Hydroxymethylglutaryl
coenzyme A (HMG-CoA) reductase inhibitors, more commonly known as statins, are
recommended as first-line agents in the reduction of low-density lipoprotein
cholesterol (LDL-C).(1) Although cholesterol is imperative for normal
cellular function, excess LCL-C leads to atherogenesis. Plaque formation
in the arteries results in coronary artery disease (CAD), heart attack, and/or
stroke. There is known morbidity and mortality benefit associated with
LDL-C reduction from statin therapy; therefore, it is vital that patients take
the medication in a way that provides the greatest effect.(2)
Although
some cholesterol comes from dietary intake, a significant amount is produced
endogenously. It was previously hypothesized that human cholesterol
production may be cyclical in nature mimicking the confirmed pattern of
cholesterol synthesis in animals. Human trials then confirmed the
fluctuation in cholesterol synthesis, noting the greatest cholesterol
production from the liver during fasting states.
The
apparent circadian rhythm of cholesterol production sparked the recommendation
that statins be dosed at bedtime to provide the greatest medication concentration
when endogenous cholesterol production is the highest.(3)
Investigation
of pharmacokinetic properties of individual statins disproved the need for all
agents to be dosed at bedtime.(1) Although all statins go through hepatic
metabolism, the elimination half-lives vary in length. Simvastatin,
fluvastatin, and lovastatin have a short elimination half-life compared to
other drugs within the class. Agents with significantly shorter
elimination half-lives require bedtime dosing to maximize efficacy - allowing
the greatest statin concentration to be present while endogenous cholesterol
synthesis is the highest. Alternatively, the longer half-lives of
rosuvastatin, atorvastatin, pitavastatin, and pravastatin allow these agents to
maintain a therapeutic drug concentration over a 24-hour period and allow
alternate administration times.(2)
Even if properly counseled to take statins with
a shorter half-life at bedtime, some patients do not comply which may result in
decreased efficacy. Agents with longer half-lives allow for greater
flexibility in administration time, which may improve compliance and ultimately
result in greater LDL-C reduction and ability to achieve cholesterol goals.
References:
- Expert panel on the detection,
evaluation, and treatment of high blood cholesterol in adults: executive
summary of the third report of the National Cholesterol Education Program
(NCEP) expert panel on detection, evaluation, and treatment of high cholesterol
in adults (adult treatment panel III). JAMA. 2001:285:2486-2497.
- Plakogiannis R, Cohen H. Optimal
low-density lipoprotein cholesterol lowering - morning versus evening
statin administration. Ann Pharmacother. 2007;41:106-110.
- Jones PJ, Schoeller DA. Evidence
for diurnal periodicity in human cholesterol synthesis. J Lipid Res.
1990;31:667-673.
- Brunton LL, Chabner BA, Knollmann BC,
eds. Goodman & Gilman's The Pharmacological Basis of
Therapeutics. 12th ed. New York: McGraw-Hill;2011.
- Kalant H, Grant DM, Mitchell J. Principles
of Medical Pharmacology. 7th ed. Toronto: Saunders
Elsevier;2007
