Regular dosing of a prescribed statin is important to its effective use. The recommended timing of the dose varies somewhat from one statin to another.1-14
Package inserts give specific guidance for simvastatin to be given in the evening.3 Immediate-release lovastatin should be taken with the evening meal and extended-release lovastatin should be taken at bedtime.4 Immediate-release fluvastatin should be taken one to two times a day if the goal is to reduce low-density lipoprotein cholesterol (LDL-C) by 25% or more; if the goal is to reduce LDL-C by less than 25%, immediate-release fluvastatin should be taken once in the evening.5 Extended-release fluvastatin can be taken once daily at any time.
The evidence for the difference in efficacy between morning and evening dosing is limited. Cholesterol synthesis reaches its peak overnight. Some evidence from small studies suggests short-acting statins like immediate-release simvastatin, lovastatin, and fluvastatin may have better lipid-lowering effects when given in the evening.15 A meta-analysis conducted by the Lipid and Blood Pressure Meta-analysis Collaboration (n=1,034) analyzed data according to the elimination half-life of the statins and found the mean difference in evening versus morning dosing of short-acting statins (lovastatin, simvastatin, pravastatin, and immediate-release fluvastatin) was 9.68 mg/dl (95% confidence interval [CI] [3.32 – 16.03], p=0.003), supporting evening dosing.16 By contrast, a Cochrane meta-analysis of eight randomized controlled trials (RCTs) (n=767) that compared morning and evening dosing of statins found no significant difference in lipid-lowering effects (mean difference in LDL-C = 4.85 mg/dL, 95% CI [-0.87 – 10.57]).17
Data from smaller RCTs summarized below is less consistent and, in some cases, limited by the study size.
Simvastatin:
Three RCTs (total n=257) demonstrated significantly better reductions in LDL-C when immediate-release simvastatin was given in the evening compared to morning dosing,18-20 while one (n=52) did not.21 Two studies (total n=254) comparing morning versus evening dosing of extended-release simvastatin showed no significant difference in their lipid-lowering effects.22-23
Lovastatin:
Two RCTs (n=24 and n=96) analyzed the lipid-lowering effect of lovastatin given in the evening versus the morning.24-25 The difference in lipid-lowering effects between the two dosage times were not statistically significant, and in one study,24 the compliance was superior in the morning dosing group.
Extended-Release Fluvastatin:
Scharnagl et al. conducted an RCT (n=236) comparing lipid-lowering effects of evening versus morning dosing of extended-release fluvastatin.26 After eight weeks of study, LDL-C reductions were similar in both groups (34.5% versus 35% reduction). A nonsignificant increased rate of adverse effects was seen in the evening (35%) versus the morning (27.4%) group.
Atorvastatin:
Ozaydin et al. conducted an RCT that compared morning and evening dosing of atorvastatin, following 152 patients with single vessel disease for 12 months.27 Approximately half were given morning dosing and the other half evening dosing, starting with 40 mg for the first month, then continuing with 10 mg thereafter. After six months, the LDL-C reductions in the evening group were slightly but significantly higher than the reductions in the morning group (51 mg/dL reduction versus 48.2 mg/dL; p<0.05). At 12 months, the evening dose was associated with a lower re-stenosis rate (relative risk [RR] = 0.14, 95% CI [0.05 – 0.34]; p<0.0001) and fewer major cardiac events. Although this small study offers insight into possible pharmacokinetic effects of dosage timing for atorvastatin, the authors point out its limitations. In addition to its small size, it was not placebo-controlled or double-blinded, and despite its randomization, the individuals in the morning group were more likely to smoke prior to their first cardiac event and had higher hs-CRP levels and lower HDL-C levels, which may have influenced these outcomes.
Pravastatin:
Hunninghake et al. compared the efficacy of pravastatin 40 mg taken in the morning and the evening in an RCT of eight weeks’ duration (n=91).28 The evening dosing was slightly but not significantly more effective than the morning dose in its lipid-lowering effects (LDL-C reduced 32.5% versus 29.5%, p≤0.001).
Pitavastatin:
Morgan et al. compared the effects of morning and evening dosing of pitavastatin 4 mg/day in 36 healthy volunteers for 28 days followed by a washout period, after which the regimens were reversed. 29 Reductions in LDL-C were comparable in both groups (37.23% for morning dosing versus 39.96% for evening dosing).
Rosuvastatin:
Martin et al. conducted an open-label crossover trial comparing morning and evening doses of rosuvastatin 10 mg/day in 24 healthy volunteers.30 Fourteen days of treatment with one dosing regimen was followed by a four-week washout, after which the dosing regimen was reversed. The LDL-C-lowering effects in the two groups were comparable (41.3% reduction for morning dosing versus 44.2% for evening dosing).
