WDAEs was not reported
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis for the placebo group [(24‐23)/24]*100 = 4.2% participants were not included in the efficacy analysis for the cerivastatin 0.3 mg/d group
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis for the placebo group [(24‐23)/24]*100 = 4.2% participants were not included in the efficacy analysis for the cerivastatin 0.3 mg/d group
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	All participants were included in the efficacy analysis for the placebo group [(24‐23)/24]*100 = 4.2% participants were not included in the efficacy analysis for the cerivastatin 0.3 mg/d group
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	All participants were included in the efficacy analysis for the placebo group [(24‐23)/24]*100 = 4.2% participants were not included in the efficacy analysis for the cerivastatin 0.3 mg/d group
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Bayer funded the trial, data may support bias for cerivastatin

Methods	10‐week run‐in washout period 24‐week, RCT
Participants	785 men and women with primary hypercholesterolaemia both familial and non‐familial LDL‐C ≥ 160 mg/dL (4.12 mmol/L) and TG ≤ 350 mg/dL (4.02 mmol/L) Exclusion criteria: MI, unstable angina, stroke, TIA, uncontrolled hypertension within the last 3 months, CABG or PTCA within the previous 6 months diabetes mellitus, clinically significant eye disease, muscular or neuromuscular disease, CK level ≥ 3 times the ULN, significant infection, malignancy, or psychosis, GI disorders that could affect drug absorption, chronic liver disease, serum lambda amylase > 1.2 times ULN, current use of immunosuppressants, corticosteroids, oral anticoagulants, androgens, or erythromycin, concomitant treatment with other hypolipidaemic drugs, probucol within 6 months, child bearing potential, drug or alcohol abuse, HMG CoA reductase inhibitor hypersensitivity, reversal of normal sleep/wake cycle and treatment with an investigational drug within 30 d of randomisation Placebo baseline LDL‐C: 5.15 mmol/L (199 mg/dL) Cerivastatin 0.05 mg/d baseline LDL‐C: 5.20 mmol/L (189 mg/dL) Cerivastatin 0.1 mg/d baseline LDL‐C: 5.07 mmol/L (196 mg/dL) Cerivastatin 0.2 mg/d baseline LDL‐C: 5.08 mmol/L (196 mg/dL) Cerivastatin 0.3 mg/d baseline LDL‐C: 4.99 mmol/L (193 mg/dL)
Interventions	Placebo evening dosing Cerivastatin 0.05 mg/d evening dosing Cerivastatin 0.1 mg/d evening dosing Cerivastatin 0.2 mg/d evening dosing Cerivastatin 0.3 mg/d evening dosing Lovastatin 40 mg/d evening dosing
Outcomes	Percentage change from baseline at 4‐12 weeks of plasma LDL‐C
Source of funding	Bayer
Notes	Lovastatin 40 mg/d group was not analysed SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind lipid parameter measurements unlikely influenced by lack of sufficient blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	LDL‐C was measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No WDAE data reported for the 3‐12‐week period
Incomplete outcome data (attrition bias)   Total cholesterol	High risk	No 3‐12‐week data
Incomplete outcome data (attrition bias)   LDL cholesterol	Unclear risk	[(154‐139)/154]100 = 9.7% participants were not included in the efficacy analysis for the placebo group [(159‐145)/159]100 = 8.8% participants were not included in the efficacy analysis for the cerivastatin 0.05 mg/d group [(157‐136)/157]100 = 13.4% participants were not included in the efficacy analysis for the cerivastatin 0.1 mg/d group [(159‐138)/159]100 = 13.2% participants were not included in the efficacy analysis for the cerivastatin 0.2 mg/d group [(156‐137)/156]100 = 12.2% participants were not included in the efficacy analysis for the cerivastatin 0.3 mg/d group [(785‐695)/785]100 = 11.5 % participants were not included in the efficacy analysis for all doses
Incomplete outcome data (attrition bias)   HDL cholesterol	High risk	No 3‐12‐week data
Incomplete outcome data (attrition bias)   Triglycerides	High risk	No 3‐12‐week data
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Bayer funded the trial, data may support bias for cerivastatin

