Effects of morning vs evening statin administration on lipid profile: A systematic review and meta-analysis

Journal of Clinical Lipidology (2017) -, -–-

1 2 3 4 Original Article 5 6 7 8 9 10 Q1 11 12 Q2 13 Q14 14 Kamal Awad*, Maria-Corina Serban, Peter Penson, Dimitri P. Mikhailidis, 15 Peter P. Toth, Steven R. Jones, Manfredi Rizzo, George Howard, Gregory Y. H. Lip, 16 Maciej Banach, Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group 17 18 19 Q3 Faculty of Medicine, Zagazig University, Egypt (Dr Awad); Student Research Unit, Zagazig University, Egypt (Dr Awad); 20 Department of Functional Sciences, Discipline of Pathophysiology, ‘‘Victor Babes’’ University of Medicine and Pharmacy, 21 Timisoara, Romania (Dr Serban); School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, 22 Liverpool, United Kingdom (Dr Penson); Department of Clinical Biochemistry, Royal Free Campus, University College 23 London Medical School, University College London (UCL), London, United Kingdom (Dr Mikhailidis); Preventive 24 Q4 Cardiology, CGH Medical Center, Sterling, IL, USA (Dr Toth); The Johns Hopkins Ciccarone Center for the Prevention of 25 Heart Disease, Baltimore, MD, USA (Drs Toth and Jones); Biomedical Department of Internal Medicine and Medical 26 Specialties, University of Palermo, Palermo, Italy (Dr Rizzo); Department of Biostatistics, School of Public Health, 27 University of Alabama at Birmingham, Birmingham, AL, USA (Dr Howard); University of Birmingham Institute of 28 Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom (Dr Lip); Department of Hypertension, Medical 29 University of Lodz, Poland (Dr Banach); and Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, 30 Poland (Dr Banach) 31 32 BACKGROUND: Evidence about the optimal time of day at which to administer statins is lacking. 33 KEYWORDS: OBJECTIVE: The objective of this study is to synthesize evidence about effects of morning vs eveCholesterol; 34 ning statin administration on lipid profile. LDL; 35 METHODS: We searched PubMed, SCOPUS, Web of Science, and Embase databases (from incepHydroxymethylglutaryl36 tion up to July 24, 2016) to identify the relevant studies. Mean differences (MDs) between the change CoA reductase inhibitors; 37 scores in lipid parameters were pooled using a fixed-effect model. Half-life; 38 RESULTS: Eleven articles with 1034 participants were eligible for the analysis. The pooled analysis Lipids 39 comparing effects of morning vs evening administration of statins on plasma total cholesterol (TC; 40 P 5 .10), high-density lipoprotein cholesterol (P 5 .90), and triglycerides (P 5 .45) was not statisti41 cally significant. Low-density lipoprotein cholesterol (LDL-C) lowering was statistically greater in 42 the evening-dose group (MD: 3.24 mg/dL, 95% CI: 1.23–5.25, P 5 .002). Subgroup analysis according 43 to statin half-lives showed that evening dose of statins was significantly superior to morning dose for lowering LDL-C in case of both short and long half-life statins (MD: 9.68 mg/dL, 95% CI: 3.32–16.03, 44 P 5 .003 and MD: 2.53 mg/dL, 95% CI: 0.41–4.64, P 5 .02, respectively) and also for TC reduction in 45 case of short half-life statins only (P 5 .0005). 46 47 48 Funding: This research did not receive any specific grant from funding E-mail address: [email protected] 49 agencies in the public, commercial, or not-for-profit sectors. Submitted November 16, 2016. Accepted for publication June 2, 2017. 50 Q5 * Corresponding author. Faculty of Medicine, Student Research Unit, 51 Zagazig University, Zagazig, El-Sharkia, Egypt 44519.

Effects of morning vs evening statin administration on lipid profile: An systematic review and meta-analysis

1933-2874/Ó 2017 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2017.06.001 FLA 5.4.0 DTD  JACL1129_proof  24 June 2017  3:40 pm

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CONCLUSIONS: LDL-C and TC lowering were significantly greater in the evening dose than in the morning dose in case of short-acting statins. Besides slight but significant effect on LDL-C, the efficacy of long-acting statins was equivalent for both regimens. Therefore, long-acting statins should be given at a time that will best aid compliance. Short-acting statins should be given in the evening. Ó 2017 National Lipid Association. All rights reserved.

Introduction Coronary heart disease is the leading cause of mortality and morbidity world wide.1,2 It is now unequivocal that elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are major risk factors for the development of atherosclerosis and coronary heart disease and that lowering these values diminishes the incidence of these diseases.3–10 Previous meta-analyses showed that for every 1.0 mmol/L (38.7 mg/dL) reduction in LDL-C, there is a corresponding 20%–25% reduction in cardiovascular disease (CVD) mortality.11 The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are very effective drugs for reducing the elevated levels of plasma cholesterol.2,12 Statins reduce both LDL-C and triglycerides (TGs) by up to 50% and 20%, respectively.2,13 Moreover, they increase highdensity lipoprotein cholesterol (HDL-C) by up to 10%.14,15 It is now well established that statins are beneficial for primary and secondary prevention of CVD.7–10,16–20 In a meta-analysis of 170,000 participants, which included data from 26 randomized controlled trials (RCTs) with statins, all-cause mortality was reduced by 10%, coronary artery disease death by 20%, risk of major coronary events by 23%, and risk of stroke by 17% per 1 mmol/L (38.7 mg/dL) reduction in LDL-C.21 Statins are considered to be the standard therapy for many types of dyslipidemia due to their ability to inhibit the endogenous biosynthesis of cholesterol and to increase the hepatic uptake of LDL-C by stimulating the expression of LDL-C receptors in the liver.11,12,22 This is important because more than 75% of cholesterol found in the body is synthesized endogenously and two-thirds of it is synthesized in the liver alone.12 Statins are usually administrated in the evening because cholesterol biosynthesis peaks during the night and also because most of them (simvastatin, pravastatin, fluvastatin, and lovastatin) have short half-lives.12,23–25 The timing of drug administration can alter patient compliance and adherence to the treatment.26–28 Patients treated with statins often receive multiple concomitant medications and this leads to more complex drug regimens, which have the potential to reduce compliance and adherence to therapy.29,30 Allowing flexibility in choosing the time, at which statins are administrated, according to the patient’s preference, is likely to improve patient compliance and decrease drug discontinuation.31 This will enable more patients to achieve their target lipid levels.32,33 Therefore, we performed this systematic review and meta-analysis to synthesize evidence about the different

effects of morning and evening statin administration on lipid profiles to discover the dosing regimen, which led to the highest therapeutic efficacy.

Material and methods We followed Preferred Reporting Items for Systematic Reviews and Meta-analyses statement guidelines during the preparation of this meta-analysis (Supplementary File 1: Table S1).34 This meta-analysis was registered in PROS- Q6 PERO, University of York (CRD42016043480).

Search strategy We searched PubMed, SCOPUS, Web of Science, and Embase from inception until July 24, 2016, using the following query: (atorvastatin OR fluvastatin OR lovastatin OR pitavastatin OR pravastatin OR rosuvastatin OR simvastatin OR cerivastatin OR mevinolin OR statin OR statins) AND (morning) AND (evening). Additional searches for potential trials included the references of review articles on that issue and the abstracts from selected congresses: scientific sessions of the European Society of Cardiology, the American Heart Association, American College of Cardiology, European Society of Atherosclerosis, and National Lipid Association. The wild-card term ‘‘*’’ was used to increase the sensitivity of the search strategy. The literature search was limited to articles published in English and to studies on humans. After removal of duplicates by Endnote X7 (Thompson Reuter, CA), 2 independent authors (K.A. and P.P.) screened the retrieved citations in 2 steps; the first step was to screen the titles and abstracts for eligibility and the second step was to screen the full texts of the eligible abstracts according to the inclusion and exclusion criteria. Disagreement was resolved by the opinion of a third author (M.B.)

Study selection Original studies were included if they met the following criteria: (1) prospective or retrospective clinical controlled studies (with randomized or nonrandomized design); (2) comparing the effects of morning administration against evening administration of statin therapy on one of the following lipid profile parameters: TC, LDL-C, HDL-C, or TG; and (3) reporting sufficient information on blood lipid levels at baseline and at the end of study in

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Morning vs evening statins for lipid profile

both groups or reporting the net change scores or the mean difference (MD) between the change scores of the 2 groups. Exclusion criteria were (1) nonclinical studies, (2) studies that contained false statements or which had been retracted by the journal, (3) studies whose full texts were not available, and (4) studies that provided insufficient data for analysis.

