Pitavastatin for lowering lipids

Stephen P Adams; Nima Alaeiilkhchi; James M Wright

doi:10.1002/14651858.CD012735.pub2

. 2020 Jun 19;2020(6):CD012735. doi: 10.1002/14651858.CD012735.pub2

Pitavastatin for lowering lipids

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

Editor: Cochrane Hypertension Group

PMCID: PMC7387421 PMID: 32557581

Abstract

Background

Pitavastatin is the newest statin on the market, and the dose‐related magnitude of effect of pitavastatin on blood lipids is not known.

Objectives

Primary objective To quantify the effects of various doses of pitavastatin on the surrogate markers: LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides in participants with and without cardiovascular disease.

To compare the effect of pitavastatin on surrogate markers with other statins.

Secondary objectives To quantify the effect of various doses of pitavastatin on withdrawals due to adverse effects.

Search methods

The Cochrane Hypertension Information Specialist searched the following databases for trials up to March 2019: the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2019), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions.

Selection criteria

RCT and controlled before‐and‐after studies evaluating the dose response of different fixed doses of pitavastatin 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 studies to be included, and extracted data. We entered data from RCT and controlled before‐and‐after studies into Review Manager 5 as continuous and generic inverse variance data, respectively. Withdrawals due to adverse effects (WDAE) information was collected from the RCTs. We assessed all included trials using the Cochrane 'Risk of bias' tool under the categories of allocation (selection bias), blinding (performance bias and detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other potential sources of bias.

Main results

Forty‐seven studies (five RCTs and 42 before‐and‐after studies) evaluated the dose‐related efficacy of pitavastatin in 5436 participants. The participants were of any age with and without cardiovascular disease, and pitavastatin effects were studied within a treatment period of three to 12 weeks. Log dose‐response data over doses of 1 mg to 16 mg revealed strong linear dose‐related effects on blood total cholesterol and LDL cholesterol and triglycerides. There was no dose‐related effect of pitavastatin on blood HDL cholesterol, which was increased by 4% on average by pitavastatin. Pitavastatin 1 mg/day to 16 mg/day reduced LDL cholesterol by 33.3% to 54.7%, total cholesterol by 23.3% to 39.0% and triglycerides by 13.0% to 28.1%. For every two‐fold dose increase, there was a 5.35% (95% CI 3.32 to 7.38) decrease in blood LDL cholesterol, a 3.93% (95% CI 2.35 to 5.50) decrease in blood total cholesterol and a 3.76% (95% CI 1.03 to 6.48) decrease in blood triglycerides. The certainty of evidence for these effects was judged to be high. When compared to other statins for its effect to reduce LDL cholesterol, pitavastatin is about 6‐fold more potent than atorvastatin, 1.7‐fold more potent than rosuvastatin, 77‐fold more potent than fluvastatin and 3.3‐fold less potent than cerivastatin. For the placebo group, there were no participants who withdrew due to an adverse effect per 109 subjects and for all doses of pitavastatin, there were three participants who withdrew due to an adverse effect per 262 subjects.

Authors' conclusions

Pitavastatin lowers blood total cholesterol, LDL cholesterol and triglyceride in a dose‐dependent linear fashion. Based on the effect on LDL cholesterol, pitavastatin is about 6‐fold more potent than atorvastatin, 1.7‐fold more potent than rosuvastatin, 77‐fold more potent than fluvastatin and 3.3‐fold less potent than cerivastatin. There were not enough data to determine risk of withdrawal due to adverse effects due to pitavastatin.

Plain language summary

Pitavastatin for lowering lipids

Review question

How do different doses of pitavastatin affect fats in our blood?

Background

Pitavastatin is the newest statin on the market. We don't know the effect of different sizes of dose on 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 pitavastatin in different dose sizes . The trials were between three and 12 weeks long.

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

Key results

People taking 1 mg to 16 mg of pitavastatin per day lowered their LDL cholesterol by 33.3% to 54.7%. The higher the dose, the lower the levels of three measures of cholesterol. The average increase in HDL cholesterol for all doses was 4%.

For lowering LDL cholesterol, pitavastatin is 6‐times stronger than atorvastatin, 1.7‐times stronger than rosuvastatin, 77‐times stronger than fluvastatin and 3.3‐times weaker than cerivastatin.

In the RCTS, no person out of 109 in the placebo group and three out of 262 people in the pitavastatin group dropped out due to adverse effects.

Certainty of the evidence

There is a high level of trust around the effects of pitavastatin on total cholesterol, LDL cholesterol and triglycerides.

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’(CTT 2005).

Description of the intervention

Pitavastatin is a new synthetic potent statin that received FDA approval in the USA in 2009. In a long‐term trial, pitavastatin has been reported to increase high‐density lipoprotein (HDL) cholesterol in people with low HDL cholesterol levels < 40 mg/dL (Teramoto 2009). Pitavastatin is rapidly absorbed, reaching peak plasma concentration within one hour and has a half‐life of 11 hours. Pitavastatin is metabolised to a small degree by cytochromes P‐450 2C8 and P‐450 2C9 to 8‐hydroxy‐pitavastatin (M13) (Mukhtar 2005). 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

Pitavastatin 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 3‐hydroxy‐3‐methylglutaryl 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 (VLDL) cholesterol (Gaw 2000). The prevailing hypothesis is that statins reduce mortality and morbidity in patients with occlusive vascular disease by reducing liver production of cholesterol and thus causing a reduction in blood LDL cholesterol and a resulting decrease in 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 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), fluvastatin (Adams 2016; Adams 2018) and cerivastatin (Adams 2017; Adams 2020). It is possible that pitavastatin will have different potency, slope of the dose‐response or variability of response. Statin‐induced myopathy is common to all statins, and limits the use of statins in many patients. 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 on the following surrogate markers to describe the dose‐response relationship of the effect of pitavastatin: total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides (Boekholdt 2012). We will use the results of this review to compare pitavastatin with rosuvastatin, atorvastatin, cerivastatin and fluvastatin. Subsequent reviews of other drugs in the class (i.e. lovastatin, pravastatin, simvastatin) will also be done, in order to compare the results of all the statins.