Methods	10‐week run‐in washout period 8‐week RCT
Participants	1170 men and women with primary hypercholesterolaemia aged 21‐75 years; participants with no atherosclerotic disease LDL‐C > 160 mg/dL (4.14 mmol/L) participants with atherosclerotic disease LDL‐C > 130 mg/dL (3.36 mmol/L) participants with ≥ 2 cardiovascular risk factors plasma HDL‐C < 35 mg/dL (0.9 mmol/L) and LDL‐C > 130 mg/dL (3.36 mmol/L) plasma TG < 400 mg/dL (4.52 mmol/L) Exclusion criteria: MI, stroke, TIA, unstable angina, PTCA or coronary bypass surgery within the previous 6 months, for hypertensive patients change in diuretic of beta‐blocker therapy, diabetes mellitus, endocrine diseases except hypothyroidism, significant renal disease, respiratory disease, active liver disease, HMG CoA reductase hypersensitivity, unstable eye disease, cancer except skin cancer, or psychosis, women of child bearing potential, drug or alcohol abuse, night shift workers, GI tract absorption impairment, significant laboratory abnormalities, use of immunosuppressants, corticosteroids, androgens, erythromycin, probucol within 6 months, H2 blockers other than cimetidine, azole antifungals, niacin, psyllium, fish oil and excess bran, treatment with cerivastatin for > 10 d within 6 months of visit 1 and therapy with any other investigational drug within 30 d prior to the screening visit Placebo baseline TC: 6.90 mmol/L (267 mg/dL)  Placebo baseline LDL‐C: 4.77 mmol/L (184 mg/dL)  Placebo baseline HDL‐C: 1.24 mmol/L (48 mg/dL) Placebo baseline TG: 1.89 mmol/L (167 mg/dL) Cerivastatin 0.4 mg/d baseline TC: 7.14 mmol/L (276 mg/dL)  Cerivastatin 0.4 mg/d baseline LDL‐C: 4.91 mmol/L (190 mg/dL)  Cerivastatin 0.4 mg/d baseline HDL‐C: 1.27 mmol/L (49 mg/dL) Cerivastatin 0.4 mg/d baseline TG: 2.04 mmol/L (181 mg/dL) Cerivastatin 0.8 mg/d baseline TC: 7.11 mmol/L (275 mg/dL)  Cerivastatin 0.8 mg/d baseline LDL‐C: 4.89 mmol/L (189 mg/dL)  Cerivastatin 0.8 mg/d baseline HDL‐C: 1.27 mmol/L (49 mg/dL) Cerivastatin 0.8 mg/d baseline TG: 2.11 mmol/L (187 mg/dL)
Interventions	Placebo Cerivastatin 0.4 mg/d Cerivastatin 0.8 mg/d
Outcomes	Percentage change from baseline at 8 weeks of serum TC, LDL‐C, HDL‐C, TG
Source of funding	Bayer
Notes	SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind lipid parameter measurements unlikely influenced by lack of adequate blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No WDAEs were reported for the 8‐week period of interest
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	[(199‐197)/199]100 = 1% participants were not included in the efficacy analysis for the placebo group [(195‐193)/195]100 = 1% participants were not included in the efficacy analysis for the cerivastatin 0.4 mg/d group [(776‐770)/776]*100 = 0.8% participants were not included in the efficacy analysis for the cerivastatin 0.8 mg/d group
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	[(199‐197)/199]100 = 1% participants were not included in the efficacy analysis for the placebo group [(195‐193)/195]100 = 1% participants were not included in the efficacy analysis for the cerivastatin 0.4 mg/d group [(776‐770)/776]*100 = 0.8% participants were not included in the efficacy analysis for the cerivastatin 0.8 mg/d group
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	[(199‐197)/199]100 = 1% participants were not included in the efficacy analysis for the placebo group [(195‐193)/195]100 = 1% participants were not included in the efficacy analysis for the cerivastatin 0.4 mg/d group [(776‐770)/776]*100 = 0.8% participants were not included in the efficacy analysis for the cerivastatin 0.8 mg/d group
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	[(199‐197)/199]100 = 1% participants were not included in the efficacy analysis for the placebo group [(195‐193)/195]100 = 1% participants were not included in the efficacy analysis for the cerivastatin 0.4 mg/d group [(776‐770)/776]*100 = 0.8% participants were not included in the efficacy analysis for the cerivastatin 0.8 mg/d group
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Bayer funded the trial, data may support bias for cerivastatin

Methods	No washout required because no participants were receiving lipid‐lowering agents before the trial 4‐week before‐and‐after study
Participants	20 elderly men and women with hyperlipidaemia TC > 240 mg/dL (6.24 mmol/L) LDL‐C > 160 mg/dL (4.16 mmol/L) for those without coronary risk factors TC > 220 mg/dL (5.72 mmol/L) LDL‐C > 140 mg/dL (3.64 mmol/L) for those with coronary risk factors TC > 200 mg/dL (5.20 mmol/L) LDL‐C > 120 mg/dL (3.20 mmol/L) for those with coronary heart disease or atherosclerotic disease Exclusion criteria: serious cardiovascular and cerebrovascular disease within 6 months, severe trauma or major surgery, severe liver and kidney dysfunction, taking other drugs that affect on blood lipids, nephrotic syndrome, hypothyroidism, uncontrolled diabetes and pregnant and lactating women Cerivastatin 0.3 mg/d baseline TC: 6.65 mmol/L (257 mg/dL)  Cerivastatin 0.3 mg/d baseline LDL‐C: 3.64 mmol/L (141 mg/dL)  Cerivastatin 0.3 mg/d baseline HDL‐C: 1.06 mmol/L (41 mg/dL) Cerivastatin 0.3 mg/d baseline TG: 2.15 mmol/L (190 mg/dL)
Interventions	Cerivastatin 0.3 mg/d evening dosing Simvastatin 20 mg/d evening dosing
Outcomes	Percentage change from baseline at 4 weeks of serum TC, LDL‐C, HDL‐C and TG
Source of funding	Unknown
Notes	Simvastatin 20 mg/d group was not analysed SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before‐and‐after design
Allocation concealment (selection bias)	High risk	Controlled before‐and‐after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	LDL‐C was measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No comparison possible
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding not reported

PERMALINK

Cerivastatin for lowering lipids

Stephen P Adams

Nicholas Tiellet

Nima Alaeiilkhchi

James M Wright

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Primary objective

Secondary objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

1.

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Summary of findings for the main comparison. Low‐density lipoprotein (LDL) cholesterol‐lowering efficacy of cerivastatin.

Summary of findings 2. Total cholesterol‐lowering efficacy of cerivastatin.

Summary of findings 3. Triglyceride‐lowering efficacy of cerivastatin.

Summary of findings 4. All doses of cerivastatin compared to placebo for withdrawal due to adverse events.

Results

Description of studies

Results of the search

Included studies

2.

3.

4.

5.

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

6.