Data extraction Eligible studies were reviewed and the following data were extracted: (1) first author’s name, (2) year of publication, (3) study location, (4) study design, (5) interventions doses, time and duration; (6) study population characteristics, (7) study results, and, (8) concentrations of TC, LDL-C, HDL-C, and TG. Data extraction was performed independently by 2 reviewers (K.A. and P.P.); disagreements were resolved by a third reviewer (M.B.).

Outcomes of interest The primary outcome was the MD between the change scores of the 2 groups in one of the following lipid parameters: TC, LDL-C, HDL-C, and TG. In addition, the secondary outcome was the compliance of patients with statin regimens.

Quantitative data synthesis Lipid concentrations were collated in mg/dL using the following site to convert mmol/L to mg/dl: (http://www. onlineconversion.com/cholesterol.htm). Change scores in the lipid levels were calculated as follows: (measure at end of follow-up) – (measure at baseline). Standard deviations (SDs) of the change scores were calculated using the following formula: SD 5 square root [(SDpretreatment)2 1 (SDposttreatment)2 – (2R ! SDpretreatment ! SDposttreatment)], assuming a correlation coefficient (R) 5 0.5.35–37 If the outcome measures were reported as median and range, mean and SD values were estimated using the method described by Hozo et al38 and if reported as mean and standard error (SE) (or confidence interval [CI]), mean and SD values were estimated using the method described by Altman et al.39 MD between the change scores of the morning and evening groups were calculated as follows: (change score of morning group) – (change score of evening group) and its SE was calculated using the following formula: SE 5 square root {[(SDtreatment group)2 O ntreatment 2 group] 1 [(SDcontrol group) O ncontrol group]}, where (n) was the sample size. If any study reported the MD between the change scores of the morning and evening groups directly with 95% CI, SE was calculated using the following formula: SE 5 [(upper confidence limit–lower confidence limit) O 3.92], where 3.92 was changed to 3.29 if a 90% CI was given rather than a 95% CI.

3 MDs between the change scores of the morning and evening groups were pooled in a meta-analysis model with a 95% CI. We used RevMan, version 5.3 (The Cochrane Collaboration, Oxford, United Kingdom), to conduct this analysis.

Subgroup analysis Data were divided into 2 subgroups according to the design of the studies as follows: (1) RCTs and (2) nonrandomized studies. To investigate the impact of statin half-lives on the results, data were separately divided into subgroups as follows: (1) short half-lives below 7 hours (lovastatin, simvastatin, pravastatin, and fluvastatin) and (2) long half-lives above 7 hours (atorvastatin, rosuvastatin, controlled release simvastatin, and extended release fluvastatin).12,40–42

Assessment of heterogeneity Heterogeneity was assessed by visual inspection of the forest plots and was measured by I-squared and chi-squared tests. We interpreted heterogeneity according to the recommendations of the Cochrane Handbook of Systematic Reviews and Meta-analysis in which an alpha level (for chisquared test) below 0.1 is considered to be a significant heterogeneity, and I-squared test is interpreted as follows: (0%–40%: might not be important; 30%–60%: may represent moderate heterogeneity; and 50%–90%: may represent substantial heterogeneity). In the case of significant heterogeneity, the random-effect model was used. Otherwise, the fixed-effect model was used in metaanalysis.

Sensitivity analysis Sensitivity analysis was conducted using leave-one-out method, that is, removing one study each time and repeating the analysis to determine whether exclusion of any one of the included studies altered the results, particularly when substantial heterogeneity was noted between trials.

Quality assessment We used the Cochrane Collaboration tool for assessing the risk of bias in included RCTs. This tool includes the following domains: sequence generation (selection bias), allocation sequence concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other potential sources of bias. The authors’ judgment is classified as ‘‘low risk,’’ ‘‘high risk,’’ or ‘‘unclear risk’’ of bias. We used the Newcastle-Ottawa Scale for assessing the risk of bias in nonrandomized studies.43 This scale uses a

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4 star system to judge 3 general domains: selection of study groups, comparability of groups, and exposure. Risk of bias assessment was performed independently by 2 reviewers (K.A. and P.P.); disagreements were resolved by a third reviewer (M.B.).

Publication bias For assessment of publication bias, the pooled effect estimate was plotted against its SE in a funnel plot generated by RevMan software and potential publication bias was explored by visual inspection of Begg’s funnel plot asymmetry, and also, we used Egger’s weighted regression test to confirm it statistically.44 We used Comprehensive Meta-Analysis (CMA) V2 software (Biostat, NJ) to perform Egger’s test.

web 4C=FPO

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Results Flow and characteristics of included studies Our search discovered 549 articles. After removal of duplicates and detailed screening, only 11 articles (12 treatment arms)45–55 met our inclusion criteria and were eligible for the meta-analysis (see Preferred Reporting Items for Systematic Reviews and Meta-analyses flow diagram; Fig. 1). In total, 1034 participants were included in our analysis. The number of participants in these studies ranged from 12 to 229. Studies included in the meta-analysis were published between 1986 and 2014 and were conducted in USA (n 5 4), Germany (n 5 2), Korea (n 5 2), Turkey, Japan, and United Kingdom. The following statin doses were administrated in the included studies: 40 mg/d atorvastatin, 2.5 to 20 mg/d simvastatin, 10 mg/d rosuvastatin, 20 mg/ d lovastatin, 40 mg/d pravastatin, and 80 mg/d fluvastatin. The duration of the included studies ranged between 4 and 12 weeks. Nine of the included studies were RCTs, one was non-RCT, and the other one was a retrospective cohort study. The summary of the included studies and their main results are shown in Table 1, and the baseline characteristics of their populations are shown in Table 2.

Quality of the included studies According to Cochrane Collaboration tool and Newcastle-Ottawa Scale, the quality of the included studies ranged from low quality to high quality. The summary of quality assessment domains of included studies is shown in Tables 3 and 4.

Efficacy analysis The overall pooled analysis of 11 studies (12 treatment arms) comparing effects of morning vs evening administration of statins on plasma TC (MD: 1.68 mg/dL, 95% CI:

Figure 1 The PRISMA flow diagram of studies’ screening and selection. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses.

20.33 to 3.69, P 5 .10, Fig. 2), HDL-C (MD: 0.05 mg/dL, 95% CI: 20.77 to 0.87, P 5 .90, Fig. 3), and TG (MD: 1.66 mg/dL, 95% CI: 22.68 to 5.99, P 5 .45, Fig. 4) was not statistically significant. However, it favored evening dose over morning dose with respect to the effect of statins on plasma LDL-C (MD: 3.24 mg/dL, 95% CI: 1.23–5.25, P 5 .002, Fig. 5). No significant heterogeneity was noted for any of the outcomes (chi-square, P . .1). The pooled analysis of the short half-life statins subgroup did not reveal any significant difference between the morning-dose and evening-dose groups in terms of HDL-C (MD: 0.28 mg/dL, 95% CI: 21.49 to 2.06, P 5 .75, Fig. 3) and TG (MD: 0.97 mg/dL, 95% CI: 213.54 to 15.48, P 5 .90, Fig. 4). However, it favored evening dose over morning dose in terms of TC (MD: 12.10 mg/dL, 95% CI: 5.25–18.95, P 5 .0005, Fig. 2) and LDL-C (MD: 9.68 mg/dL, 95% CI: 3.32, 16.03, P 5 .003, Fig. 5). For all outcomes, there was no significant heterogeneity (chisquare, P . .1). The pooled analysis of the long half-life statins subgroup did not show any significant difference for TC (MD: 0.70 mg/dL, 95% CI: 21.40 to 2.80, P 5 .51, Fig. 2), HDL-C (MD: 20.01 mg/dL, 95% CI: 20.94 to 0.92, P 5 .98, Fig. 3), and TG (MD: 1.72 mg/dL, 95%CI: 22.82 to 6.27, P 5 .46, Fig. 4). However, it favored evening dose over morning dose in terms of LDL-C (MD: 2.53 mg/dL, 95% CI: 0.41–4.64, P 5 .02, Fig. 5). No significant heterogeneity was noted for any of the outcomes (chi-square, P . .1). The pooled analysis of RCTs subgroup did not reveal any significant difference between the 2 groups concerning their effects on plasma TC (MD: 1.59 mg/dL, 95% CI: 20.45 to 3.63, P 5 .13, Supplementary File 2: Fig. S1),

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439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 Summary of the included studies Year

Location

Design

Duration

Statin used

Population

Result

Hunninghake et al

1990

USA

8 wk

Pravastatin (40 mg)

Illingworth et al

1986

USA

Randomized, double-blind, placebo-controlled, parallel trial Nonrandomized, controlled, trial