Objectives

Primary objective

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

We recognise that the outcomes important to patients are mortality and cardiovascular morbidity, however, that is not the objective of this systematic review. The aim of this review is to examine the pharmacology of pitavastatin by characterising the dose‐related effect and variability of the effect of pitavastatin on surrogate markers and to compare these to the other statins.

Secondary objectives

To quantify the effect of various doses of pitavastatin on withdrawals due to adverse effects.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised placebo‐controlled trials (RCTs) as well as controlled before‐and‐after studies. Before‐and‐after studies were included, because it has been shown that there is no placebo effect of statins on lipid parameters and that a placebo control is therefore not essential (Tsang 2002). We included data from cross‐over trials if the 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 data were reported in a similar manner during all treatment periods.

Types of participants

Participants may 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

Pitavastatin 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 pitavastatin dose per day for a period of three to 12 weeks. We chose this administration time window to allow at least three weeks for a steady‐state effect of pitavastatin to occur and to keep it short enough to minimise participants dropping out. We included studies where pitavastatin 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 participants follow 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

Pitavastatin 1 mg/day, 2 mg/day and 4 mg/day were the primary doses as these are the recommended and predominantly prescribed doses.

Lipid parameters: for the RCTs, we presented the mean percentage change from baseline for different doses of pitavastatin 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 presented the mean percentage change from baseline of different doses of pitavastatin. RCT data and before‐and‐after study data were combined because it was shown previously (Adams 2014; Adams 2015) that the two study designs yielded similar results (Tsang 2002).

Primary outcomes

LDL cholesterol

Secondary outcomes

Total cholesterol
HDL cholesterol
Triglycerides
End of treatment variability (standard deviation (SD)) and coefficient of variation of all lipid measurements for each dose of pitavastatin. It is important to know whether pitavastatin 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 (WDAEs) could only be assessed in the placebo‐controlled trials.

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) via the Cochrane Register of Studies (CRS‐Web) (searched 4 March 2019);
MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations (searched 4 March 2019);
Embase Ovid (from 1974 onwards) (searched 4 March 2019);
ClinicalTrials.gov (www.clinicaltrials.gov) (searched 4 March 2019);
World Health Organization International Clinical Trials Registry Platform (www.who.it.trialsearch) (searched 4 March 2019).
Epistemonikos (https://www.epistemonikos.org) searched 4 March 2019).

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

Systematic searches in the following databases were conducted for before‐and‐after studies in MEDLINE, Embase, CENTRAL, CRS‐Web, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and Epistemonikos. No filters were used to retrieve RCTs and before‐and‐after studies because we wanted to retrieve all available documents on the subject.

Searching other resources

The Cochrane Hypertension Information Specialist searched the Hypertension Specialised Register segment (which includes searches of MEDLINE, Embase, and Epistemonikos for systematic reviews) to retrieve existing reviews relevant to this systematic review, so that we could scan their reference lists for additional trials. The Specialised Register also includes searches for controlled trials in the Allied and Complementary Medicine Database (AMED), CAB Abstracts & Global Health, CINAHL, and Web of Science.
We checked the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.
Where necessary, we contacted authors of key papers and abstracts to request additional information about their trials.

We included grey literature by searching other resources.

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

These resources were searched using the following keywords: pitavastatin, alipza, itavastatin, nisvastatin, livalo, livazo, NK‐104.

Data collection and analysis

Selection of studies, data extraction and management and assessment of risk of bias in included studies were all done using Covidence systematic review software (Covidence 2019).

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 NA) analysed the full‐text papers independently, to decide on the studies to be included. We resolved disagreements by recourse to the third review author (JMW). Two review authors (SA and NA) independently extracted the appropriate data from each of the included studies.

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%, the data were not included in the review. We extracted standard deviations (SDs) and standard errors (SEs) from the report or calculated them when possible using the following calculations (Appendix 3). We entered the data from RCT and controlled before‐and‐after studies into Review Manager 5 (RevMan 2020) 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 allocation (selection bias), blinding (performance bias and detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other potential sources of bias. We produced 'Risk of bias' tables' as outlined in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 8 (Higgins 2011). Controlled before‐after‐studies were considered 'high risk' and 'low grading' compared to RCTs. With respect to before‐and‐after studies, having only one study group is considered 'high risk' for random sequence generation and allocation concealment but other features in this study design might be at lower risk, and 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, they were considered unlikely to be affected by the study 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 studies (Tsang 2002).

Measures of treatment effect

We analysed the treatment effects as mean difference (MD) 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 study designs were not statistically different, we re‐analysed all efficacy study data using the generic inverse variance to determine the overall weighted treatment effects and their 95% confidence intervals (CIs) for blood total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides.

Unit of analysis issues

The unit of analysis is the mean value for the people completing the study. We expected follow‐up to be reasonably high for these short‐term studies. The data, however, represented treatment efficacy and not real world effectiveness of pitavastatin on these lipid parameters.