Other potential sources of bias

Effects of interventions

Overall efficacy of cerivastatin

1. Cerivastatin overall efficacy.

Primary outcome

LDL cholesterol

1.1. Analysis.

2.1. Analysis.

2.5. Analysis.

3.1. Analysis.

3.5. Analysis.

4.1. Analysis.

Methods	10‐week run‐in/washout period 8‐week RCT
Participants	349 men and women aged from 21‐75 years old with primary hypercholesterolaemia (LDL‐C ≥ 190 mg/dL; TG ≤ 350 mg/dL, or LDL‐C ≥ 160 mg/dL; TG ≤ 350 mg/dL in the presence of additional CAD risk factors Exclusion criteria: none reported No baseline data provided
Interventions	Placebo evening dosing Cerivastatin 0.3 mg/d evening dosing Cerivastatin 0.4 mg/d evening dosing
Outcomes	Percentage change from baseline at 8 weeks of plasma LDL‐C, HDL‐C and TG
Source of funding	Unknown
Notes	Only European phase IIB higher‐dose trial was analysed. US phase shows 6‐ and 12‐month data, and Canadian phase shows 32‐week data only SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of sufficient blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	WDAEs data were not reported
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding not reported

Methods	6‐8‐week run‐in phase 8‐week before‐and‐after study
Participants	479 men and women with type IIa or IIb hypercholesterolaemia age 18‐75 years old TG < 350 mg/dL (3.95 mmol/L) Exclusion criteria: history of MI, angina, stroke, recent TIA, recent coronary revascularisation, uncontrolled hypertension or hypothyroidism, type 2 diabetes, chronic liver disease, renal dysfunction, alcohol or drug abuse, CPK values are 3 x ULN Cerivastatin 0.3 mg/d baseline TC: 6.7 mmol/L (259 mg/dL)  Cerivastatin 0.3 mg/d baseline LDL‐C: 4.49 mmol/L (174 mg/dL)  Cerivastatin 0.3 mg/d baseline HDL‐C: 1.3 mmol/L (50 mg/dL) Cerivastatin 0.3 mg/d baseline TG: 1.99 mmol/L (176 mg/dL) Cerivastatin 0.4 mg/d baseline TC: 6.75 mmol/L (261 mg/dL)  Cerivastatin 0.4 mg/d baseline LDL‐C: 4.55 mmol/L (176 mg/dL)  Cerivastatin 0.4 mg/d baseline HDL‐C: 1.3 mmol/L (50 mg/dL) Cerivastatin 0.4 mg/d baseline TG: 1.98 mmol/L (175 mg/dL)
Interventions	Cerivastatin 0.3 mg/d evening dosing Cerivastatin 0.4 mg/d evening dosing Pravastatin 20 mg/d evening dosing Pravastatin 40 mg/d evening dosing
Outcomes	Percentage change from baseline at 8 weeks of serum TC, LDL‐C, HDL‐C and TG
Source of funding	Bayer
Notes	Pravastatin 20 mg/d and pravastatin 40 mg/d groups were not analysed
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before‐and‐after design
Allocation concealment (selection bias)	High risk	Controlled before‐and‐after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No comparison possible
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Bayer funded the trial, data may support bias for cerivastatin