9 wk

Mevinolin

Patients with primary hypercholesterolemia who were between the ages of 20 and 72 years Patients with severe type II hypercholesterolemia (persistent primary hypercholesterolemia greater than 350 mg/dL)

Kim et al

2013

Korea

Randomized, double-blind, controlled, parallel trial

8 wk

Controlled release simvastatin (20 mg)

Patients with LDL-C levels between 100 and 220 mg/dL and triglyceride levels of 400 mg/dL

Kruse et al

1993

Germany

Randomized, single-blind, controlled, parallel trial

4 wk

Lovastatin (20 mg)

Patients with familial hypercholesterolemia

Martin et al

2002

USA

Randomized, open-label, controlled, crossover trial

8 wk

Rosuvastatin (10 mg)

Healthy adult volunteers, ranging in age from 19–61 years and weighing 57–100 kg

Ozaydin et al

2006

Turkey

Randomized, controlled, parallel trial

6 mo

Atorvastatin (40 mg)

Patients with single-vessel coronary disease who underwent first elective percutaneous coronary intervention (PCI)

Plakogiannis et al

2005

USA

Retrospective cohort

4 wk

Atorvastatin (40 mg)

Hyperlipidemic patients at the New York Harbor Healthcare System (NYHHS)

Pravastatin was well tolerated and was associated with a low incidence of adverse events Once daily administration of mevinolin, particularly in the evening, is an effective hypocholesterolemic regimen in patients with familial hypercholesterolemia Although controlled release simvastatin significantly reduces LDL-C levels with good tolerability in Korean adults with dyslipidemia, the time of administration does not affect its efficacy The present study adds further evidence that drug use seems to be more regular in the morning than in the evening The therapeutic benefit of rosuvastatin is not dose-time dependent, and that morning or evening administration is equally effective in regulating lipid levels Compared with the intake of atorvastatin in the morning, intake in the evening before PCI was associated with a more pronounced decrease in total cholesterol, LDL cholesterol, and triglyceride values, and an increase in HDL cholesterol levels Changes in the levels of total cholesterol, LDL cholesterol, triglycerides, and HDL cholesterol were similar among hyperlipidemic patients receiving atorvastatin calcium 40 mg daily, regardless of the time of day the drug was administered

Morning vs evening statins for lipid profile

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Study

Awad et al

Table 1

(continued on next page)

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Table 1

(continued ) Year

Location

Design

Duration

Statin used

Population

Result

Saito et al

1991

Japan

Double-blind, placebo-controlled, parallel trial

12 wk

Simvastatin (2.5 or 5 mg)

Scharnagl et al

2006

Germany

Randomized, double-blind, controlled, parallel trial

8 wk

Fluvastatin extended release (80 mg)

When simvastatin was administered orally once per day in the evening, it reduced cholesterol levels to a significantly greater degree than when it was given in the morning The efficacy and safety profiles of fluvastatin extended release are equivalent for morning and evening administration

Wallace et al

2003

UK

Randomized, controlled, parallel trial

8 wk

Simvastatin (10 or 20 mg)

Yi et al

2014

Korea

Randomized, double-blind, controlled, parallel trial

8 wk

Simvastatin (20 mg)

Patients diagnosed as having hyperlipidemia (a serum cholesterol value of at least 220 mg/dL, including patients with familial hypercholesterolemia) Patients aged 35–80 years and have type IIa/b hypercholesterolemia (Frederickson), and LDL-C $ 160 mg/dL and triglycerides (TGs) , 400 mg/dL in the absence of lipid-lowering treatment Adults stable on 10 or 20 mg of simvastatin at night for primary or secondary prevention of coronary heart disease, stroke, or peripheral vascular disease Patients, 20–75 years of age, with CKD stage 3, 4, or 5 (predialysis) were enrolled if their serum LDL-C levels were between 100 and 220 mg/dL and their serum triglyceride (TG) levels were , 400 mg/dL

Simvastatin is probably best taken at night because concentrations of total cholesterol and of low-density lipoprotein are significantly greater when it is taken in the morning The efficacy of morning administration of CR simvastatin was noninferior to evening administration of IR simvastatin in patients with CKD. Morning administration of CR simvastatin is expected to increase patient compliance and therefore better control of dyslipidemia in CKD patients

CKD, chronic kidney disease; CR, controlled release; HDL, high-density lipoprotein; IR, immediate release; LDL-C, low-density lipoprotein cholesterol.

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Study

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663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 Awad et al

Baseline characteristics of the included studies

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Total cholesterol (mg/dL)

LDL-C (mg/dL)

HDL-C (mg/dL)

Triglycerides (mg/dL)

245.6 244.8 357 357 155.0 160.6 338.7 379.7 120.7 119.5 140 138 188.3 195.0 182.7 195.9 194.2 204.3 189.9 188.5 92.8

44.5 44.5 54 54 48.6 50.3 36.3 40.2 49.5 47.6 35 37 46.4 40.8 54.38 46.95 52.71 53.15 58 59.4 50

127.5 126.7 147 147 157.1 147.3 178.9 130.2 105.4 112.5 175 170 434.0 468.5 179.6 160.3 152.5 156.3 176 176.4 141.7

Study

Year

Group (# of patients)

Age (y)

Weight (kg)

Gender (m/f)

Hunninghake et al

1990

Illingworth et al

1986

Kim et al

2013

Kruse et al

1993

Martin et al

2002

Ozaydin et al

2006

Plakogiannis et al

2005

Saito et al

1991

Scharnagl et al

2006

Wallace et al

2003

53.3 54.0 54 54 58.7 58.5 48.4 45 NS NS 59 58 58.5 57.8 NS NS NS NS 60.1 60.6 66

79.1 76.4 67 67 66.1 66.6 74.7 74.3 NS NS NS NS NS NS NS NS NS NS NS NS NS

36/12 30/13 4/8 4/8 26/35 29/33 9/3 8/4 NS NS 59/14 59/20 32/0 32/0 8/22 6/22 8/24 4/25 38/71 49/71 27/33

320.2 320.6 440 440 236.0 238.4 424.6 450.9 191 189.5 211 206 321.4 329.2 273.0 274.9 277.4 288.8 282.3 282.5 170.1

Yi et al

2014

Pravastatin qam (n 5 48) Pravastatin qpm (n 5 43) Mevinolin qam vs Mevinolin qpm (n 5 12) Simvastatin qam (n 5 61) Simvastatin qpm (n 5 62) Lovastatin qam (n 5 12) Lovastatin qpm (n 5 12) Rosuvastatin qam (n 5 21) Rosuvastatin qpm (n 5 21) Atorvastatin qam (n 5 73) Atorvastatin qpm (n 5 79) Atorvastatin qam (n 5 32) Atorvastatin qpm (n 5 32) Simvastatin 2.5 mg qam (n 5 30) Simvastatin 2.5 mg qpm (n 5 28) Simvastatin 5 mg qam (n 5 32) Simvastatin 5 mg qpm (n 5 29) Fluvastatin qam (n 5 109) Fluvastatin qpm (n 5 120) Simvastatin qam vs Simvastatin qpm (n 5 60) CR simvastatin qam (n 5 59) IR simvastatin qpm (n 5 59)

28/31 29/30

228.7 (36.8) 220.0 (36.4)

(13.9) (13.9) (8.3) (9.5) (11.4) (9.7)

(6) (5) (7.8) (7.8)

56.9 (10.5) 57.0 (12.1)

(10.4) (10.4) (11.0) (9.5) (5.2) (11.8)

64.3 (11.1) 63.7 (10.4)

(69.7) (73.5) (48.5) (48.5) (28.9) (31.1) (129.9) (87.1)

(26) (18) (28.0) (23.3) (39.6) (37.2) (49.8) (46.9) (32.6) (35.4) (30.9)

(67) (73.5) (48.5) (48.5) (22.3) (25.0) (111.2) (80.4)

(14) (13) (13.0) (10.4) (46.8) (36.7) (48.1) (52.2) (27.6) (32.9) (23)

143.9 (28.1) 137.0 (28.4)

(10.7) (12.7) (17.3) (17.3) (9.7) (11.3) (10.7) (8)

(3) (4) (8.9) (5.5) (24.26) (15.00) (17.94) (12.97) (16.5) (16.3) (11.6)

46.9 (14.5) 48.8 (13.5)

(49) (69.7) (45) (45) (65.2) (63.1) (92) (52)

Morning vs evening statins for lipid profile

Table 2

(27) (21) (87.2) (93.0) (105.3) (72.3) (77.4) (68.9) (80.7) (74.4) (70.9)

190.3 (73.0) 167.6 (70.7)

CR, controlled release; f, female; HDL-C, high-density lipoprotein cholesterol; IR, immediate release; LDL-C, low-density lipoprotein cholesterol; m, male; NS, not stated; qam, every morning; qpm, every evening. Continuous variables are described as mean or mean (SD), and categorical variables are described as N.

