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


Kamal Awad | Maria-Corina Serban | Peter Penson | Dimitri P. Mikhailidis | Peter P. Toth | Steven R. Jones | Manfredi Rizzo | George Howard | Gregory Y.H. Lip | Maciej Banach | Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group
First published: June 14, 2017 | https://doi.org/10.1016/j.jacl.2017.06.001



Evidence about the optimal time of day at which to administer statins is lacking.


The objective of this study is to synthesize evidence about effects of morning vs evening statin administration on lipid profile.


We searched PubMed, SCOPUS, Web of Science, and Embase databases (from inception up to July 24, 2016) to identify the relevant studies. Mean differences (MDs) between the change scores in lipid parameters were pooled using a fixed-effect model.


Eleven articles with 1034 participants were eligible for the analysis. The pooled analysis comparing effects of morning vs evening administration of statins on plasma total cholesterol (TC; P = .10), high-density lipoprotein cholesterol (P = .90), and triglycerides (P = .45) was not statistically significant. Low-density lipoprotein cholesterol (LDL-C) lowering was statistically greater in the evening-dose group (MD: 3.24 mg/dL, 95% CI: 1.23–5.25, P = .002). Subgroup analysis according 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, P = .003 and MD: 2.53 mg/dL, 95% CI: 0.41–4.64, P = .02, respectively) and also for TC reduction in case of short half-life statins only (P = .0005).


LDL-C and TC lowering was 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.