References
- Rosuvastatin [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals, 2010.
- Atorvastatin [package insert]. Dublin, Ireland: Pfizer Parke-Davis, 2009.
- Simvastatin [package insert]. Cramlington, UK: Merck, Sharpe & Dohme, LTD, 2010.
- Lovastatin [package insert]. Morgantown, WV: Mylan Pharmaceuticals.
- Fluvastatin [package insert]. East Hanover, NJ: Novartis Pharmaceuticals, 2012.
- Pitavastatin [package insert]. Tokyo, Japan: Kowa Pharmaceuticals, 2012.
- Pravastatin [package insert]. Princeton, NJ: Bristol-Myers Squibb Company
- Atorvastatin. Micromedex Solutions [database online]. Truven Health Analytics. http://www.micromedexsolutions.com. Accessed 3/30/2020.
- Rosuvastatin. Micromedex Solutions [database online]. Truven Health Analytics. http://www.micromedexsolutions.com. Accessed 3/30/2020.
- Pravastatin. Micromedex Solutions [database online]. Truven Health Analytics. http://www.micromedexsolutions.com. Accessed 3/30/2020.
- Simvastatin. Micromedex Solutions [database online]. Truven Health Analytics. http://www.micromedexsolutions.com. Accessed 3/30/2020.
- Lovastatin. Micromedex Solutions [database online]. Truven Health Analytics. http://www.micromedexsolutions.com. Accessed 3/30/2020.
- Fluvastatin. Micromedex Solutions [database online]. Truven Health Analytics. http://www.micromedexsolutions.com. Accessed 3/30/2020.
- Pitavastatin. Micromedex Solutions [database online]. Truven Health Analytics. http://www.micromedexsolutions.com. Accessed 3/30/2020.
- Awad K, Banach M. The optimal time of day for statin administration: a review of current evidence. Curr Opin Lipid 2018; 29(4): 340-345.
- Awad K, Serban M-C, Penson P, et al. Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Effects of morning vs evening statin administration on lipid profile: a systematic review and meta-analysis. J Clin Lipidol 2017; 11: 972.e9-985.e9
- Izquierdo-Palomares JM, Fernandez-Tabera JM, Plana MN, et al. Chronotherapy versus conventional statins therapy for the treatment of hyperlipidaemia. Cochrane Database Syst Rev 2016; 11:CD009462.
- Saito Y, Yoshida S, Nakaya N, et al. Comparison between morning and evening doses of simvastatin in hyperlipidemic subjects. A double-blind comparative study. Atheroscler Thromb. 1991; 11:816-826.
- Wallace A, Chinn D, Rubin G, et al. Taking simvastatin in the morning compared with in the evening: randomized control trial. BMJ 2003; 327-788.
- Lund TM, Torsvik H, Falch D et al. Effect of morning vs evening intake of simvastatin on the serum cholesterol level in patients with coronary artery disease. Am J Cardiol 2002; 90: 784-786.
- Tharavanij T, Wongtanakarn S, Lerdvuthisopon N, et al. Lipid-lowering efficacy of morning versus evening simvastatin treatment: a randomized double-blind study. J Med Assoc Thai 2010; 93 (Suppl 7) S109-S113.
- 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.e1 – 1360 e1.
- 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 in chronic kidney disease patients with dyslipidemia. Clin Ther 2014; 36: 1182-1190.
- Kruse W, Nikolaus T, Rampmaier J, et al. Actual versus prescribed timing of lovastatin doses assessed by electronic compliance monitoring. Eur J Clin Pharmacol 1993; 45:211-215.
- The Lovastatin Study Group IV. A multicenter comparison of lovastatin and probucol for treatment of severe primary hypercholesterolemia. Am J Cardiol 1990; 66:B22-B30
- Scharnagl H, Vogel M, Abletshauser C, et al. Efficacy and safety of fluvastatin-extended release in hypercholesterolemic patients: morning administration is equivalent to evening administration. Cardiology 2006; 106:241-248.
- 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.
- Hunninghake DB, Mellies MJ, Goldberg AC, et al. Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. II. Once-daily versus twice-daily dosing. Atherosclerosis 1990; 85:219-227.
- Morgan RE, Inagaki Y, Arana GF, Hunt T. MS390 Time of day dosing does not influence steady-state pharmacokinetics or LDL-C reduction produced by pitavastatin. Atheroscler Suppl 2010; 11:188-189.
- 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; 54:472-477.