7 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774

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8 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830

Table 3

Assessment of risk of bias in the included randomized controlled trials using Cochrane criteria

Study

Sequence generation

Allocation concealment

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data

Selective outcome reporting

Other potential threats to validity

Hunninghake (1990) Kim (2013) Kruse (1993) Martin (2002) Ozaydin (2006) Saito (1991) Scharnagl (2006) Wallace (2003) Yi (2014)

U L U U U U U U U

U L U U U U U U U

L L L H H L L H L

U U H H L U U H U

L L L L L L L L L

U U U U U U U U U

L L L L H* L L L H†

H, high risk of bias; L, low risk of bias; U, unclear risk of bias. *Differences in baseline characteristics. †Different formulation used: controlled release in the morning and immediate release in the evening groups.

HDL-C (MD: 0.03 mg/dL, 95% CI: 20.82 to 0.87, P 5 .95, Supplementary File 2: Fig. S2), and TG (MD: 1.65 mg/dL, 95% CI: 22.73 to 6.03, P 5 .46, Supplementary File 2: Fig. S3). However, it favored evening dose over morning dose with respect to the effect of statins on plasma LDLC (MD: 3.49 mg/dL, 95% CI: 1.31–5.68, P 5 .002, Supplementary File 2: Fig. S4). No significant heterogeneity was noted for any outcomes (chi-square, P . .1). The combined analysis of nonrandomized studies did not reveal any significant difference between the morning-dose and evening-dose groups on any of the investigated outcomes: plasma TC (MD: 4.22 mg/dL, 95% CI: 26.62 to 15.06, P 5 .45, Supplementary File 2: Fig. S1), HDL-C (MD: 0.55 mg/dL, 95% CI: 23.2 to 4.3, P 5 .77, Supplementary File 2: Fig. S2), TG (MD: 2.06 mg/dL, 95% CI: 227.85 to 31.97, P 5 .89, Supplementary File 2: Fig. S3), and LDL-C (MD: 1.86 mg/dL, 95% CI: 23.27 to 6.98, P 5 .48, Supplementary File 2: Fig. S4). No significant heterogeneity was noted for any outcomes (chi-square P . .1).

Compliance with both regimens Only 3 studies46,47,52 of the 11 included in this metaanalysis reported the rates of compliance with both statin regimens. Two of them46,52 revealed no significant difference between the 2 regimens, and 1 study47 indicated that drug compliance was better when the drug was taken in the morning than in the evening. Compared with morning dosing, evening dosing of lovastatin was associated with a 7% reduction in the number of prescribed doses, which were taken by the patient.47

Sensitivity analysis For all efficacy outcomes, the overall pooled effect size was robust, and the statistical significance or nonsignificance

of the differences between groups was not altered in the leave-one-out sensitivity analysis. This means that none of the included studies individually changed the overall result. However, the pooled analyses of effects of morning dose vs evening dose of short half-life statins on LDL-C and TC were sensitive to the study by Wallace et al52 because of the substantial weight of this study, that is, removing this study from the analysis led to no significant difference being detectable between the groups. In long half-life statins, the pooled effect on LDL-C was sensitive to the studies by Martin et al48 and Ozaydin et al49 because of the substantial weights of these studies. Summary of the leave-one-out sensitivity analysis is shown in (Supplementary File 3: Table S2).

Publication bias Visual inspection of the funnel plots suggested a potential publication bias for the effects of morning dose vs evening dose of statin on plasma TC and LDL-C (Supplementary File 2: Figs. S5 and S6). However, the funnel plots were symmetric in the case of the effects of statins on TG and HDL-C (Supplementary File 2: Figs. S7 and S8). In contrast, the Egger’s test statistically excluded the presence of publication bias for all outcomes (2-tailed P . .05).

Discussion To our knowledge, this meta-analysis is the first to compare the effects of morning and evening doses of statin therapy on lipid profiles. Data from 11 studies showed that the LDL-C–lowering effect of the drugs was significantly greater when statins were taken in the evening than when they were taken in the morning. This effect was independent of the half-live of the drugs used. In the case of short half-life statins, evening dosing resulted in a larger TC-

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831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886

8 8 * * * * * * * * * *

Year

1986 2005

Author

Illingworth Plakogiannis

†Comparability of selection of baseline day and night groups. ‡Reporting of baseline plasma lipid values.

* * * *

Ascertainment of the exposure Selection of the nonexposed cohort† Representativeness of the sample

* *

Adequacy of follow-up of cohorts Assessment of outcome

Was follow-up long enough for outcomes to occur Subjects in different outcome groups are comparable

Outcome (max. 3 stars)

Demonstration that outcome of interest was not present at the start of study‡

Comparability (max. 2 stars) Selection (max. 5 stars)

Domain and topic (max. 10 stars)

Assessment of the quality of nonrandomized studies using the Newcastle-Ottawa Scale Table 4

887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942

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Awad et al

9 lowering effect. The evening dosing and morning dosing regimens were equivalent with respect to the effects of statins on HDL-C and TG. The US Food and Drug Administration recommends evening administration of lovastatin,56 simvastatin,57 and fluvastatin.58 This is based on their short half-lives (2–3, 2–3, and 0.5–2.3 hours, respectively) and the fact that peak cholesterol biosynthesis occurs during the night.12,25,40,59 It is advised that atorvastatin,60 rosuvastatin,61 and extended release fluvastatin42,58 can be given at any time of day due to their long half-lives (15–30, 30, and 7.3–10.5 hours, respectively). The results of this meta-analysis are in line with these recommendations. However, the Food and Drug Administration advises that pravastatin can be taken at any time of the day despite its short half-life (1.3– 2.8 hours).12,40,62 This might be because the systemic bioavailability of pravastatin is decreased by 60% when administrated in the evening compared with that following the morning dose.63 However, the evening dose of pravastatin was found to be marginally more effective than the morning dose. Our finding that LDL-C lowering was greater when statins with long half-lives were administered in the evening, than when they were taken in the morning is somewhat unexpected. However, it should be noted that the difference between the groups is small and might be not clinically relevant. However, under the assumption that a 1 mmol/L (38.7 mg/dL) reduction in LDL-C is associated with a 20%–25% reduction in CVD mortality,11 this difference might have been associated with a 0.3%–3% reduction in CVD mortality at the population level. Adherence to statin treatment remains problematic and affects the clinical effectiveness of these drugs.64,65 There are many factors that affect statin adherence such as adverse effects (statin associated muscle symptoms/statin intolerance), complex drug regimens, drug-drug interactions, patient preference (rather than provider preference), cost, age, and gender.66–70 Good adherence to statin has been associated with a 15%–20% lower risk of CVD events.71 Some other studies have reported a much greater reduction that may reach up to 40%.72–77 Regimens requiring evening doses of cardiovascular drugs have been associated with a 5%–25% drop in compliance when compared with administration in the morning.78–80 One of the studies included in this meta-analysis reported a 7% reduction in the number of the prescribed doses of lovastatin, which were taken when the drug was directed to be taken in the evening, compared with morning doses.47 One important factor that may help to improve adherence is to allow patients to decide at which time of the day they prefer to take their statin (eg, with other medication in the morning).31,80 This selected time should be the one most likely to result in an uninterrupted intake of the medicine.31 However, some prescribers may insist on patients taking statins in the evening because they are under the impression that these drugs are substantially more effective when taken at night. Based on the results of this metaanalysis, evening dosing appears to be important for

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943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998

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Figure 2 Forest plot displaying the results of the meta-analysis of morning vs evening statins on total cholesterol with subgrouping according to half-lives of statins. CI, confidence interval; df, degrees of freedom; SE, standard error.

short-acting statins, but in the case of statins with long halflives, prescribing instructions should allow more patientbased choice. In addition, it should be emphasized that taking the statin at the same time every day (eg, developing a morning routine) might result in better adherence.31,80 Patients treated with statins often receive multiple concomitant drugs.30 Polypharmacy and complex drug regimens have been associated with decreased adherence.29

Taking multiple medications at the same time or in the form of a ‘‘polypill’’ has been proposed a possible solution to the complexity of drug regimens and has been associated with increased adherence.81,82 However, many of the drugs, which might be administered concomitantly with statins are usually administrated in the morning (eg, antihypertensive drugs and aspirin).83 The results of our analysis are important because they clearly confirm that administration of

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999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054