Dealing with missing data

We expected follow‐up to be reasonably high for these short‐term trials. The data, however, represented treatment efficacy and not real‐world effectiveness of pitavastatin on these lipid parameters. When data were missing, we requested them from the 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 studies where it was 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 Furukawa 2006.

Assessment of heterogeneity

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

The I² was assessed as moderate heterogeneity when ranging from 30% to 50% and high heterogeneity when greater than 50%.

Assessment of reporting biases

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

Data synthesis

We entered all RCTs into Review Manager 5 (RevMan 2020) as mean difference fixed‐effect model data to determine the weighted treatment effect and 95% CIs for blood total cholesterol, LDL 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 effects in the RCTs were not statistically significantly different from the before‐and‐after studies, we entered all trials for each dose as generic inverse variance to determine the best overall weighted treatment effect for each dose.

We recorded data of each study 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 placebo‐controlled trials, who prematurely withdrew due to at least one adverse effect in Review Manager 5 (RevMan 2020) as dichotomous data for each dose and all combined doses of pitavastatin and reported these as RR versus placebo.

The relative potency of pitavastatin with respect to fluvastatin, atorvastatin, rosuvastatin and cerivastatin, was determined as the ratio of the milligram (mg) amount of pitavastatin to the mg amount of fluvastatin or atorvastatin or rosuvastatin or cerivastatin needed to produce the same specified effect. These values were calculated from the log dose response curves of pitavastatin, fluvastatin, atorvastatin, rosuvastatin and cerivastatin for LDL cholesterol, total cholesterol and triglycerides. The relative potencies were estimated from these dose ratios. The relative potency results are mentioned in the Effects of interventions subsection of the Results section.

Subgroup analysis and investigation of heterogeneity

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

We analysed subgroups based on the following factors.

Placebo‐controlled trials versus before‐and‐after trials (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
Kowa funded versus non‐Kowa funded trials
Twice‐daily versus once‐daily administration

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 subjects were reported to have type IIa or familial hypercholesterolaemia versus trials whose subjects were not reported to have genetic hypercholesterolaemia. Trials were not included in the comparison if the subjects had 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.

RCTs and before‐and‐after studies were analysed separately in the Data and analyses section.

Summary of findings and assessment of the certainty of the evidence

We used Grading of Recommendations, Assessment, Development and Evaluation (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 the Table 1, Table 2 and Table 3. We did not summarise the findings on HDL cholesterol in a 'Summary of findings' table because pitavastatin doses ranging from 1 mg/day to 8 mg/day had no dose‐related effect on HDL cholesterol. There were not enough data to determine risk of withdrawal due to adverse effects due to pitavastatin, therefore, there was no 'Summary of findings' table for WDAEs.

Summary of findings 1. Low‐density lipoprotein (LDL) cholesterol‐lowering efficacy of pitavastatin.

Low‐density lipoprotein (LDL) cholesterol‐lowering efficacy of pitavastatin
Patient or population: participants with normal or abnormal lipid profiles Settings: ambulatory clinics Intervention: different fixed doses of pitavastatin Comparison: placebo or baseline
pitavastatin dose	Anticipated absolute effects mmol/L (95%CI)		Percentage change from baseline (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments

	LDL‐cholesterol before exposure to pitavastatin^a	LDL‐cholesterol after exposure to pitavastatin
1 mg/day	5.06 (4.39 to 5.74)	3.38 (3.32 to 3.44)	‐33.2 (‐34.3 to ‐32.1)	759 (10)	⊕⊕⊕⊕ high	Effect predicted from log dose‐response curve, ‐33.3%
2 mg/day	4.51 (4.24 to 4.79)	2.77 (2.75 to 2.79)	‐38.65 (‐39.1 to ‐38.2)	3847 (36)	⊕⊕⊕⊕ high	Effect predicted from log dose‐response curve, ‐38.6%
4 mg/day	5.04 (4.24 to 5.85)	2.82 (2.73 to 2.91)	‐44.0 (‐45.8 to ‐42.3)	469 (7)	⊕⊕⊕⊕ high	Effect predicted from log dose‐response curve, ‐44.0%
CI: Confidence interval
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Total cholesterol‐lowering efficacy ofpitavastatin
Patient or population: participants with normal or abnormal lipid profiles Settings: ambulatory clinics Intervention: different fixed doses of pitavastatin Comparison: placebo or baseline
Pitavastatin dose	Anticipated absolute effects mmol/L (95%CI)		Percentage change from baseline (95% CI)	№ of participants (trials)	Certainty of the evidence (GRADE)	Comments

	Total cholesterol before exposure to pitavastatin^a	Total cholesterol after exposure to pitavastatin
1 mg/day	7.24 (6.67 to 7.82)	5.55 (5.49 to 5.60)	‐23.4 (‐24.2 to ‐22.7)	777 (10)	⊕⊕⊕⊕ high	Effect predicted from log dose‐response equation is ‐23.3%
2 mg/day	6.65 (6.33 to 6.97)	4.84 (4.81 to 4.87)	‐27.25 (‐27.65 to ‐26.84)	2789 (32)	⊕⊕⊕⊕ high	Effect predicted from log dose‐response equation is ‐27.3%
4 mg/day	7.21 (6.49 to 7.94)	4.97 (4.87 to 5.07)	‐31.1 (‐32.4 to ‐29.7)	477 (7)	⊕⊕⊕⊕ high	Effect predicted from log dose‐response equation is ‐31.2%
CI: Confidence interval
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Triglyceride‐lowering efficacy of pitavastatin
Patient or population: participants with normal or abnormal lipid profiles Settings: ambulatory clinics Intervention: different fixed doses of pitavastatin Comparison: placebo or baseline
Pitavastatin dose	Anticipated absolute effects mmol/L (95%CI)		Percentage change from baseline (95% CI)	№ of participants (trials)	Certainty of the evidence (GRADE)	Comments

