Class act is a feature of Clinical Correlations written by NYU 3rd and 4th year medical students. These posts focus on evidenced based answers to clinical questions related to patients seen by our students in the clinics or on the wards. Prior to publication, each commentary is thoroughly reviewed for content by a faculty member. Enjoy…
Commentary by David Leaf, MSIV
HMG-CoA reductase inhibitors (statins) are the most powerful drugs used for lowering LDL cholesterol, with median reductions in the range of 30 to 63 percent.(1,2,3) Consequently, these drugs have emerged as a first line treatment in patients with coronary artery disease or coronary risk equivalents, and have been shown to cause substantial reductions in mortality.(4)
Patients have traditionally been instructed by their physicians to take statins in the evening for maximal effect.(5) The rationale for this recommendation comes from evidence that hepatic HMG-CoA reductase activity6 and cholesterol biosynthesis(7) are greatest at night, while the half-lives of many statins are relatively short. For example, Lovastatin, (8) Fluvastatin, (9) and Simvastatin (10) all have half-lives less than six hours. Thus, in order to achieve maximal LDL lowering, it has been advised to administer statins in the evening in order to inhibit the enzyme while it is most active. Indeed, early studies with simvastatin found that evening administration resulted in significantly greater reductions in LDL cholesterol when compared to daytime administration (21% versus 15% reduction, respectively).(11)
While the evening administration of statins has become commonplace, several studies have evaluated the applicability of the above “conventional wisdom” to the newer, more potent, HMG-CoA reductase inhibitors such as Atorvastatin and Rosuvastatin. These statins have significantly longer half-lives (14 and 19 hours, respectively)(12,13) than their older counterparts, therefore calling into question the importance of morning versus evening administration. As might be expected based on their slower metabolism, studies have in fact demonstrated that the LDL-lowering efficacy of Atorvastatin (14,15) and Rosuvastatin(16) is independent of the time of day of drug administration. Similarly, the efficacy of extended-release Fluvastatin was also recently shown to be uninfluenced by the time of intake.(17)
Because treatment with statins is usually chronic, or even lifelong, compliance to therapy is essential.(18) Given that once-daily dosage regimens have been shown to facilitate patient compliance,(19)one may extrapolate that complicating a previously once-daily (morning) regimen by adding an evening medication might decrease compliance. Clinicians should therefore be aware that not all statins have similar pharmacodynamic and pharmacokinetic properties, and many statins can achieve equal LDL-lowering efficacy (and arguably improved compliance) when administered in the morning as compared with the evening.
1. Levy, RI. A quarter century of drug treatment of dyslipoproteinemia, with a focus on the new HMG-CoA reductase inhibitor fluvastatin. Circulation 1993; 87(4 Suppl):III45.
2. Jones, P, Kafonek, S, Laurora, I, et al for the CURVES Investigators. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998; 81:582.
3. Rosenson, RS. Rosuvastatin: a new inhibitor of HMG-coA reductase for the treatment of dyslipidemia. Expert Rev Cardiovasc Ther 2003; 1:495.
4. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383.
5. Knopp, RH. Drug Treatment of lipid disorders. N Engl J Med 1999; 341: 498-511.
6. Parker, TS, McNamara, DJ, Brown, C, Garrigan, O, Kolb, R, Batwin, H, Ahrens, EH Jr. Mevalonic acid in human plasma: relationship of concentration and circadian rhythm to cholesterol synthesis rates in man. Proc Natl Acad Sci USA 1982; 79: 3037–3041.
7. Jones, PJ, Schoeller, DA. Evidence for diurnal periodicity in human cholesterol synthesis. J Lipid Res 1990; 31: 667–673. 8. Mevacor (lovastatin) package insert. Whitehouse Station, NJ: Merck Pharmaceuticals; 2004.
9. Lescol (fluvastatin) package insert. East Hanover, NJ: Novartis Pharmaceuticals; 2004.
10. Zocor (simvastatin) package insert. Whitehouse Station, NJ: Merck Pharmaceuticals; 2004.
11. 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; 11:816-26.
12. Lipitor (atorvastatin calcium) package insert. Morris Plains, NJ: Pfizer Pharmaceuticals; 2003.
13. Crestor (rosuvastatin) package insert. Wilmington, DE: AstraZeneca; 2003.
14. Cilla, DD Jr, Gibson, DM, Whitfield, LR, Sedman, AJ. Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening. J Clin Pharmacol. 1996; 36:604-9.
15. 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):2491-4.
16. 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; 54:472-7.
17. Fauler, G, Abletshauser, C, Erwa, W, Loser, R, Witschital, K, Marz, W. Time-of-intake (morning versus evening) of extended-release fluvastatin in hyperlipemic patients is without influence on the pharmacodynamics (mevalonic acid excretion) and pharmacokinetics. Int J Clin Pharmacol Ther. 2007; 45(6): 328-34.
18. Report of the National Cholesterol Education Program on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. The Expert Panel. Arch Intern Med. 1988; 148(1): 36-69.
19. Greenberg, RN. Overview of patient compliance with medication dosing: a literature review. Clin Ther. 1984; 6(5):592-9.