  1. Barquera S., Pedroza-Tobías A., Medina C., et al.
    Global Overview of the Epidemiology of Atherosclerotic Cardiovascular Disease.
    Arch Med Res. 2015; 46: 328-338
  2. Calderon R.M., Cubeddu L.X.
    Goldberg R.B., Schiff E.R.
    Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma.
    Mayo Clin Proc. 2010; 85: 349-356
  3. The Lipid Research Clinics Coronary Primary Prevention Trial Results II
    The Relationship of Reduction in Incidence of Coronary Heart Disease to Cholesterol Lowering.
    JAMA. 1984; 251: 365-374
  4. The Lipid Research Clinics Coronary Primary Prevention Trial Results I
    Reduction in Incidence of Coronary Heart Disease.
    JAMA. 1984; 251: 351-364
  5. Lowering Blood Cholesterol to Prevent Heart Disease.
    JAMA. 1985; 253: 2080
  6. Kannel W.B., Castelli W.P.
    Gordon T., McNamara P.M.
    Serum cholesterol, lipoproteins, and the risk of coronary heart disease. The Framingham study.
    Ann Intern Med. 1971; 74: 1-12
  7. Pedersen T.R., Glsson A.G.
    Faergeman O., et al.
    Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S).
    Circulation. 1998; 97: 1453-1460
  8. Mabuchi H., Kita T., Matsuzaki M., et al.
    Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in japanese patients with hypercholesterolemia and coronary heart disease.
    Circ J. 2002; 66: 1096-1100
  9. Sacks F.M., Pfeffer M.A., Moye L.A., et al.
    The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.
    N Engl J Med. 1996; 335: 1001-1009
  10. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
    Lancet. 1994; 344: 1383-1389
  11. Perk J., De Backer G.
    Gohlke H., et al.
    European Guidelines on cardiovascular disease prevention in clinical practice (version 2012).
    Atherosclerosis. 2012; 223: 1-68
  12. De Angelis G.
    The influence of statin characteristics on their safety and tolerability.
    Int J Clin Pract. 2004; 58: 945-955
  13. Taylor F., Huffman M.D., Macedo A.F., et al.
    Statins for the primary prevention of cardiovascular disease.
    in: Huffman M.D. Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd, Chichester, UK2013: CD004816
  14. Huang W.-C., Lin T.-W., Chiou K.-R., et al.
    The effect of intensified low density lipoprotein cholesterol reduction on recurrent myocardial infarction and cardiovascular mortality.
    Acta Cardiol Sin. 2013; 29: 404-412
  15. Odden M.C., Pletcher M.J., Coxson P.G., et al.
    Cost-effectiveness and population impact of statins for primary prevention in adults aged 75 years or older in the United States.
    Ann Intern Med. 2015; 162: 533-541
  16. Cheung B.M.Y., Lauder I.J., Lau C.-P., Kumana C.R.
    Meta-analysis of large randomized controlled trials to evaluate the impact of statins on cardiovascular outcomes.
    Br J Clin Pharmacol. 2004; 57: 640-651
  17. Pyörälä K., Ballantyne C.M., Gumbiner B., et al.
    Reduction of cardiovascular events by simvastatin in nondiabetic coronary heart disease patients with and without the metabolic syndrome: subgroup analyses of the Scandinavian Simvastatin Survival Study (4S).
    Diabetes Care. 2004; 27: 1735-1740
  18. Morales D., Chung N., Zhu J.-R., et al.
    Efficacy and safety of simvastatin in Asian and non-Asian coronary heart disease patients: a comparison of the GOALLS and STATT studies.
    Curr Med Res Opin. 2004; 20: 1235-1243
  19. Shepherd J., Cobbe S.M., Ford I., et al.
    Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.
    N Engl J Med. 1995; 333: 1301-1308
  20. Group TL-TI with P in ID (LIPID) S
    Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
    N Engl J Med. 1998; 339: 1349-1357
  21. Baigent C., Blackwell L., Emberson J., et al.
    Cholesterol Treatment Trialists’ (CTT) Collaboration
    Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
    Lancet. 2010; 376: 1670-1681
  22. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults E and T of HBC in A
    Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
    JAMA. 2001; 285: 2486-2497
  23. Parker T.S., McNamara D.J., Brown C., et al.
    Mevalonic acid in human plasma: relationship of concentration and circadian rhythm to cholesterol synthesis rates in man.
    Proc Natl Acad Sci U S A. 1982; 79: 3037-3041
  24. Parker T.S., McNamara D.J., Brown C.D., et al.
    Plasma mevalonate as a measure of cholesterol synthesis in man.
    J Clin Invest. 1984; 74: 795-804
  25. Jones P.J., Schoeller D.A.
    Evidence for diurnal periodicity in human cholesterol synthesis.
    J Lipid Res. 1990; 31: 667-673
  26. Munger M.A., Van Tassell B.W., LaFleur J.
    Medication nonadherence: an unrecognized cardiovascular risk factor.
    MedGenMed. 2007; 9: 58
  27. Tsai K.-T., Chen J.-H., Wen C.-J., et al.
    Medication adherence among geriatric outpatients prescribed multiple medications., Am J Geriatr Pharmacother. 2012; 10: 61-68
  28. Williams B., Shaw A., Durrant R., Crinson I., Pagliari C., de Lusignan S.
    Patient perspectives on multiple medications versus combined pills: a qualitative study.
    QJM. 2005; 98: 885-893
  29. Corsini A.
    The safety of HMG-CoA reductase inhibitors in special populations at high cardiovascular risk.
    Cardiovasc Drugs Ther. 2003; 17: 265-285
  30. Kiortsis D.N., Giral P., Bruckert E., Turpin G.
    Factors associated with low compliance with lipid-lowering drugs in hyperlipidemic patients.
    J Clin Pharm Ther. 2000; 25: 445-451
  31. Walter P., Arnet I., Romanens M., Tsakiris D.A., Hersberger K.E.
    Pattern of timing adherence could guide recommendations for personalized intake schedules.
    J Pers Med. 2012; 2: 267-276
  32. Cutler D.M., Everett W.
    Thinking outside the pillbox — medication adherence as a priority for health care reform.
    N Engl J Med. 2010; 362: 1553-1555
  33. Parris E.S., Lawrence D.B., Mohn L.A., Long L.B.
    Adherence to statin therapy and LDL cholesterol goal attainment by patients with diabetes and dyslipidemia.
    Diabetes Care. 2005; 28: 595-599
  34. Moher D., Liberati A., Tetzlaff J.
    Altman D.G., PRISMA Group