	Triglycerides before exposure to pitavastatin^a	Triglycerides after exposure to pitavastatin
1 mg/day	1.71 (1.27 to 2.15)	1.49 (1.45 to 1.52)	‐13.1 (‐15.4 to ‐10.85)	673 (8)	⊕⊕⊕⊕ high	Effect predicted from log dose‐response equation is ‐13.0%
2 mg/day	1.88 (1.75 to 2.02)	1.56 (1.54 to 1.59)	‐16.8 (‐18.2 to ‐15.5)	2035 (26)	⊕⊕⊕⊕ high	Effect predicted from log dose‐response equation is ‐16.8%
4 mg/day	2.04 (1.29 to 2.79)	1.67 (1.57 to 1.77)	‐18.0 (‐23.0 to ‐13.0)	424 (6)	⊕⊕⊕⊕ high	Effect predicted from log dose‐response equation is ‐20.6%
CI: Confidence interval
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Pitavastatin dose mg/day	1	2	4	8	16
Mean percentage change from control of LDL‐C^a (95% confidence interval)	‐33.2 (‐34.3 to ‐32.1)	‐38.65 (‐39.1 to ‐38.2)	‐44.0 (‐45.8 to ‐42.3)	‐48.7 (‐52.4 to ‐45.0)	‐54.5 (‐59.4 to ‐49.6)
Mean percentage change from control of total cholesterol (95% confidence interval)	‐23.4 (‐24.2 to ‐22.7)	‐27.25 (‐27.65 to ‐26.84)	‐31.1 (‐32.4 to ‐29.7)	‐37.0 (‐41.4 to ‐32.6)
Mean percentage change from control of triglycerides (95% confidence interval)	‐13.1 (‐15.4 to ‐10.85)	‐16.8 (‐18.2 to ‐15.5)	‐18.0 (‐23.0 to ‐13.0)	‐32.9 (‐45.0 to ‐20.8)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 LDL cholesterol RCTs	3	255	Mean Difference (IV, Fixed, 95% CI)	‐26.85 [‐29.89, ‐23.81]
1.2 Total cholesterol RCTs	3	255	Mean Difference (IV, Fixed, 95% CI)	‐19.43 [‐21.90, ‐16.97]
1.3 HDL cholesterol RCTs	2	202	Mean Difference (IV, Fixed, 95% CI)	6.28 [3.36, 9.20]
1.4 Triglycerides RCTs	2	202	Mean Difference (IV, Fixed, 95% CI)	‐19.22 [‐28.52, ‐9.91]
1.5 LDL‐cholesterol non‐RCTs	7	504	Mean Difference (IV, Random, 95% CI)	‐33.37 [‐35.87, ‐30.86]
1.6 Total cholesterol non‐RCTs	7	522	Mean Difference (IV, Random, 95% CI)	‐23.51 [‐25.98, ‐21.04]
1.7 HDL‐cholesterol non‐RCTs	5	402	Mean Difference (IV, Random, 95% CI)	3.71 [‐1.29, 8.70]
1.8 Triglycerides non‐RCTs	6	471	Mean Difference (IV, Fixed, 95% CI)	‐12.72 [‐15.05, ‐10.38]
1.9 WDAE	2		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 LDL cholesterol RCTs	3	253	Mean Difference (IV, Fixed, 95% CI)	‐31.00 [‐34.09, ‐27.90]
2.2 Total cholesterol RCTs	3	253	Mean Difference (IV, Fixed, 95% CI)	‐22.77 [‐25.32, ‐20.22]
2.3 HDL cholesterol RCTs	2	200	Mean Difference (IV, Fixed, 95% CI)	6.25 [3.32, 9.19]
2.4 Triglycerides RCTs	2	200	Mean Difference (IV, Fixed, 95% CI)	‐24.63 [‐33.45, ‐15.80]
2.5 LDL‐cholesterol non‐RCTs	33	3594	Mean Difference (IV, Random, 95% CI)	‐37.97 [‐39.53, ‐36.41]
2.6 Total cholesterol non‐RCTs	29	2536	Mean Difference (IV, Fixed, 95% CI)	‐27.36 [‐27.77, ‐26.96]
2.7 HDL‐cholesterol non‐RCTs	28	1996	Mean Difference (IV, Random, 95% CI)	3.98 [2.40, 5.55]
2.8 Triglycerides non‐RCTs	24	1835	Mean Difference (IV, Fixed, 95% CI)	‐16.66 [‐18.00, ‐15.31]
2.9 WDAE	2		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 LDL‐cholesterol RCTs	4	315	Mean Difference (IV, Fixed, 95% CI)	‐39.97 [‐42.86, ‐37.08]
3.2 Total cholesterol RCTs	4	315	Mean Difference (IV, Random, 95% CI)	‐28.09 [‐32.73, ‐23.46]
3.3 HDL cholesterol RCTs	3	264	Mean Difference (IV, Fixed, 95% CI)	6.65 [3.57, 9.73]
3.4 Triglycerides RCTs	3	264	Mean Difference (IV, Fixed, 95% CI)	‐24.81 [‐32.20, ‐17.41]
3.5 LDL‐cholesterol non‐RCTs	3	154	Mean Difference (IV, Fixed, 95% CI)	‐46.39 [‐48.54, ‐44.24]
3.6 Total cholesterol non‐RCTs	3	162	Mean Difference (IV, Fixed, 95% CI)	‐32.28 [‐33.95, ‐30.60]
3.7 HDL‐cholesterol non‐RCTs	4	319	Mean Difference (IV, Random, 95% CI)	6.69 [‐1.04, 14.43]
3.8 Triglycerides non‐RCTs	3	160	Mean Difference (IV, Fixed, 95% CI)	‐12.00 [‐18.87, ‐5.14]
3.9 WDAE	3		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 LDL cholesterol RCTs	2	256	Mean Difference (IV, Random, 95% CI)	‐48.96 [‐54.93, ‐43.00]
4.2 Total cholesterol RCTs	1	100	Mean Difference (IV, Fixed, 95% CI)	‐37.00 [‐41.46, ‐32.54]
4.3 HDL cholesterol RCTs	1	100	Mean Difference (IV, Fixed, 95% CI)	6.00 [0.44, 11.56]
4.4 Triglycerides RCTs	1	100	Mean Difference (IV, Fixed, 95% CI)	‐32.90 [‐45.17, ‐20.63]