Methods	4‐week placebo run‐in washout period 12‐week before‐and‐after study
Participants	294 men and women with type IIa, type IIb and type IV hypercholesterolaemia aged 20‐70 years old with moderate hypertension, mild diabetes mellitus, obese, cholelithiasis, TC ≥ 220 mg/dL (5.69 mmol/L) and TG ≤ 400 mg/dL (4.52 mmol/L) Exclusion criteria: hypothyroidism, Cushings syndrome, obstructive gallbladder disease, SLE, nephrosis, poorly controlled diabetes, severe hypertension, alcohol abuse, drug induced hyperlipidaemia, diet therapy for obesity, secondary hyperlipidaemia, severe heart, brain, kidney, liver diseases, MI within 3 months, cerebrovascular disorder, statin hypersensitivity, pregnancy potential and lactation Cerivastatin 0.05 mg/d baseline TC: 7.30 mmol/L (282 mg/dL)  Cerivastatin 0.05 mg/d baseline LDL‐C: 5.22 mmol/L (202 mg/dL) Cerivastatin 0.05 mg/d baseline HDL‐C: 1.31 mmol/L (51 mg/dL) Cerivastatin 0.05 mg/d baseline TG: 1.86 mmol/L (165 mg/dL) Cerivastatin 0.10 mg/d baseline TC: 7.21 mmol/L (279 mg/dL)  Cerivastatin 0.10 mg/d baseline LDL‐C: 5.20 mmol/L (201 mg/dL) Cerivastatin 0.10 mg/d baseline HDL‐C: 1.23 mmol/L (48 mg/dL) Cerivastatin 0.10 mg/d baseline TG: 1.94 mmol/L (172 mg/dL) Cerivastatin 0.15 mg/d baseline TC: 7.13 mmol/L (276 mg/dL)  Cerivastatin 0.15 mg/d baseline LDL‐C: 5.04 mmol/L (195 mg/dL) Cerivastatin 0.15 mg/d baseline HDL‐C: 1.39 mmol/L (54 mg/dL)  Cerivastatin 0.15 mg/d baseline TG: 1.60 mmol/L (142 mg/dL) Cerivastatin 0.20 mg/d baseline TC: 7.25 mmol/L (280 mg/dL)  Cerivastatin 0.20 mg/d baseline LDL‐C: 5.11 mmol/L (198 mg/dL) Cerivastatin 0.20 mg/d baseline HDL‐C: 1.40 mmol/L (54 mg/dL)  Cerivastatin 0.20 mg/d baseline TG: 1.84 mmol/L (163 mg/dL)
Interventions	Cerivastatin 0.05 mg/d evening dosing Cerivastatin 0.1 mg/d evening dosing Cerivastatin 0.15 mg/d evening dosing Cerivastatin 0.2 mg/d evening dosing
Outcomes	Percentage change from baseline at 4‐12 weeks of blood TC, LDL‐C, HDL‐C and TG
Source of funding	Unknown
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before‐and‐after design
Allocation concealment (selection bias)	High risk	Controlled before‐and‐after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No comparison possible
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	[(71‐65)/71]100 = 8.5% participants were not included in the efficacy analysis for the cerivastatin 0.05 mg/d group for total cholesterol [(79‐73)/79]100 = 7.6% participants were not included in the efficacy analysis for the cerivastatin 0.1 mg/d group for total cholesterol [(70‐67)/70]100 = 4.3% participants were not included in the efficacy analysis for the cerivastatin 0.15 mg/d group for total cholesterol [(74‐70)/74]100 = 5.4% participants were not included in the efficacy analysis for the cerivastatin 0.2 mg/d group for total cholesterol
Incomplete outcome data (attrition bias)   LDL cholesterol	High risk	[(71‐61)/71]100 = 14.1% participants were not included in the efficacy analysis for the cerivastatin 0.05 mg/d group [(79‐66)/79]100 = 16.5% participants were not included in the efficacy analysis for the cerivastatin 0.1 mg/d group [(70‐63)/70]100 = 10.0% participants were not included in the efficacy analysis for the cerivastatin 0.15 mg/d group [(74‐64)/74]100 = 13.5% participants were not included in the efficacy analysis for the cerivastatin 0.2 mg/d group [(294‐254)/294]*100 = 13.6% participants were not included in the efficacy analysis for all doses
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	[(71‐65)/71]100 = 8.5% participants were not included in the efficacy analysis for the cerivastatin 0.05 mg/d group [(79‐73)/79]100 = 7.6% participants were not included in the efficacy analysis for the cerivastatin 0.1 mg/d group [(70‐67)/70]100 = 4.3% participants were not included in the efficacy analysis for the cerivastatin 0.15 mg/d group [(74‐70)/74]100 = 5.4% participants were not included in the efficacy analysis for the cerivastatin 0.2 mg/d group
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	[(71‐63)/71]100 = 11.3% participants were not included in the efficacy analysis for the cerivastatin 0.05 mg/d group [(79‐70)/79]100 = 8.9% participants were not included in the efficacy analysis for the cerivastatin 0.1 mg/d group [(70‐65)/70]100 = 7.1% participants were not included in the efficacy analysis for the cerivastatin 0.15 mg/d group [(74‐69)/74]100 = 6.8% participants were not included in the efficacy analysis for the cerivastatin 0.2 mg/d group
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding not reported

Methods	4‐week optional washout /dietary stabilisation 6‐week placebo run‐in period 8‐week RCT
Participants	349 men and women with hypercholesterolaemia aged 18‐75 years old LDL‐C level of ≥ 190 mg/dL (≥ 4.90 mmol/L) or ≥ 160 mg/dL (≥ 4.12 mmol/L) if associated with one or more of the following risk factors: male sex; family history of premature coronary heart disease (definite MI or sudden death < 55 years of age in a parent or sibling); current cigarette smoker (> 10 cigarettes/d); hypertension; coronary disease; low HDL‐C concentration < 35 mg/dL (< 0.9 mmol/L), history of definite cerebrovascular or occlusive PVD, obesity, TG ≤ 350 mg/dL (≤ 3.99 mmol/L) Exclusion criteria: established contraindications for statin intake; unstable CVD including severe hypertension, MI within the past 6 months, cerebrovascular events, congestive heart failure (NYHA class 3 or 4), cardiac arrhythmias; diabetes mellitus, hypothyroidism; HIV‐positive; malignancy; hepatic or renal disorders; history of pancreatitis; known muscular or neuromuscular disease; GI disease (e.g. Crohri's disease) which could result in impaired absorption of the trial drug; clinically significant ophthalmic abnormalities; nightshift workers (reversal of normal sleep/wake cycle); concomitant medication affecting lipid levels or known to interact with statins including immunosuppressants, erythromycin, vitamin tablets containing > 50 mg/d niacin, regular therapeutic use of psyllium, fish oil or excess bran for lipid‐lowering purposes, corticosteroids (including inhalation formulation) and androgens history of hypersensitivity to HMG CoA reductase inhibitors; CK > 3 times ULN and/or hepatic transaminases (ALT, AST) > 1.5 times ULN; treatment with any other investigational drug within 30 d prior to screening Placebo baseline TC: 8.12 mmol/L (314 mg/dL)  Placebo baseline LDL‐C: 5.99 mmol/L (232 mg/dL)  Placebo baseline HDL‐C: 1.42 mmol/L (55 mg/dL) Placebo baseline TG: 1.56 mmol/L (138 mg/dL) Cerivastatin 0.3 mg/d baseline TC: 7.92 mmol/L (306 mg/dL)  Cerivastatin 0.3 mg/d baseline LDL‐C: 5.77 mmol/L (223 mg/dL)  Cerivastatin 0.3 mg/d baseline HDL‐C: 1.42 mmol/L (55 mg/dL) Cerivastatin 0.3 mg/d baseline TG: 1.61 mmol/L (143 mg/dL) Cerivastatin 0.4 mg/d baseline TC: 7.77 mmol/L (300 mg/dL)  Cerivastatin 0.4 mg/d baseline LDL‐C: 5.64 mmol/L (218 mg/dL)  Cerivastatin 0.4 mg/d baseline HDL‐C: 1.39 mmol/L (54 mg/dL) Cerivastatin 0.4 mg/d baseline TG: 1.63 mmol/L (144 mg/dL)
Interventions	Placebo Cerivastatin 0.3 mg/d Cerivastatin 0.4 mg/d
Outcomes	Percentage change from baseline at 8 weeks of serum TC, LDL‐C, HDL‐C, TG and WDAEs
Source of funding	Unknown
Notes	SDs were imputed by the method of Furukawa 2006 except for LDL‐C
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind tablets were identical in appearance
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	Unclear risk	Blinding method was not described
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Bayer helped with the statistical analysis

