Pharmacology Update
Atorvastatin Calcium: The Newest Statin
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Atorvastatin (lipitor, parke-davis) is the new-est HMG-CoA reductase inhibitor ("statin") to arrive on the already crowded lipid-lowering drug market. The drug was approved for marketing by the FDA in December 1996, just weeks after receiving approval in Europe.
Although similar in action to other statins, atorvastatin appears to be more potent than other agents in reducing LDL cholesterol, and it has an interesting additional benefitthe drug is effective at lowering elevated triglyceride levels and has received FDA approval for this indication.
The drug was developed by Parke-Davis, a division of Warner-Lambert, but is being co-marketed by Pfizer in this country after the two companies entered into a recent agreement.
Indications
Atorvastatin is indicated as an adjunct to diet to reduce elevated total cholesterol, LDL-cholesterol, apolipoprotein B, and triglycerides in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb). Atorvastatin is also indicated to reduce total and LDL cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.1
Potential Advantages
Atorvastatin appears to be the most potent agent (on a mg for mg basis) in reducing elevated plasma cholesterol. A mean reduction from baseline of up to 45% for total cholesterol and 60% for LDL cholesterol has been reported.1 The drug produces a slight but variable (not dose-dependent) increase in HDL cholesterol levels. Two small studies did show about a 12% increase in HDL-C with the 20 mg dose.2,3
Atorvastatin is the only marketed HMG-CoA reductase inhibitor that is approved for the reduction of elevated triglycerides. Dosages ranging from 10 to 80 mg of atorvastatin produce a mean reduction of triglycerides of 27-45%.1,4 While the mechanism by which the drug lowers triglycerides is unknown, it appears that atorvaststin decreases the synthesis and secretion of very low density lipoprotein (VLDL).2
Potential Disadvantages
HMG-CoA reductase inhibitors affect cholesterol synthesis and, in theory, may affect biosynthesis of cholesterol-based compounds such as adrenal and/or gonadal steroids. The higher potency of atorvastatin may enhance the theoretical potential for this effect. Changes in basal plasma cortisol levels and adrenal reserve have not been reported during clinical trials.1 Other adverse effects of excessive lowering of cholesterol are not known.
Adverse reactions to atorvastatin are similar to other statins and are mild and transient. Gastrointestinal symptoms such as constipation, flatulence, and abdominal pain are most commonly reported.
Dosing
Atorvastatin is supplied in tablets of 10 mg, 20 mg, and 40 mg. The starting dose is 10 mg taken as a single daily dose with or without food any time of day. Many patients will achieve target levels with this dose; however, dose adjustments up to 80 mg/d may be needed.
Comments
Atorvastatin is the latest HMG-CoA reductase inhibitor to be marketed, although the drug does have some unique attributes. It is the only agent of this class to be indicated for the reduction of elevated triglycerides and for patients with homozygous familial hypercholesterolemia. On a mg basis, atorvastatin appears to be the most potent HMG-CoA reductase inhibitor currently available. Whether the higher potency of this agent will affect the biosynthesis of cholesterol based hormones is not known.
Clinical Implications
Atorvastatin is an effective and potent drug for lowering LDL-C. The high potency of this drug would be especially useful in patients with coronary heart disease and LDL-cholesterol higher than 160 mg/dL. These patients would require a 40% or greater reduction to achieve NCEP target levels of 100 mg/dL or lower.5 This degree of reduction is generally not achievable with HMG-CoA reductase inhibitor monotherapy.6 It is estimated that 25% of men with coronary artery disease have LDL-cholesterol in the range above 160 mg/dL.7
The drug also appears to be an attractive alternative to niacin or combination therapy with gemfibrozil in treating combined hyperlipidemia. A dose of 40-80 mg provides a similar effect to gemfibrozil in lowering triglyceride levels.
Atorvastatin appears to be well tolerated by patients. The drug is priced competitively with other statins.
References
1. Lipitor Product Information. Parke-Davis. December 1996.
2. Bakker-Arkema S, et al. JAMA 1996;275:128-133.
3. Nawrocki JW, et al. Arterioscler Thromb Vasc Biol 1995;15:678-682.
4. Gmereck A, et al. Congress of the European Atherosclerosis Society. July 1996.
5. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol Levels in Adults. JAMA 1993;269:3015-3021.
6. Maracelino JJ, et al. Am J Med 1996;100:605-610.
7. Rubin HB, et al. Am J Cardiol 1995;75:1196-1201.
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