*Study characteristics*
Methods	Study design: Randomised controlled trial Study grouping: Parallel group Methods: 5‐week dietary run‐in period; 12‐week randomised, double‐blind, placebo‐controlled trial
Participants	Baseline Characteristics 1 mg N: 26 Age, years: 10.5 Male sex, n: 12 Female sex, n: 14 Genetic FH diagnosis, n: 26 Total cholesterol: 300.6 mg/dL (7.77 mmol/L) LDL cholesterol: 231.4 mg/dL (5.98 mmol/L) 2 mg N: 27 Age, years: 11.1 Male sex, n: 10 Female sex, n: 17 Genetic FH diagnosis, n: 26 Total cholesterol: 295.0 mg/dL (7.63 mmol/L) LDL cholesterol: 223.1 mg/dL (5.77 mmol/L) 4 mg N: 26 Age, years: 10.3 Male sex, n: 14 Female sex, n: 12 Genetic FH diagnosis, n: 25 Total cholesterol: 307.2 mg/dL (7.94 mmol/L) LDL cholesterol: 240.7 mg/dL (6.22 mmol/L) Placebo N: 27 Age, years: 10.4 Male sex, n: 12 Female sex, n: 15 Genetic FH diagnosis, n: 26 Total cholesterol: 310.1 mg/dL (8.02 mmol/L) LDL cholesterol: 240.5 mg/dL (6.22 mmol/L) Overall N: 106 Age, years: 10.6 Male sex, n: 48 Female sex, n: 58 Genetic FH diagnosis, n: 103 Included criteria: Children, aged 6‐17 years were eligible if they had diet‐controlled fasting LDL‐C ≥ 160 (4.1 mmol/L) mg/dL,or LDL‐C ≥ 130 mg/dL (3.4 mmol/L) with one of the following risk factors: male; family history of premature cardiovascular disease; presence of low high‐density lipoprotein cholesterol (HDL‐C) 45 mg/dL or high triglycerides > 150 mg/dL; increased lipoprotein(a) > 75 nmol/L; type 2 diabetes mellitus diagnosed by treating physician according to current guidance; or systolic and diastolic blood pressures above the 95th percentile for age and height. Originally, children with an LDL‐C > 190 mg/dL without a risk factor and > 160 mg/dL with a risk factor could be enroled. These levels were changed to > 160 mg/dL without a risk factor and > 130 mg/dL with a risk factor Excluded criteria: None Baseline Group Characteristics: In general, the treatment groups were comparable with respect to all demographic and clinical characteristics
Interventions	Intervention Characteristics 1 mg 2 mg 4 mg Placebo
Outcomes	Total cholesterol Outcome type: Continuous Reporting: Fully reported Unit of measure: Percentage change from baseline Direction: Lower is better Data value: Change from baseline LDL‐cholesterol Outcome type: Continuous Unit of measure: Percentage change from baseline Direction: Lower is better WDAE Outcome type: Dichotomous Reporting: Fully reported Unit of measure: Risk ratio Direction: Lower is better
Notes	Stephen P on 01/02/2018 10:33 Outcomes Given versus calculated percentage changes from baseline for HDL cholesterol for each dose had a greater than 10% difference (placebo 1.1 vs ‐0.8), (1 mg/day 6.1 vs 4.9), (2 mg/day 2.4 vs ‐3.5) and (4 mg/day 3.1 vs ‐4.2) and triglycerides were expressed as medians; therefore, HDL cholesterol and triglyceride outcomes could not be reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Judgement Comment: method of sequence generation not reported
Allocation concealment (selection bias)	Unclear risk	Judgement Comment: method of allocation concealment not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Judgement Comment: double‐blind placebo‐controlled trial
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Judgement Comment: Lipid parameters were measured in a remote laboratory.
Selective reporting (reporting bias)	Low risk	Judgement Comment: LDL‐C outcome was reported.
Other bias	High risk	Judgement Comment: Kowa Research Europe Ltd. supported the trial.
Incomplete outcome data (attrition bias) Total cholesterol	Low risk	All placebo and pitavastatin 1 mg/day participants were included in the efficacy analysis, [(27 ‐ 26)/27]100 = 3.7%, pitavastatin 2 mg/day participants were not included in the efficacy analysis and [(26 ‐ 24)/26]100 = 7.7% pitavastatin 4 mg/day participants were not included in the efficacy analysis.
Incomplete outcome data (attrition bias) LDL cholesterol)	Low risk	All placebo and pitavastatin 1 mg/day participants were included in the efficacy analysis, [(27 ‐ 26)/27]100 = 3.7%, pitavastatin 2 mg/day participants were not included in the efficacy analysis and [(26 ‐ 24)/26]100 = 7.7% pitavastatin 4 mg/day participants were not included in the efficacy analysis.
Incomplete outcome data (attrition bias) HDL cholesterol	High risk	Given versus calculated percentage changes from baseline for HDL cholesterol for each dose had a greater than 10% difference; HDL cholesterol was not included in the analysis
Incomplete outcome data (attrition bias) Triglycerides	High risk	Triglycerides were expressed as medians, therefore triglycerides were not included in the analysis.
Blinding of outcome assessment (detection bias)WDAEs	Unclear risk	Blinding method was not described.
Selective reporting (reporting bias) for WDAEs	Low risk	WDAE outcome reported