Methods	10‐week dietary run‐in period 4‐week RCT
Participants	647 men and women with primary hypercholesterolaemia age 21‐65 years were randomised to cerivastatin 33 men and women with primary hypercholesterolaemia age 21‐65 years were randomised to lovastatin 31 men and women with primary hypercholesterolaemia age 21‐65 years were randomised to simvastatin LDL‐C > 160 mg/dL (4.14 mmol/L) or < 250 mg/dL (6.465 mmol/L), TG < 350 mg/dL (3.95 mmol/L) Exclusion criteria: cardiovascular or cerebrovascular disease, diabetes mellitus, renal or respiratory disease, homozygous FH, clinically significant eye disease, muscular or neuromuscular disease, child bearing potential, CK > 3 x ULN significant infection, malignancy or psychosis, GI tract disease, liver dysfunction, pancreatitis, use of corticosteroids, erythromycin, oral anticoagulants, beta‐blockers, diuretics, digitalis, H2 blockers, androgens, progestins, estrogens or other lipid‐lowering drugs, drug or alcohol use, history of statin hypersensitivity, patients with reversal of the normal sleep/wake cycle, anyone treated with an investigational drug within 30 d of randomisation Placebo baseline TC: 7.40 mmol/L (286 mg/dL)  Placebo baseline LDL‐C: 5.21 mmol/L (201 mg/dL)  Placebo baseline HDL‐C: 1.38 mmol/L (53 mg/dL) Placebo baseline TG: 1.76 mmol/L (156 mg/dL) Cerivastatin 0.025 mg/d baseline TC: 7.20 mmol/L (278 mg/dL)  Cerivastatin 0.025 mg/d baseline LDL‐C: 5.12 mmol/L (198 mg/dL)  Cerivastatin 0.025 mg/d baseline HDL‐C: 1.25 mmol/L (48 mg/dL) Cerivastatin 0.025 mg/d baseline TG: 1.82 mmol/L (161 mg/dL) Cerivastatin 0.05 mg/d baseline TC: 7.22 mmol/L (279 mg/dL)  Cerivastatin 0.05 mg/d baseline LDL‐C: 5.08 mmol/L (196 mg/dL)  Cerivastatin 0.05 mg/d baseline HDL‐C: 1.22 mmol/L (47 mg/dL) Cerivastatin 0.05 mg/d baseline TG: 2.01 mmol/L (178 mg/dL) Cerivastatin 0.1 mg/d baseline TC: 7.27 mmol/L (281 mg/dL)  Cerivastatin 0.1 mg/d baseline LDL‐C: 5.15 mmol/L (199 mg/dL)  Cerivastatin 0.1 mg/d baseline HDL‐C: 1.21 mmol/L (47 mg/dL) Cerivastatin 0.1 mg/d baseline TG: 2.01 mmol/L (178 mg/dL) Cerivastatin 0.2 mg/d baseline TC: 7.20 mmol/L (278 mg/dL)  Cerivastatin 0.2 mg/d baseline LDL‐C: 5.11 mmol/L (198 mg/dL)  Cerivastatin 0.2 mg/d baseline HDL‐C: 1.25 mmol/L (48 mg/dL) Cerivastatin 0.2 mg/d baseline TG: 1.84 mmol/L (163 mg/dL)
Interventions	Placebo Cerivastatin 0.025 mg/d Cerivastatin 0.05 mg/d Cerivastatin 0.1 mg/d Cerivastatin 0.2 mg/d; 0.1 mg twice a day or 0.2 mg evening dosing Lovastatin 40 mg/d Simvastatin 20 mg/d
Outcomes	Percentage change from baseline at 4 weeks of plasma TC, LDL‐C, HDL‐C, TG and WDAEs
Source of funding	Bayer
Notes	Lovastatin 40 mg/d and simvastatin 20 mg/d groups were not analysed SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind Trial drug was packaged in brown glass bottles; cerivastatin and placebo tablets were all identical in appearance
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	Unclear risk	Blinding method was not described
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	[(115‐110)/115]100 = 4.3% participants were not included in the efficacy analysis for the placebo group [(68‐65)/68]100 = 4.4% participants were not included in the efficacy analysis for the 0.025 mg/d group [(69‐65)/68]100 = 5.9% participants were not included in the efficacy analysis for the 0.05 mg/d group [(68‐64)/68]100 = 5.9% participants were not included in the efficacy analysis for the 0.1 mg/d group [(340‐325)/340]*100 = 4.4% participants were not included in the efficacy analysis for the 0.2 mg/d group
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	[(115‐110)/115]100 = 4.3% participants were not included in the efficacy analysis for the placebo group [(68‐65)/68]100 = 4.4% participants were not included in the efficacy analysis for the 0.025 mg/d group [(69‐65)/68]100 = 5.9% participants were not included in the efficacy analysis for the 0.05 mg/d group [(68‐64)/68]100 = 5.9% participants were not included in the efficacy analysis for the 0.1 mg/d group [(340‐325)/340]*100 = 4.4% participants were not included in the efficacy analysis for the 0.2 mg/d group
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	[(115‐110)/115]100 = 4.3% participants were not included in the efficacy analysis for the placebo group [(68‐65)/68]100 = 4.4% participants were not included in the efficacy analysis for the 0.025 mg/d group [(69‐65)/68]100 = 5.9% participants were not included in the efficacy analysis for the 0.05 mg/d group [(68‐64)/68]100 = 5.9% participants were not included in the efficacy analysis for the 0.1 mg/d group [(340‐325)/340]*100 = 4.4% participants were not included in the efficacy analysis for the 0.2 mg/d group
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	[(115‐110)/115]100 = 4.3% participants were not included in the efficacy analysis for the placebo group [(68‐65)/68]100 = 4.4% participants were not included in the efficacy analysis for the 0.025 mg/d group [(69‐65)/68]100 = 5.9% participants were not included in the efficacy analysis for the 0.05 mg/d group [(68‐64)/68]100 = 5.9% participants were not included in the efficacy analysis for the 0.1 mg/d group [(340‐325)/340]*100 = 4.4% participants were not included in the efficacy analysis for the 0.2 mg/d group
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Bayer funded the trial, data may support bias for cerivastatin