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10

Figure 3 Forest plot displaying the results of the meta-analysis of morning vs evening statins on high-density lipoprotein cholesterol with subgrouping according to half-lives of statins. CI, confidence interval; df, degrees of freedom; SE, standard error. FLA 5.4.0 DTD  JACL1129_proof  24 June 2017  3:40 pm

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11

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1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166

Morning vs evening statins for lipid profile

Figure 4 Forest plot displaying the results of the meta-analysis of morning vs evening statins on triglycerides with subgrouping according to half-lives of statins. CI, confidence interval; df, degrees of freedom; SE, standard error.

was relatively short (4–12 weeks). Second, some of the included studies did not have a well-defined exclusion criterion.48,52,54 Third, the difference in effects of morning dose vs evening dose of statins was a secondary finding in some of included studies.45,47,49,54 Fourth, the patient population in the included studies was heterogeneous with respect to various factors including health, hyperlipidemia, and chronic kidney disease. Finally, most of the included

web 4C=FPO

long-acting statins in the morning is as efficacious as administration in the evening. Therefore, the efficacy of long-acting statins will not be altered when administrated, in a polypill, with these concomitant medications in the morning. This meta-analysis has several limitations: most importantly, the sample size of each individual study was relatively small (12–229 participants), and the follow-up

Figure 5 Forest plot displaying the results of the meta-analysis of morning vs evening statins on low-density lipoprotein cholesterol with subgrouping according to half-lives of statins. CI, confidence interval; df, degrees of freedom; SE, standard error. FLA 5.4.0 DTD  JACL1129_proof  24 June 2017  3:40 pm

1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222

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12 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 Q11

studies did not report the results of patients’ compliance with statin regimens. Bearing in mind the limitations of the current evidence, further well-designed, large-scale RCTs are required to confirm our results and to investigate long-term compliance with morning and evening regimens of statins. In 2011, Wright et al80 investigated the effect of the timing of simvastatin on its efficacy in a pharmacokinetic–pharmacodynamics model. They found no clinically important difference between morning and evening doses. They explained this result by the relativity slow turnover of the cholesterol in the plasma (3–4 days) and, in turn, the delayed peak effect of simvastatin on LDL-C reduction.84,85 Therefore, the chronobiologic effects of short-acting statins should be further established in large-scale RCTs. In conclusion, the current meta-analysis shows that LDL-C and TC lowering were significantly greater in the evening dose than in the morning dose in case of shortacting statins. However, apart from a small but statistically significant effect on LDL-C, the efficacy of long-acting statins was equivalent for morning and evening administration. Therefore, it would be appropriate to consider choosing the time of administration of long-acting statins based on what will best aid compliance. On the other hand, short-acting statins should be taken in evening. Future welldesigned, large-scale, prospective RCTs are recommended, especially on short-acting statins, to confirm our findings.

Acknowledgment Author Contributions: Dr Awad helped in protocol writing, literature search, screening, data extraction, data analysis, and manuscript writing; Dr Serban in protocol writing, literature search, data analysis, manuscript writing, and revision; Dr Penson in screening, data extraction, manuscript writing, and revision; Drs Mikhailidis, Toth, Jones, Rizzo, Howard, and Lip in manuscript writing and revision; and Dr Banach in study design, supervision, coordination, and preparation of the revision. All authors have approved the final article.

Financial disclosures The authors have no conflicts of interest to disclose.

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1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334

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13 44. Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ. 1997;315(7109): 629–634. 45. Hunninghake DB, Mellies MJ, Goldberg AC, et al. Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. II. Oncedaily versus twice-daily dosing. Atherosclerosis. 1990;85(2–3): 219–227. 46. Kim S-H, Kim M-K, Seo H-S, et al. Efficacy and safety of morning versus evening dose of controlled-release simvastatin tablets in patients with hyperlipidemia: a randomized, double-blind, multicenter phase III trial. Clin Ther. 2013;35(9):1350–1360.e1. 47. Kruse W, Nikolaus T, Rampmaier J, Weber E, Schlierf G. Actual versus prescribed timing of lovastatin doses assessed by electronic compliance monitoring. Eur J Clin Pharmacol. 1993;45(3):211–215. 48. Martin PD, Mitchell PD, Schneck DW. Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers. Br J Clin Pharmacol. 2002;54(5):472–477. 49. Ozaydin M, Dede O, Dogan A, et al. Effects of morning versus evening intake of atorvastatin on major cardiac event and restenosis rates in patients undergoing first elective percutaneous coronary intervention. Am J Cardiol. 2006;97(1):44–47. 50. Saito Y, Yoshida S, Nakaya N, Hata Y, Goto Y. Comparison between morning and evening doses of simvastatin in hyperlipidemic subjects. A double-blind comparative study. Arterioscler Thromb. 1991;11(4): 816–826. 51. Scharnagl H, Vogel M, Abletshauser C, Freisinger F, Stojakovic T, M€arz W. Efficacy and safety of fluvastatin-extended release in hypercholesterolemic patients: morning administration is equivalent to evening administration. Cardiology. 2006;106(4):241–248. 52. Wallace A, Chinn D, Rubin G, et al. Taking simvastatin in the morning compared with in the evening: randomised controlled trial. BMJ. 2003;327(7418):788. 53. Yi YJ, Kim HJ, Jo SK, et al. Comparison of the efficacy and safety profile of morning administration of controlled-release simvastatin versus evening administration of immediate-release simvastatin in chronic kidney disease patients with dyslipidemia. Clin Ther. 2014; 36(8):1182–1190. 54. Illingworth DR. Comparative efficacy of once versus twice daily mevinolin in the therapy of familial hypercholesterolemia. Clin Pharmacol Ther. 1986;40(3):338–343. 55. Plakogiannis R, Cohen H, Taft D. Effects of morning versus evening administration of atorvastatin in patients with hyperlipidemia. Am J Health Syst Pharm. 2005;62(23):2491–2494. 56. Mevacor Tablets Label - FDA. Available at: http://www.accessdata. fda.gov/drugsatfda_docs/label/2012/019643s085lbl.pdf. Accessed March 18, 2017. 57. ZOCOR (simvastatin) Tablets - FDA. Available at: http://www. accessdata.fda.gov/drugsatfda_docs/label/2012/019766s085lbl.pdf. Accessed March 18, 2017. 58. Lescol Label - FDA. Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2012/021192s019lbl.pdf. Accessed March 18, 2017. 59. Plakogiannis R, Cohen H. Optimal low-density lipoprotein cholesterol lowering–morning versus evening statin administration. Ann Pharmacother. 2007;41(1):106–110. 60. Lipitor - FDA. Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2009/020702s057lbl.pdf. Accessed March 18, 2017. 61. Crestor (rosuvastatin calcium) tablets - FDA. Available at: http://www. accessdata.fda.gov/drugsatfda_docs/label/2010/021366s016lbl.pdf. Accessed March 18, 2017. 62. Pravachol Label - FDA. Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2012/019898s062lbl.pdf. Accessed March 18, 2017. 63. Triscari J, Rossi L, Pan HY. Chronokinetics of Pravastatin Administered in the PM Compared with AM Dosing. Am J Ther. 1995;2(4): 265–268.

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1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416 1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446

1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 1501 1502

Q13

14

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64. Mikhailidis DP, Katsiki N, Athyros VG. Adherence to statin treatment: an important issue in clinical practice. Curr Med Res Opin. 2016. 65. Banach M, Stulc T, Dent R, Toth PP. Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement. Int J Cardiol. 2016;225:184–196. 66. Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015;11(1):1–23. 67. Peng JA, Ancock BP, Conell C, Almers LM, Chau Q, Zaroff JG. Nonutilization of Statins in a Community-based Population with a History of Coronary Revascularization. Clin Ther. 2016;38(2):288–296.e2. 68. Wei MY, Ito MK, Cohen JD, Brinton EA, Jacobson TA. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education. J Clin Lipidol. 2013;7(5):472–483. 69. Lewey J, Shrank WH, Bowry ADK, Kilabuk E, Brennan TA, Choudhry NK. Gender and racial disparities in adherence to statin therapy: a meta-analysis. Am Heart J. 2013;165(5):665–678 678.e1. 70. Kaya H, Beton O, Yilmaz MB, et al. How to increase level of patients’ awareness regarding the importance of statins despite the influence of the media? Int J Cardiol. 2016;207:164. 71. Rannanheimo PK, Tiittanen P, Hartikainen J, et al. Impact of Statin Adherence on Cardiovascular Morbidity and All-Cause Mortality in the Primary Prevention of Cardiovascular Disease: A PopulationBased Cohort Study in Finland. Value Health. 2015;18(6):896–905. 72. Corrao G, Scotti L, Zambon A, et al. Cost-effectiveness of enhancing adherence to therapy with statins in the setting of primary cardiovascular prevention. Evidence from an empirical approach based on administrative databases. Atherosclerosis. 2011;217(2):479–485. 73. Shalev V, Goldshtein I, Porath A, Weitzman D, Shemer J, Chodick G. Continuation of statin therapy and primary prevention of nonfatal cardiovascular events. Am J Cardiol. 2012;110(12):1779–1786. 74. Shalev V, Chodick G, Silber H, Kokia E, Jan J, Heymann AD. Continuation of statin treatment and all-cause mortality: a population-based cohort study. Arch Intern Med. 2009;169(3):260–268. 75. Corrao G, Conti V, Merlino L, Catapano AL, Mancia G. Results of a retrospective database analysis of adherence to statin therapy and risk