*Study characteristics*
Methods	Study design: Historically controlled trial Study grouping: Parallel group Methods: 6 to 8‐week dietary lead‐in period; 12‐week before‐and‐after trial
Participants	Baseline Characteristics 2 mg n: 316 Age (years): 58.4 Male: 142 Female: 174 Familial hypercholesterolaemia: 1 Total cholesterol: 263.5 mg/dL (6.81mmol/L) LDL cholesterol: 183.5 mg/dL (4.75 mmol/L) HDL cholesterol: 48.5 mg/dL (1.25 mmol/L) Triglycerides: 157.7 mg/dL (1.78 mmol/L) 2 mg then uptitrated to 4 mg at week 4 n: 300 Age (years): 57.9 Male: 136 Female: 164 Familial hypercholesterolaemia: 2 Total cholesterol: 263.3 mg/dL (6.81 mmol/L) LDL cholesterol: 181.8 mg/dL (4.70 mmol/L) HDL cholesterol: 49.9 mg/dL (1.29 mmol/L) Triglycerides: 157.4 mg/dL (1.78 mmol/L) 2 mg combined data n: 616 Age (years): Male: 278 Female: 338 Familial hypercholesterolaemia: 3 Overall n: 616 Included criteria: men and non‐pregnant, nonlactating women, aged 18 to 75 years, diagnosed with primary hypercholesterolaemia or combined dyslipidaemia. mean fasting LDL‐C levels of 160 mg/dL or more (4.1 mmol/L) and less than or equal to 220 mg/dL (5.7mmol/L), and TG levels of less than or equal to 400 mg/dL (4.5 mmol/L) at the end of the lead‐in period Excluded criteria: previous contraindications or intolerance to statin therapy, homozygous familial hypercholesterolaemia, familial hypoalpha‐lipoproteinaemia, conditions that might have caused secondary dyslipidaemia, uncontrolled diabetes mellitus, pregnancy, conditions affecting absorption, distribution, metabolism or excretion of drugs, symptomatic heart failure (New York Heart Association classification III or IV), significant cardiovascular disease, impaired pancreatic function, liver enzyme levels greater than 1.5‐times the upper limit of normal, impaired renal function, impaired urinary tract function, uncontrolled hypothyroidism, symptomatic cerebrovascular disease, left ventricular ejection fraction less than 0.25, uncontrolled hypertension, muscular or neuromuscular disease, neoplastic disease, treatment with other lipid‐lowering drugs and treatment that would interact with the pharmacokinetics of statins. Women of childbearing potential were only allowed to participate if they were using a reliable contraceptive method. Baseline Group Characteristics: The treatment groups were well matched in terms of age, vital statistics (height, weight and BMI) and disease diagnosis and duration. Approximately 79% of patients in each treatment group had primary hypercholesterolaemia (78.4 to 79.1%) and most of the remainder had combined dyslipidaemia. The groups were also well matched in diagnosis of hypertension and in baseline lipid values. Study subjects included slightly more women than men, and this balance was reflected across the treatment groups
Interventions	Intervention Characteristics 2 mg 2 mg then uptitrated to 4 mg at week 4 2 mg combined data
Outcomes	Total cholesterol Outcome type: Continuous Unit of measure: Percentage change from baseline Direction: Lower is better LDL cholesterol Outcome type: Continuous Unit of measure: Percentage change from baseline Direction: Lower is better HDL cholesterol Outcome type: Continuous Unit of measure: Percentage change from baseline Direction: Lower is better Triglycerides Outcome type: Continuous Unit of measure: Percentage change from baseline Direction: Lower is better
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Judgement Comment: Controlled before‐and‐after design
Allocation concealment (selection bias)	High risk	Judgement Comment: Controlled before‐and‐after design
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Judgement Comment: Lipid parameters were measured in a remote laboratory.
Selective reporting (reporting bias)	Low risk	Judgement Comment: LDL‐cholesterol outcome was reported.
Other bias	High risk	Judgement Comment: Kowa Research Europe Ltd. sponsored the trial.
Incomplete outcome data (attrition bias) Total cholesterol	Low risk	[(316 ‐ 315)/316]100 = 0.3% were not included in the efficacy analysis for the pitavastatin 2 mg/day; [(300 ‐ 298)/300]100 = 0.7% were not included in the efficacy analysis for the pitavastatin 2 mg/day then titrated to 4 mg/day at week 4.
Incomplete outcome data (attrition bias) LDL cholesterol)	Low risk	[(316 ‐ 315)/316]100 = 0.3% were not included in the efficacy analysis for the pitavastatin 2 mg/day; [(300 ‐ 298)/300]100 = 0.7% were not included in the efficacy analysis for the pitavastatin 2 mg/day then titrated to 4 mg/day at week 4.
Incomplete outcome data (attrition bias) HDL cholesterol	Low risk	[(316 ‐ 315)/316]100 = 0.3% were not included in the efficacy analysis for the pitavastatin 2 mg/day; [(300 ‐ 298)/300]100 = 0.7% were not included in the efficacy analysis for the pitavastatin 2 mg/day then titrated to 4 mg/day at week 4.
Incomplete outcome data (attrition bias) Triglycerides	Low risk	[(316 ‐ 315)/316]100 = 0.3% were not included in the efficacy analysis for the pitavastatin 2 mg/day; [(300 ‐ 298)/300]100 = 0.7% were not included in the efficacy analysis for the pitavastatin 2 mg/day then titrated to 4 mg/day at week 4.
Blinding of outcome assessment (detection bias)WDAEs	High risk	No comparison possible
Selective reporting (reporting bias) for WDAEs	High risk	No WDAE outcome reported