Methods	4‐week washout period 6‐week before‐and‐after study
Participants	107 men and women with primary hypercholesterolaemia age 18‐80 years old LDL‐C ≥ 160 mg/dL (4.14 mmol/L) and TG ≤ 400 mg/dL (4.52 mmol/L) Exclusion criteria: pregnancy or breast feeding, hyperlipoproteinaemia secondary to uncontrolled primary hypothyroidism, nephrotic syndrome or renal dysfunction; diabetes mellitus type 1 or uncontrolled diabetes mellitus type 2; active liver disease or hepatic dysfunction; CK levels > 3 x ULN; uncontrolled hypertension (systolic BP ≥140 mm Hg or diastolic BP ≥ 90 mm Hg); current or recent history of alcohol abuse; unreliability as a trial participant based on the investigator’s prior knowledge of the patient, such as inability or unwillingness to adhere to a lipid‐lowering diet; participation in another clinical trial within the 30‐d period before consideration for entry into this trial; known hypersensitivity to HMG CoA reductase inhibitors; MI, coronary angioplasty, CABG, or severe or unstable angina within 3 months before screening; significant abnormalities that the investigator believed could compromise the patient’s safety in participating in the trial; and use of any drugs known to affect lipid levels, immunosuppressive agents, drugs associated with rhabdomyolysis in combination with HMG CoA reductase inhibitors (e.g. cyclosporine and erythromycin), or mibefradil dihydrochloride Cerivastatin 0.3 mg/d baseline TC: 7.4 mmol/L (286 mg/dL)  Cerivastatin 0.3 mg/d baseline LDL‐C: 5.22 mmol/L (202 mg/dL)  Cerivastatin 0.3 mg/d baseline HDL‐C: 1.28 mmol/L (49.5 mg/dL) Cerivastatin 0.3 mg/d baseline TG: 1.96 mmol/L (174 mg/dL)
Interventions	Cerivastatin 0.3 mg/d evening dosing Atorvastatin 10 mg/d evening dosing
Outcomes	Percentage change from baseline at 6 weeks of blood TC, LDL‐C, HDL‐C, and TG
Source of funding	Pfizer Inc
Notes	Atorvastatin group was not analysed
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before‐and‐after design
Allocation concealment (selection bias)	High risk	Controlled before‐and‐after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No comparison possible
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	[(107‐106)/107]*100 = 0.9% participants were not included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	[(107‐106)/107]*100 = 0.9% participants were not included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	[(107‐106)/107]*100 = 0.9% participants were not included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	[(107‐106)/107]*100 = 0.9% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Pfizer Inc funded the trial data may support bias against cerivastatin