    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
    BMJ. 2009; 339: b2535
  35. Balk E.M., Earley A., Patel K., Trikalinos T.A., Dahabreh I.J.
    Empirical Assessment of Within-Arm Correlation Imputation in Trials of Continuous Outcomes.
    Agency for Healthcare Research and Quality (Rockville, MD, US), 2012
  36. Follmann D., Elliott P., Suh I., Cutler J.
    Variance imputation for overviews of clinical trials with continuous response.
    J Clin Epidemiol. 1992; 45: 769-773
  37. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Agency for Healthcare Research and Quality (Rockville, MD, US), 2008
  38. Hozo S.P., Djulbegovic B., Hozo I., et al.
    Estimating the mean and variance from the median, range, and the size of a sample.
    BMC Med Res Methodol. 2005; 5: 13
  39. Altman D.G., Bland J.M.
    Standard deviations and standard errors.
    BMJ. 2005; 331: 903
  40. Schachter M.
    Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update.
    Fundam Clin Pharmacol. 2005; 19: 117-125
  41. Jang S.B., Lee Y.J., Lim L.A., et al.
    Pharmacokinetic comparison of controlled-release and immediate-release oral formulations of simvastatin in healthy Korean subjects: a randomized, open-label, parallel-group, single- and multiple-dose study.
    Clin Ther. 2010; 32: 206-216
  42. Barilla D., Prasad P., Hubert M., Gumbhir-Shah K.
    Steady-state pharmacokinetics of fluvastatin in healthy subjects following a new extended release fluvastatin tablet, Lescol XL.
    Biopharm Drug Dispos. 2004; 25: 51-59
  43. Wells G, Shea B, Peterson J, Welch V, Losos M. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. medicine.mcgill.ca.
  44. Egger M., Davey Smith G., Schneider M., Minder C.
    Bias in meta-analysis detected by a simple, graphical test.
    BMJ. 1997; 315: 629-634
  45. Hunninghake D.B., Mellies M.J., Goldberg A.C.
    Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. II. Once-daily versus twice-daily dosing.
    Atherosclerosis. 1990; 85: 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: 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: 211-215
  48. Martin P.D., Mitchell P.D., Schneck D.W.
    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: 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: 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: 816-826
  51. Scharnagl H., Vogel M., Abletshauser C., Freisinger F., Stojakovic T., März W.
    Efficacy and safety of fluvastatin-extended release in hypercholesterolemic patients: morning administration is equivalent to evening administration.
    Cardiology. 2006; 106: 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: 788
  53. Yi Y.J., Kim H.J., Jo S.K., 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: 1182-1190
  54. Illingworth D.R.
    Comparative efficacy of once versus twice daily mevinolin in the therapy of familial hypercholesterolemia.
    Clin Pharmacol Ther. 1986; 40: 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: 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.f. 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: 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 H.Y.
    Chronokinetics of Pravastatin Administered in the PM Compared with AM Dosing.
    Am J Ther. 1995; 2: 265-268
  64. Mikhailidis D.P., Katsiki N., Athyros V.G.
    Adherence to statin treatment: an important issue in clinical practice.
    Curr Med Res Opin. 2016; 32: 1639-1640
  65. Banach M., Stulc T., Dent R., Toth P.P.
    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 P.P., et al.
    Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel.
    Arch Med Sci. 2015; 11: 1-23
  67. Peng J.A., Ancock B.P., Conell C., Almers L.M., Chau Q., Zaroff J.G.
    Nonutilization of Statins in a Community-based Population with a History of Coronary Revascularization.
    Clin Ther. 2016; 38: 288-296.e2
  68. Wei M.Y., Ito M.K., Cohen J.D., Brinton E.A., Jacobson T.A.
    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: 472-483
  69. Lewey J., Shrank W.H., Bowry A.D.K. ,Kilabuk E., Brennan T.A., Choudhry N.K.
    Gender and racial disparities in adherence to statin therapy: a meta-analysis.
    Am Heart J. 2013; 165 (678.e1): 665-678
  70. Kaya H., Beton O., Yilmaz M.B., 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 P.K., 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 Population-Based Cohort Study in Finland.
    Value Health. 2015; 18: 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: 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: 1779-1786
  74. Shalev V., Chodick G., Silber H., Kokia E., Jan J., Heymann A.D.
    Continuation of statin treatment and all-cause mortality: a population-based cohort study.
    Arch Intern Med. 2009; 169: 260-268
  75. Corrao G., Conti V., Merlino L., Catapano A.L., 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: 300-310
  76. 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: 1013-1024
  77. Slejko J.F., Ho M., Anderson H.D., Nair K.V., Sullivan P.W., Campbell J.D.
    Adherence to statins in primary prevention: yearly adherence changes and outcomes.
    J Manag Care Pharm. 2014; 20: 51-57
  78. Mengden T., Binswanger B., Spühler 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: 1403-1411
  79. 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: 1114-1117
  80. Wright D.F.B., Pavan Kumar V.V., Al-Sallami H.S., Duffull S.B.
    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: 494-498
  81. Chapman R.H., Benner J.S., Petrilla A.A., et al.
    Predictors of adherence with antihypertensive and lipid-lowering therapy.
    Arch Intern Med. 2005; 165: 1147-1152
  82. 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: 918-929
  83. Lafeber M., Grobbee D.E., Schrover I.M., 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
  84. Faltaos D.W., 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: 321-330
  85. Shepherd J.
    Combined lipid lowering drug therapy for the effective treatment of hypercholesterolaemia.
    Eur Heart J. 2003; 24: 685-689