of nonfatal ischemic heart disease in daily clinical practice in Italy. Clin Ther. 2010;32(2):300–310. Perreault S, Dragomir A, Blais L, et al. Impact of better adherence to statin agents in the primary prevention of coronary artery disease. Eur J Clin Pharmacol. 2009;65(10):1013–1024. Slejko JF, Ho M, Anderson HD, Nair KV, Sullivan PW, Campbell JD. Adherence to statins in primary prevention: yearly adherence changes and outcomes. J Manag Care Pharm. 2014;20(1):51–57. Mengden T, Binswanger B, Sp€uhler T, Weisser B, Vetter W. The use of self-measured blood pressure determinations in assessing dynamics of drug compliance in a study with amlodipine once a day, morning versus evening. J Hypertens. 1993;11(12):1403–1411. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. 2008;336(7653): 1114–1117. Wright DFB, Pavan Kumar VV, Al-Sallami HS, Duffull SB. The influence of dosing time, variable compliance and circadian low-density lipoprotein production on the effect of simvastatin: simulations from a pharmacokinetic-pharmacodynamic model. Basic Clin Pharmacol Toxicol. 2011;109(6):494–498. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med. 2005;165(10):1147–1152. Thom S, Poulter N, Field J, et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD. JAMA. 2013;310(9):918–929. Lafeber M, Grobbee DE, Schrover IM, et al. Comparison of a morning polypill, evening polypill and individual pills on LDL-cholesterol, ambulatory blood pressure and adherence in high-risk patients; a randomized crossover trial. Int J Cardiol. 2015;181:193–199. Faltaos DW, Urien S, Carreau V, et al. Use of an indirect effect model to describe the LDL cholesterol-lowering effect by statins in hypercholesterolaemic patients. Fundam Clin Pharmacol. 2006;20(3): 321–330. Shepherd J. Combined lipid lowering drug therapy for the effective treatment of hypercholesterolaemia. Eur Heart J. 2003;24(8): 685–689.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

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1503 1504 1505 1506 1507 1508 1509 1510 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540 1541 1542 1543 1544 1545 1546 1547 1548 1549 1550 1551 1552 1553 1554 1555 1556 1557 1558

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Figure S1 A forest plot displaying the results of the meta-analysis of morning vs evening statins on total cholesterol with subgrouping according to the design of included studies. CI, confidence interval; df, degrees of freedom; SE, standard error.

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1559 1560 1561 1562 1563 1564 1565 1566 1567 1568 1569 1570 1571 1572 1573 1574 1575 1576 1577 1578 1579 1580 1581 1582 1583 1584 1585 1586 1587 1588 1589 1590 1591 1592 1593 1594 1595 1596 1597 1598 1599 1600 1601 1602 1603 1604 1605 1606 1607 1608 1609 1610 1611 1612 1613 1614

Morning vs evening statins for lipid profile

Figure S2 A forest plot displaying the results of the meta-analysis of morning vs evening statins on high-density lipoprotein cholesterol with subgrouping according to the design of included studies. CI, confidence interval; df, degrees of freedom; SE, standard error. FLA 5.4.0 DTD  JACL1129_proof  24 June 2017  3:40 pm

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Figure S3 A forest plot displaying the results of the meta-analysis of morning vs evening statins on triglycerides with subgrouping according to the design of included studies. CI, confidence interval; df, degrees of freedom; SE, standard error.

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Figure S4 A forest plot displaying the results of the meta-analysis of morning vs evening statins on low-density lipoprotein cholesterol with subgrouping according to the design of included studies. CI, confidence interval; df, degrees of freedom; SE, standard error. FLA 5.4.0 DTD  JACL1129_proof  24 June 2017  3:40 pm

1727 1728 1729 1730 1731 1732 1733 1734 1735 1736 1737 1738 1739 1740 1741 1742 1743 1744 1745 1746 1747 1748 1749 1750 1751 1752 1753 1754 1755 1756 1757 1758 1759 1760 1761 1762 1763 1764 1765 1766 1767 1768 1769 1770 1771 1772 1773 1774 1775 1776 1777 1778 1779 1780 1781 1782

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1783 1784 1785 1786 1787 1788 1789 1790 1791 1792 1793 1794 1795 1796 1797 1798 1799 1800 1801 1802 1803 1804 1805 1806 1807 1808 1809 1810 1811 1812 1813 1814 1815 1816 1817 1818 1819 1820 1821 1822 1823 1824 1825 1826 1827 1828 1829 1830 1831 1832 1833 1834 1835 1836 1837 1838

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Figure S7 A funnel plot displaying publication bias in the studies that compared the effects of morning vs evening statins on triglycerides. MD, mean difference; SE, standard error.

Figure S6 A funnel plot displaying publication bias in the studies that compared the effects of morning vs evening statins on low-density lipoprotein cholesterol. MD, mean difference; SE, standard error.

Figure S8 A funnel plot of the studies that compared the effects of morning vs evening statins on high-density lipoprotein cholesterol. MD, mean difference; SE, standard error.

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Figure S5 A funnel plot displaying publication bias in the studies that compared the effects of morning vs evening statins on total cholesterol. MD, mean difference; SE, standard error.

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1839 1840 1841 1842 1843 1844 1845 1846 1847 1848 1849 1850 1851 1852 1853 1854 1855 1856 1857 1858 1859 1860 1861 1862 1863 1864 1865 1866 1867 1868 1869 1870 1871 1872 1873 1874 1875 1876 1877 1878 1879 1880 1881 1882 1883 1884 1885 1886 1887 1888 1889 1890 1891 1892 1893 1894

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14.e4 1895 1896 1897 1898 1899 1900 1901 1902 1903 1904 1905 1906 1907 1908 1909 1910 1911 1912 1913 1914 1915 1916 1917 1918 1919 1920 1921 1922 1923 1924 1925 1926 1927 1928 1929 1930 1931 1932 1933 1934 1935 1936 1937 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 1948 1949 1950

Table S1

Q7

Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) checklist

Section/topic

#

Checklist item

Reported on page#

LE Title

1

Identify the report as a systematic review, meta-analysis or both.

1

Abstract Structured summary

2

Provide a structured summary, including, as applicable: background; objectives; data sources; study eligibility criteria; participants and interventions; study appraisal and synthesis methods, results, limitations, conclusions and implications of key findings; and systematic review registration number.

2

Introduction Rationale

3

3, 4

Objectives

4

Describe the rationale for the review in the context of what is already known. Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes and study design (PICOS). Indicate if a review protocol exists, if and where it can be accessed (eg, web address), and if available, provide registration information, including the registration number. Specify study characteristics (eg, PICOS and length of follow-up) and report characteristics (eg, years considered, language, and publication status) used as criteria for eligibility, giving the rationale. Describe all information sources (eg, databases with dates of coverage and contact with study authors to identify additional studies) in the search and date last searched. Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. State the process for selecting studies (ie, screening, eligibility, included in systematic review, and if applicable, included in the meta-analysis). Describe the method of data extraction from reports (eg, piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. List and define all variables for which data were sought (eg, PICOS and funding sources) and any assumptions and simplifications made. Describe the methods used for assessing the risk of bias of individual studies (including specification of whether this was done at the study or outcome level) and how this information is to be used in any data synthesis. State the principal summary measures (eg, risk ratio, difference in means). Describe the methods of handling data and combining the results of studies, if done, including measures of consistency (eg, Item 2) for each meta-analysis. Specify any assessment of the risk of bias that may affect the cumulative evidence (eg, publication bias and selective reporting within studies). Describe methods of additional analyses (eg, sensitivity or subgroup analyses and meta-regression), if done, indicating which were prespecified.