Methods	10‐week dietary washout period 8‐week RCT
Participants	1170 men and women with hypercholesterolaemia age 18‐75 years LDL‐C was to be ≥ 160 mg/dL for those without definite atherosclerotic disease and < cardiovascular risk factors or ≥ 130 mg/dL for those with definite atherosclerotic disease or ≥ 2 cardiovascular risk factors Exclusion criteria: MI, unstable angina, stroke, TIA, or uncontrolled hypertension within 3 months of enrolment; a coronary revascularisation procedure within 6 months of enrolment; a change in diuretic or β‐blocker therapy for hypertension within 2 months of enrolment; diabetes mellitus; other endocrine disorders (except for hypothyroidism on stable replacement therapy with TSH 140% of ideal; homozygous FH; history of malignancy (except squamous or basal cell skin cancer), psychosis or GI disorders that might impair absorption of trial medications; night‐shift work that reverses the normal sleep/wake cycle; pregnancy/ breast‐feeding/childbearing potential; ingestion of other lipid‐lowering substances (including fish oil, psyllium, bran or niacin > 100 mg 4 times daily); and hypersensitivity to HMG CoA reductase inhibitors, concomitant use of corticosteroids (except low‐dose inhaled agents for asthma), macrolide antibiotics, azole antifungals (including ketoconazole and itraconazole), androgens, oral anticoagulants, rifampin, immunosuppressants or H2‐antagonists (except cimetidine); use of another investigational product within 30 d of enrolment; or use of cerivastatin (for > 10 d) or probucol within 6 months of enrolment Placebo baseline TC: 6.88 mmol/L (266 mg/dL)  Placebo baseline LDL‐C: 4.74 mmol/L (183 mg/dL)  Placebo baseline HDL‐C: 1.25 mmol/L (48 mg/dL) Placebo baseline TG: 1.95 mmol/L (173 mg/dL) Cerivastatin 0.4 mg/d baseline TC: 7.15 mmol/L (276 mg/dL)  Cerivastatin 0.4 mg/d baseline LDL‐C: 4.94 mmol/L (191 mg/dL)  Cerivastatin 0.4 mg/d baseline HDL‐C: 1.26 mmol/L (49 mg/dL) Cerivastatin 0.4 mg/d baseline TG: 2.07 mmol/L (183 mg/dL) Cerivastatin 0.8 mg/d baseline TC: 7.10 mmol/L (275 mg/dL) Cerivastatin 0.8 mg/d baseline LDL‐C: 4.89 mmol/L (189 mg/dL)  Cerivastatin 0.8 mg/d baseline HDL‐C: 1.27 mmol/L (49 mg/dL) Cerivastatin 0.8 mg/d baseline TG: 2.06 mmol/L (182 mg/dL)
Interventions	Placebo evening dosing Cerivastatin 0.4 mg/d evening dosing Cerivastatin 0.8 mg/d evening dosing
Outcomes	Percentage change from baseline at 8 weeks of plasma TC, LDL‐C, HDL‐C, TG and WDAEs
Source of funding	Bayer and SmithKline Beecham
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind lipid parameter measurements unlikely influenced by lack of sufficient blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	Unclear risk	Blinding method was not described
Incomplete outcome data (attrition bias)   Total cholesterol	High risk	[(199 ‐177)/199]100 = 11.1% participants were not included in the efficacy analysis for the placebo group [(195 ‐164)/195]100 = 15.9% participants were not included in the efficacy analysis for the cerivastatin 0.4 mg/d group [(776 ‐ 656)/776]*100 = 15.5% participants were not included in the efficacy analysis for the cerivastatin 0.8 mg/d group
Incomplete outcome data (attrition bias)   LDL cholesterol	High risk	[(199 ‐177)/199]100 = 11.1% participants were not included in the efficacy analysis for the placebo group [(195 ‐164)/195]100 = 15.9% participants were not included in the efficacy analysis for the cerivastatin 0.4 mg/d group [(776 ‐ 656)/776]*100 = 15.5% participants were not included in the efficacy analysis for the cerivastatin 0.8 mg/d group
Incomplete outcome data (attrition bias)   HDL cholesterol	High risk	[(199 ‐177)/199]100 = 11.1% participants were not included in the efficacy analysis for the placebo group [(195 ‐164)/195]100 = 15.9% participants were not included in the efficacy analysis for the cerivastatin 0.4 mg/d group [(776 ‐ 656)/776]*100 = 15.5% participants were not included in the efficacy analysis for the cerivastatin 0.8 mg/d group
Incomplete outcome data (attrition bias)   Triglycerides	High risk	[(199 ‐177)/199]100 = 11.1% participants were not included in the efficacy analysis for the placebo group [(195 ‐164)/195]100 = 15.9% participants were not included in the efficacy analysis for the cerivastatin 0.4 mg/d group [(776 ‐ 656)/776]*100 = 15.5% participants were not included in the efficacy analysis for the cerivastatin 0.8 mg/d group
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Bayer and SmithKline Beecham funded the trial

Methods	10‐week washout period 12‐week before‐and‐after study
Participants	200 men and women aged 18‐75 years with documented primary hypercholesterolaemia LDL‐C ≥ 157.5 mg/dL (4.07 mmol/L) or ≥ 130 mg/dL (3.36 mmol/L) with documented CAD of ≥ 2 cardiovascular risk factors plasma TG ≤ 400 mg/dL (4.52 mmol/L) have a food rating score ≤ 15 Exclusion criteria: clinically active CVD, hypertension with alterations in diuretic or beta blocker therapy within 2 months of entry, uncontrolled diabetes mellitus or other endocrine abnormalities and uncontrolled hypothyroidism, ophthalmic abnormalities, cancer other than basil cell or squamous cell carcinoma, psychosis, hepatic dysfunction, weight 140% ideal body weight, statin hypersensitivity, significant GI tract disorders, child bearing potential homozygous FH, renal dysfunction, current use of other medications that would interfere with the trial, treatment with other hypolipidaemic drugs within 10 weeks of entry, drug or alcohol abuse, night shift workers, therapy with another investigational product within 30 d, other medical conditions which might interfere with the trial Cerivastatin 0.2 mg/d baseline TC: 6.94 mmol/L (268 mg/dL)  Cerivastatin 0.2 mg/d baseline LDL‐C: 4.74 mmol/L (183 mg/dL)  Cerivastatin 0.2 mg/d baseline HDL‐C: 1.24 mmol/L (48 mg/dL) Cerivastatin 0.2 mg/d baseline TG: 2.03 mmol/L (180 mg/dL)
Interventions	Fluvastatin 20 mg/d for 0‐6 weeks evening dosing Fluvastatin 40 mg/d for 6‐12 weeks evening dosing Cerivastatin 0.2 mg/d for 0‐6 weeks evening dosing Cerivastatin 0.3 mg/d for 6‐12 weeks evening dosing
Outcomes	Percentage change from baseline at 6 weeks of plasma TC, LDL‐C, HDL‐C, and TG
Source of funding	Novartis
Notes	Fluvastatin 20 mg/d for 0‐6 weeks Fluvastatin 40 mg/d for 6‐12 weeks Cerivastatin 0.3 mg/d for 6‐12 weeks Fluvastatin groups were not included in the efficacy analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before‐and‐after design
Allocation concealment (selection bias)	High risk	Controlled before‐and‐after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No comparison possible
Incomplete outcome data (attrition bias)   Total cholesterol	High risk	[(200‐174)/200]*100 = 13% participants were not included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	High risk	[(200‐174)/200]*100 = 13% participants were not included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	High risk	[(200‐174)/200]*100 = 13% participants were not included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	High risk	[(200‐174)/200]*100 = 13% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Novartis funded the trial, data may support bias against cerivastatin