Study	Reason for exclusion
Aberg 2017	Confounding factor: protease inhibitors of treating HIV
CTRI201305003686 2013	Dose is 2‐4 mg/day pitavastatin one/two Pitavastatin 2 mg tablets per day
CTRI201307003842 2013	Washout period unclear
CTRI201309004003 2013	Washout period unclear
Horiuchi 2010	Combined different statins
Huang 2016	Trial excluded because dose was 1‐2 mg/day and lipids had median percentage change from baseline
Hyogo 2011	Run‐in washout period not reported
Inami 2007	Some participants may have had at least 3‐week washout period but others only 2 weeks.
Jing 2008	Dose unclear
Joshi 2017	Confounding factor: protease inhibitors of treating HIV
JPRN JMA IIA00056 2011	Dose is 1‐4 mg/day dose range
JPRN UMIN000000685 2007	Participants may be receiving lipid altering agents at baseline no washout period reported
JPRN UMIN000001600 2009	Dose is 1 or 2 mg/day dose not specific
JPRN UMIN000002507 2009	Participants were receiving lipid altering agents at baseline
JPRN UMIN000002680 2009	Patients received cholesterol lowering drugs at baseline
JPRN UMIN000003554 2010	no 3‐12 week lipid data 12‐16 weeks
JPRN UMIN000003628 2010	Dose is 1‐4 mg/day dose range
JPRN UMIN000005489 2011	Participants may be receiving lipid altering agents at baseline no washout period reported
JPRN UMIN000005501 2011	Participants may be receiving lipid altering agents at baseline no washout period reported
JPRN UMIN000007130 2012	Participants may be receiving non statin lipid altering agents at baseline no washout period reported
JPRN UMIN000007695 2012	Participants may be receiving non statin lipid altering agents at baseline no washout period reported
JPRN UMIN000009241 2012	Participants may be receiving lipid altering agents at baseline no washout period reported
JPRN UMIN000013384 2014	Participants are receiving a statin excluding pitavastatin at baseline
JPRN UMIN000019020 2015	Participants may be receiving lipid altering agents at baseline no washout period reported
Kawashiri 2008	Confounding factor in 5 of the 19 subjects
Matsubara 2012	Confounding factor
Minai 2008	Trial period reported as 8 weeks or more
Muto 2013	Some participants received lipid‐lowering agents at baseline
Nakamura 2006	Subjects may be receiving lipid altering agents at baseline
Nakaya 2001	Baseline washout period too short
NCT02670434 2016	Terminated The study was aborted and the investigators provided no data
NCT02799758 2016	Terminated The study was aborted and the investigators provided no data
Nishiguchi 2018	Median percent change from baseline
Nomura 2008	Some participants may have had at least a 3‐week washout period but others only 2 weeks.
Nozue 2015	Median percent change from baseline
Rui 2014	Article not available from any library
Watanabe 2015	Dose unclear
Wongprikorn 2016	Confounding factor
Yagi 2011	Some participants were treated for 12 weeks while some were treated for more than 12 weeks.
Yao 2016	Article retracted
Zhu 2010	Washout period of all previous lipid‐lowering drugs not clear

Methods	Historically controlled trial Participants were not receiving lipid altering medications within 4 weeks of the study no washout required
Participants	Male and Female 20‐80 years old with NASH/NAFLD Included criteria: 1)The patients with fatty liver 2)The patients with the level of ALT (42‐120IU/L) 3)The patients with high cholesterol levels Exclusion criteria: 1)The patients with the use of drugs for dyslipidaemia within 4 weeks 2)The patients with chronic kidney disease (serum Cre>2.0) or severe liver dysfunction 3)The patients who are pregnant or giving the breast to a baby or want to be pregnant within the period of trial 4)The patients with cyclosporin 5)The patients with liver dysfunction by drug, alcohol, virus, or autoimmune factors
Interventions	pitavastatin calcium
Outcomes	The level of alanine aminotransferase
Notes	treatment period not reported

Study name	STA study
Methods	Historically controlled trial Parallel Participants were not receiving lipid altering medications no washout required 8 week trial
Participants	Male and Female 18 years or greater Included criteria: 1) Unstable angina, non‐ST‐segment elevation acute coronary syndrome receiving optimal reperfusion therapy 2) Evidence of coronary artery disease 3) low density lipoprotein cholesterol >70mg/dl, triglyceride <500mg/dl 4) agree to informed consent Exclusion criteria: 1) contraindication to statin therapy 2) pregnant women 3) life expectancy less than 2 years 4) abnormal renal, liver function 5) prescribed other lipid lowering medication (fibrate, omega 3, niacin)
Interventions	pitavastatin 2 mg/day pitavastatin 4 mg/day
Outcomes	Lipid profile (total cholesterol, triglyceride, LDL‐C, HDL‐C) in each group
Starting date	2015‐06‐23
Contact information	Kyeong Ho Yun MD Wonkwang University Hospital 895 Muwang‐ro, Iksan, Korea, 54538
Notes