4

Methods Protocol and registration

5

Eligibility criteria

6

Information sources

7

Search

8

Study selection

9

Data collection process

10

Data items

11

Risk of bias in individual studies

12

Summary measures

13

Synthesis of results

14

Risk of bias across studies

15

Additional analyses

16

4

5, 6

5

5 5, 6

6

6

9, 10

7 7, 8, 9

9

8

(continued on next page)

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Q8

1951 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Awad et al 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 2051 2052 2053 2054 2055 2056 2057 2058 2059 2060 2061 2062

Table S1

Morning vs evening statins for lipid profile (continued )

Section/topic

#

Checklist item

Results Study selection

17

Give numbers of studies screened, assessed for eligibility and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. For each study, present characteristics for which data were extracted (eg, study size, PICOS, follow-up period) and provide the citations. Present data on the risk of bias of each study and, if available, any outcome level assessment (see Item 12). For all outcomes considered (benefits or harms), present, for each study: (1) simple summary data for each intervention group and (2) effect estimates and confidence intervals, ideally with a forest plot. Present results of each meta-analysis done, including confidence intervals and measures of consistency. Present results of any assessment of the risk of bias across studies (see Item 15). Give results of additional analyses, if done (eg, sensitivity or subgroup analyses and meta-regression [see Item 16]).

Study characteristics

18

Risk of bias within studies

19

Results of individual studies

20

Synthesis of results

21

Risk of bias across studies

22

Additional analysis

23

Discussion Summary of evidence

24

Limitations

25

Conclusions

26

Funding Funding

14.e5

27

Reported on page# 10

12

17 17

20, 24 17 26

Summarize the main findings, including the strength of evidence for each main outcome; consider their relevance to key groups (eg, health care providers, users, and policy makers). Discuss limitations at the study and outcome level (eg, the risk of bias) and at the review level (eg, incomplete retrieval of identified research and reporting bias). Provide a general interpretation of the results in the context of other evidence and implications for future research.

27, 28, 29

Describe sources of funding for the systematic review and other support (eg, supply of data) and the role of funders in the systematic review.

—

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29, 30

30

2063 2064 2065 2066 2067 2068 2069 2070 2071 2072 2073 2074 2075 2076 2077 2078 2079 2080 2081 2082 2083 2084 2085 2086 2087 2088 2089 2090 2091 2092 2093 2094 2095 2096 2097 2098 2099 2100 2101 2102 2103 2104 2105 2106 2107 2108 2109 2110 2111 2112 2113 2114 2115 2116 2117 2118

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14.e6 2119 2120 2121 2122 2123 2124 2125 2126 2127 2128 2129 2130 2131 2132 2133 2134 2135 2136 2137 2138 2139 2140 2141 2142 2143 2144 2145 2146 2147 2148 2149 2150 2151 2152 2153 2154 2155 2156 2157 2158 2159 2160 2161 2162 2163 2164 2165 2166 2167 2168 2169 2170 2171 2172 2173 2174

Table S2 Leave-one-out sensitivity analysis for the overall pool analysis and for the pooled analysis of each subgroup (in term of total cholesterol) Excluded study Q9

Pooled MD

LCI 95%

Overall pooled analysis Hunninghake et al 1.639645 20.3733 Illingworth et al 1.614305 20.39596 Kim et al 1.588973 20.45405 Kruse et al 1.667263 20.34078 Martin et al 3.508938 20.01515 Ozaydin et al 1.986503 20.13304 Plakogiannis et al 1.655563 20.38433 Saito et al (2.5 mg) 1.664274 20.3509 Saito et al (5 mg) 1.709452 20.30654 Scharnagl et al 1.855404 20.19838 Wallace et al 0.831849 21.23993 Yi et al 1.645168 20.38788 Pooled analysis of ‘‘short half-lives’’ subgroup Hunninghake et al 12.31529 5.239881 Illingworth et al 11.66971 4.708457 Kruse et al 12.03049 5.159567 Saito et al (2.5 mg) 12.92683 5.752888 Saito et al (5 mg) 13.62119 6.410284 Wallace et al 5.707825 27.03512 Pooled analysis of ‘‘long half-lives’’ subgroup Kim et al 0.562186 21.57831 Martin et al 0.414787 23.69527 Ozaydin et al 0.915169 21.31382 Plakogiannis et al 0.638705 21.49819 Scharnagl et al 0.843026 21.30986 Yi et al 0.634778 21.49425

HCI 95% 3.652594 3.624565 3.631994 3.675309 7.033025 4.106048 3.695457 3.679449 3.72544 3.90919 2.903629 3.678216 19.39071 18.63097 18.90142 20.10078 20.8321 18.45077 2.702678 4.52484 3.144161 2.775603 2.995909 2.763809

P value

Cochran Q

c2

I2

.11 .12 .13 .1 .05 .07 .11 .11 .1 .08 .43 .11

13.73953 12.57146 13.79402 13.7776 12.47714 13.22526 13.99431 13.98342 13.90668 13.37512 3.499602 13.9678

0.185207 0.248628 0.182596 0.18338 0.254391 0.211349 0.173251 0.173749 0.177291 0.203448 0.967112 0.174465

27.21731 20.45473 27.50482 27.4184 19.85341 24.38712 28.54241 28.48672 28.09211 25.23433 0 28.40677

.0006 .001 .0006 .0004 .0002 .38*

2.984933 2.587934 2.983631 2.465453 1.296348 1.682909

0.56035 0.628962 0.560568 0.650832 0.861995 0.79382

0 0 0 0 0 0

.61 .84 .42 .56 .44 .56

0.820276 1.21404 0.919567 1.148953 0.888797 1.109318

0.935709 0.875782 0.921737 0.88643 0.926163 0.892791

0 0 0 0 0 0

MD, mean difference. *P value . .05.

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2175 2176 2177 2178 2179 2180 2181 2182 2183 2184 2185 2186 2187 2188 2189 2190 2191 2192 2193 2194 2195 2196 2197 2198 2199 2200 2201 2202 2203 2204 2205 2206 2207 2208 2209 2210 2211 2212 2213 2214 2215 2216 2217 2218 2219 2220 2221 2222 2223 2224 2225 2226 2227 2228 2229 2230

Awad et al 2231 2232 2233 2234 2235 2236 2237 2238 2239 2240 2241 2242 2243 2244 2245 2246 2247 2248 2249 2250 2251 2252 2253 2254 2255 2256 2257 2258 2259 2260 2261 2262 2263 2264 2265 2266 2267 2268 2269 2270 2271 2272 2273 2274 2275 2276 2277 2278 2279 2280 2281 2282 2283 2284 2285 2286

Morning vs evening statins for lipid profile

14.e7

Table S3 Leave-one-out sensitivity analysis for the overall pool analysis and for the pooled analysis of each subgroup (in term of lowdensity lipoprotein) Excluded study

Pooled MD

LCI 95%

Overall pooled analysis Hunninghake et al 3.220151 1.205328 Illingworth et al 3.19166 1.179368 Kim et al 3.053291 0.981325 Kruse et al 3.233151 1.223283 Martin et al 3.40358 0.962909 Ozaydin et al 3.323991 0.995656 Plakogiannis et al 3.54979 1.369906 Saito et al (2.5 mg) 3.150155 1.13332 Saito et al (5 mg) 3.248012 1.230815 Scharnagl et al 3.427401 1.34598 Wallace et al 2.72186 0.633112 Yi et al 3.463271 1.408583 Pooled analysis of ‘‘short half-lives’’ subgroup Hunninghake et al 9.838183 3.293752 Illingworth et al 9.373416 2.914192 Kruse et al 9.641569 3.261185 Saito et al (2.5 mg) 9.227573 2.613186 Saito et al (5 mg) 10.30737 3.680167 Wallace et al 9.700178 22.97901 Pooled analysis of ‘‘long half-lives’’ subgroup Kim et al 2.266147 0.0745 Martin et al 2.319186 20.32406 Ozaydin et al 2.339901 20.16231 Plakogiannis et al 2.733465 0.412879 Scharnagl et al 2.677115 0.474269 Yi et al 2.738552 0.567324

HCI 95% 5.234974 5.203952 5.125257 5.243019 5.84425 5.652326 5.729674 5.166991 5.26521 5.508821 4.810608 5.517958 16.38261 15.83264 16.02195 15.84196 16.93457 22.37936 4.457794 4.962433 4.842111 5.054051 4.87996 4.90978

P value

Cochran Q

c2

I2

.002 .002 .004 .002 .006 .005 .001 .002 .002 .001 .01 .001

7.169745 6.500771 6.715185 7.159161 7.191694 7.225415 6.733135 6.216417 7.238995 6.794218 4.068073 6.221503

0.709329 0.771584 0.752032 0.710339 0.707232 0.704007 0.750376 0.796765 0.702706 0.744719 0.944224 0.796323

0 0 0 0 0 0 0 0 0 0 0 0

.003 .004 .003 .006 .002 .13*

0.8875 0.661489 0.914397 0.698359 0.492566 0.929413

0.926347 0.955992 0.922486 0.951531 0.974221 0.920304

0 0 0 0 0 0

.04 .09* .07* .02 .02 .01

1.121288 1.876143 1.866715 1.761074 1.70792 1.19535

0.89088 0.758526 0.760257 0.779596 0.789278 0.878864

0 0 0 0 0 0

MD, mean difference. *P value . .05.