Methods	4‐week run‐in stabilisation period 12‐week before‐and‐after study
Participants	21 men and women with type IIa or IIb hyperlipidaemia aged 20‐70 years old TC ≥ 220 mg/dL (5.7 mmol/L) and TG < 400 mg/dL (4.52 mmol/L) Exclusion criteria: severe organ disease, history of stroke, MI history, child bearing potential, statin hypersensitivity Cerivastatin 0.2 mg/d baseline TC: 7.029 mmol/L (272 mg/dL)  Cerivastatin 0.2 mg/d baseline LDL‐C: 5.0168 mmol/L (194 mg/dL)  Cerivastatin 0.2 mg/d baseline HDL‐C: 1.3395 mmol/L (52 mg/dL) Cerivastatin 0.2 mg/d baseline TG: 1.47 mmol/L (130 mg/dL)
Interventions	Cerivastatin 0.2 mg/d evening dosing
Outcomes	Percentage change from baseline at 4‐12 weeks of serum TC, LDL‐C, HDL‐C, and TG
Source of funding	Unknown
Notes	SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before‐and‐after design
Allocation concealment (selection bias)	High risk	Controlled before‐and‐after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	No comparison possible
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	[(21 ‐ 20)/21]*100 = 4.8% participants were not included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	[(21 ‐ 20)/21]*100 = 4.8% participants were not included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	[(21 ‐ 20)/21]*100 = 4.8% participants were not included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	[(21 ‐ 20)/21]*100 = 4.8% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding not reported

Methods	4‐week placebo run‐in period 6‐week RCT Allocations via block randomisation in groups of 6
Participants	32 men and women with primary hypercholesterolaemia aged 18‐75 years. Average LDL‐C measured during diet‐stabilisation and placebo run‐in stage had to be > 160 mg/dL (4.14 mmol/L) with definite personal history of coronary heart disease and each measurement had to be not > ± 12% from the average (> 130 mg/dL (3.36 mmol/L) for participants with > 2 risk factors for CAD or CVD) fasting plasma TG below 350 mg/dL (3.95 mmol/L) for all participants, consent received from all participants During period A, included participants had to have diet satisfied by dietician (i.e. meeting dietician recommendations). Compliance rate to placebo during period A was between 80%‐120%; 26 did not finish placebo run‐in period A; 47 participants were randomised Exclusion criteria: women of childbearing age but not on IUD or OCP; pregnant or breastfeeding; participants with history of MI, unstable angina, stroke, TIA, and uncontrolled hypertension within 3 months of starting trial; CABG or PCI within 6 months of starting trial. Regardless of whether they're on treatment or not, if fasting glucose is > 140 mg/dL or having other endocrine disease, or someone with systolic BP > 180 mmHg or diastolic BP > 110 mmHg; clinically known to have cataract or malignant tumour or psychiatric condition or chronic seizures or “homogenous hypercholesterolaemia” (homogenous family history?). BMI > 30, SCr > 2 mg/dL, AST/ALT/amylase > 1.5 ULN or CK > 3, chronic or acute infection, if require regular care visits or compliance expected to be affected, if alcohol or drug abuse in medical history (> 14 drinks/week for alcohol use), if occupational shift work requiring working overnight, bodybuilders or weightlifters, people on other cholesterol medications are excluded; if they stop the statin 4 weeks before or fibrates 8 weeks before or probucol 6 months before, then they can be included in the trial; people with sensitivities to statins, anyone involved with any other trial within 30 d of starting this trial Placebo baseline TC: 6.42 mmol/L (248 mg/dL)  Placebo baseline LDL‐C: 4.36 mmol/L (169 mg/dL)  Placebo baseline HDL‐C: 1.26 mmol/L (49 mg/dL) Placebo baseline TG: 1.77 mmol/L (157 mg/dL) Cerivastatin 0.1 mg/d baseline TC: 6.97 mmol/L (270 mg/dL)  Cerivastatin 0.1 mg/d baseline LDL‐C: 4.86 mmol/L (188 mg/dL)  Cerivastatin 0.1 mg/d baseline HDL‐C: 1.19 mmol/L (46 mg/dL) Cerivastatin 0.1 mg/d baseline TG: 2.01 mmol/L (178 mg/dL) Cerivastatin 0.3 mg/d baseline TC: 6.77 mmol/L (262 mg/dL) Cerivastatin 0.3 mg/d baseline LDL‐C: 4.59 mmol/L (177 mg/dL)  Cerivastatin 0.3 mg/d baseline HDL‐C: 1.31 mmol/L (51 mg/dL) Cerivastatin 0.3 mg/d baseline TG: 1.90 mmol/L (168 mg/dL)
Interventions	Placebo evening dosing Cerivastatin 0.1 mg/d evening dosing Cerivastatin 0.3 mg/d evening dosing
Outcomes	Percentage change from baseline at 4‐6 weeks of blood TC, LDL‐C, HDL‐C, and TG
Source of funding	Unknown
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of sufficient blinding
Blinding of outcome assessment (detection bias)   LDL‐C	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAE	High risk	WDAEs were not reported
Incomplete outcome data (attrition bias)   Total cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   LDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   HDL cholesterol	Low risk	All participants were included in the efficacy analysis
Incomplete outcome data (attrition bias)   Triglycerides	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not reported