Study name	COCTAIL
Methods	Study design: Randomised controlled trial Study grouping: Parallel group Methods: 8 week randomised, double‐blind, placebo‐controlled trial
Participants	Males and females aged 20 years or older Included criteria: Patients with Dyslipidemia Patients with hypertension Patients who voluntarily signed the consent form. Exclusion criteria: Blood PressureIn case there is a sitting systolic blood pressure difference of 20mmHg and over or sitting diastolic blood pressure is 10mmHg and over in selected arm.Patients with symptomatic orthostatic hypotension.Patients having the history of Secondary hypertension or suspected to be Secondary hypertension, e.g., aortic coarctation, hyperaldosteronism, renal artery stenosis, Cushing's disease, pheochromocytoma, polycystic renal disease, etc. Patients with severe heart diseases (NYHA class‐III and IV), with Ischaemic heart diseases (angina pectoris and myocardial infarction) and with peripheral vascular diseases, and patients who underwent percutaneous transluminal coronary angioplasty (PTCA) or treatments for coronary artery bypass graft within 6 months. Patients with clinically significant ventricular tachycardia or atrial fibrillation or atrial flutter, and patients with arrhythmia judged to be clinically significant by investigators. Patients with hypertrophic obstructive cardiomyopathy, severe obstructive CAD, aortic stenosis and haemodynamically significant aortostenosis or mitral stenosis. Patients with severe cerebrovascular diseases. Patients with severe or malignant retinosis. Patients with consumption diseases or autoimmune diseases or connective tissue diseases Patients with endocrine or metabolic diseases that are known to affect serum lipid or lipoprotein.Patients with uncontrollable diabetesPatients with uncontrollable thyroid dysfunction Patients who underwent treatments that may affect lipid before the clinical trial. Patients having the history of myopathy or rhabdomyolysis. Patients with severe renal disorders or hepatic disorders. Patients with gastrointestinal diseases that may affect drug absorption, distribution, metabolism and excretion or who underwent such operations, or patients with present active gastritis or gastrointestinal haemorrhage or proctorrhagia or active and inflammatory bowel syndrome that has occurred within 12 months. All of patients with chronic inflammatory diseases whereto anti‐inflammatory treatments need to be applied. Patients having the history of drug or alcohol abuse. Pregnant women and/or women in the lactation period or the child‐bearing period. Patients who are hypersensitive to Pitavastatin and Valsartan. Patients who have taken other investigational drugs within 3 months before undergoing the screening test for this clinical trial. Patients judged to be unsuitable for this clinical trial by investigators.
Interventions	Placebo Pitavastatin 4 mg/day
Outcomes	Total cholesterol, LDL cholesterol, HDL cholesterol, Triglycerides
Starting date	June 2011
Contact information	Gyu Rok Han, MD Dept. of Cardiology, Hallym University Medical Center
Notes

Study name	Efficacy and Safety Study of Pitavastatin for Hypercholesterolemia
Methods	Historically controlled trial 4 week washout period of all previous lipid lowering drugs 12 week study
Participants	Females or males aged between 20 and 80 years Included criteria: Subjects who meet All of the following diagnosis at screening visit:Primary hypercholesterolaemia or combined dyslipidaemia TC ≥ 220 mg/dL or LDL‐C ≥ 130 mg/dL TG < 400 mg/dL Subjects who is willing and able to provide ICF. Exclusion criteria: Females who are pregnant, breast‐feeding or intent to be pregnant during study period, or those of childbearing potential not using effective contraception Subject with documented homozygous familial hypercholesterolaemia Subject with documented HIV Subject with documented hypothyroidism and inadequate treatment judged by investigator Subjects with unstable cardiovascular disease (CVD) prior to randomisation Subjects with hepatic or biliary disorders, such as acute hepatitis, acute exacerbation of chronic hepatitis, liver cirrhosis, liver cancer and jaundice Any condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs. Subjects with the following lab data at screening visit:serum creatine kinase (CK) > 5 x upper limit of normal (ULN) ALT or AST of > 3 x ULN serum creatinine ≥ 1.5 mg/dL HbA1c > 8.0% Subject with the following past histories:hypersensitivity to statins or any other ingredients of study drugs resistant to statins treatment Use of any lipid‐lowering agents within 4 weeks prior to the initiation of study treatment Use of any investigational product within 4 weeks prior to screening Any unstable concomitant disease or clinical condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk to participate in the study or confounds the ability to interpret data from the study
Interventions	1PC002 (Pitavastatin) 2 mg/day
Outcomes	Total cholesterol, LDL cholesterol, HDL cholesterol, Triglycerides
Starting date	October 18, 2012
Contact information	Orient Pharma Co., Ltd.
Notes

PERMALINK

Pitavastatin for lowering lipids

Stephen P Adams

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 1. Low‐density lipoprotein (LDL) cholesterol‐lowering efficacy of pitavastatin.

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

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

Results

Description of studies

Results of the search

Included studies

2.

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Overall efficacy of pitavastatin

1. Pitavastatin overall efficacy.

Primary Outcome

LDL cholesterol

1.1. Analysis.

1.5. Analysis.

2.1. Analysis.

2.5. Analysis.

3.1. Analysis.

3.5. Analysis.

4.1. Analysis.

5.1. Analysis.

3.

Secondary Outcomes

Total cholesterol

1.2. Analysis.