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Q10

2287 2288 2289 2290 2291 2292 2293 2294 2295 2296 2297 2298 2299 2300 2301 2302 2303 2304 2305 2306 2307 2308 2309 2310 2311 2312 2313 2314 2315 2316 2317 2318 2319 2320 2321 2322 2323 2324 2325 2326 2327 2328 2329 2330 2331 2332 2333 2334 2335 2336 2337 2338 2339 2340 2341 2342

Journal of Clinical Lipidology, Vol -, No -, - 2017

14.e8 2343 2344 2345 2346 2347 2348 2349 2350 2351 2352 2353 2354 2355 2356 2357 2358 2359 2360 2361 2362 2363 2364 2365 2366 2367 2368 2369 2370 2371 2372 2373 2374 2375 2376 2377 2378 2379 2380 2381 2382 2383 2384 2385 2386 2387 2388 2389 2390 2391 2392 2393 2394 2395 2396 2397 2398

Table S4 Leave-one-out sensitivity analysis for the overall pool analysis and for the pooled analysis of each subgroup (in term of high-density lipoprotein) Excluded study

Pooled MD

Overall pooled analysis Hunninghake et al 0.097661 Illingworth et al 0.037208 Kim et al 0.084814 Kruse et al 0.056598 Martin et al 0.15672 Ozaydin et al 0.130141 Plakogiannis et al 0.038841 Saito et al (2.5 mg) 0.066598 Saito et al (5 mg) 0.053105 Scharnagl et al 20.0053 Wallace et al 20.07731 Yi et al 20.00426 Pooled analysis of ‘‘short half-lives’’ subgroup Hunninghake et al 0.567411 Illingworth et al 0.227211 Kruse et al 0.331697 Saito et al (2.5 mg) 0.370252 Saito et al (5 mg) 0.30954 Wallace et al 20.84448 Pooled analysis of ‘‘long half-lives’’ subgroup Kim et al 0.026974 Martin et al 0.120814 Ozaydin et al 20.06304 Plakogiannis et al 20.03232 Scharnagl et al 20.08849 Yi et al 20.08582

LCI 95%

HCI 95%

P value

Cochran Q

c2

I2

20.73815 20.7883 20.75761 20.77301 20.67614 21.19489 20.80351 20.76009 20.77486 20.84463 20.97071 20.83832

0.933471 0.862716 0.927236 0.886205 0.98958 1.455175 0.881195 0.893288 0.881067 0.834028 0.816097 0.829813

.82 .93 .84 .89 .71 .85 .93 .87 .90 .99 .87 .99

4.924614 5.134502 5.206319 5.337378 2.490382 5.330249 5.336799 5.147046 5.348678 4.896694 4.830562 4.689077

0.896157 0.882014 0.876976 0.867532 0.991015 0.868054 0.867575 0.881141 0.866703 0.897971 0.902205 0.910957

0 0 0 0 0 0 0 0 0 0 0 0

21.34142 21.56768 21.50654 21.43688 21.511 24.07477

2.476243 2.0221 2.169932 2.177384 2.13008 2.385804

.56 .80 .72 .69 .74 .61

0.603747 1.046869 1.196301 0.976842 1.219549 0.562907

0.962646 0.902608 0.878707 0.913287 0.87487 0.967095

0 0 0 0 0 0

20.92989 20.82211 22.05249 20.98909 21.04083 21.0305

0.983841 1.063738 1.926415 0.924444 0.863846 0.858856

.96 .8 .95 .95 .86 .86

3.908778 1.229912 4.030023 4.007156 3.530251 3.324047

0.418492 0.87315 0.401958 0.405038 0.473294 0.505131

0 0 0.744982 0.17857 0 0

MD, mean difference.

FLA 5.4.0 DTD  JACL1129_proof  24 June 2017  3:40 pm

2399 2400 2401 2402 2403 2404 2405 2406 2407 2408 2409 2410 2411 2412 2413 2414 2415 2416 2417 2418 2419 2420 2421 2422 2423 2424 2425 2426 2427 2428 2429 2430 2431 2432 2433 2434 2435 2436 2437 2438 2439 2440 2441 2442 2443 2444 2445 2446 2447 2448 2449 2450 2451 2452 2453 2454

Awad et al 2455 2456 2457 2458 2459 2460 2461 2462 2463 2464 2465 2466 2467 2468 2469 2470 2471 2472 2473 2474 2475 2476 2477 2478 2479 2480 2481 2482 2483 2484 2485 2486 2487 2488 2489 2490 2491 2492 2493 2494 2495 2496 2497 2498 2499 2500 2501 2502 2503 2504 2505 2506 2507 2508 2509 2510

Morning vs evening statins for lipid profile

14.e9

Table S5 Leave-one-out sensitivity analysis for the overall pool analysis and for the pooled analysis of each subgroup (in term of triglycerides) Excluded study

Pooled MD

LCI 95%

Overall pooled analysis Hunninghake et al 1.09443 23.31862 Illingworth et al 1.672325 22.67982 Kim et al 1.899027 22.51445 Kruse et al 1.514959 22.82664 Martin et al 20.6354 26.06043 Ozaydin et al 2.125497 23.54235 Plakogiannis et al 1.634852 22.72546 Saito et al (2.5 mg) 2.132149 22.22254 Saito et al (5 mg) 2.023314 22.34465 Scharnagl et al 2.591394 21.86385 Wallace et al 1.559511 22.80743 Yi et al 1.694942 22.70717 Pooled analysis of ‘‘short half-lives’’ subgroup Hunninghake et al 29.66172 228.4155 Illingworth et al 1.077419 214.1893 Kruse et al 20.72496 215.5545 Saito et al (2.5 mg) 6.802614 28.57483 Saito et al (5 mg) 5.725742 210.269 Wallace et al 20.48057 216.4253 Pooled analysis of ‘‘long half-lives’’ subgroup Kim et al 1.993442 22.63959 Martin et al 20.89683 26.74615 Ozaydin et al 2.333028 23.82406 Plakogiannis et al 1.700553 22.8711 Scharnagl et al 2.759873 21.92155 Yi et al 1.768129 22.85176

P value

Cochran Q

c2

I2

5.507482 6.024471 6.312503 5.856562 4.789637 7.793343 5.995167 6.486835 6.391278 7.046638 5.926452 6.097055

.63 .45 .40 .49 .82 .46 .46 .34 .36 .25 .48 .25

11.96232 13.7061 13.39242 12.62002 11.81464 13.64807 13.70232 9.057937 12.00965 10.58706 13.58395 13.70222

0.287586 0.186824 0.202551 0.2457 0.297654 0.189658 0.187008 0.526614 0.284411 0.390581 0.192829 0.187012

16.40418 27.0398 25.33088 20.7608 15.35923 26.72955 27.01967 0 16.73363 5.545045 26.3837 27.01914

9.092059 16.34414 14.10455 22.18006 21.7205 15.46415

.31 .89 .92 .39 .48 .95

6.099223 9.174397 7.998801 4.147322 7.261873 8.990604

0.19186 0.056885 0.091622 0.386435 0.12268 0.061335

34.41787 56.40041 49.99251 3.55221 44.91779 55.50911

6.626473 4.952485 8.490113 6.272201 7.44129 6.388022

.40 .76 .46 .47 .25 .45

4.198927 2.583499 4.443219 4.517289 1.358042 4.515501

0.379753 0.629749 0.349333 0.340502 0.851454 0.340713

4.737575 0 9.975174 11.45131 0 11.41626

HCI 95%

MD, mean difference.

FLA 5.4.0 DTD  JACL1129_proof  24 June 2017  3:40 pm

2511 2512 2513 2514 2515 2516 2517 2518 2519 2520 2521 2522 2523 2524 2525 2526 2527 2528 2529 2530 2531 2532 2533 2534 2535 2536 2537 2538 2539 2540 2541 2542 2543 2544 2545 2546 2547 2548 2549 2550 2551 2552 2553 2554 2555 2556 2557 2558 2559 2560 2561 2562 2563 2564 2565 2566