Home » Drug Information » FDA Approved Drugs » 1996
Medical Areas: Cardiology/Vascular Diseases
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Lipitor (atorvastatin calcium)
The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
Approval Status: Approved December 1996
Treatment Area: cardiovascular disease, hyperlipidemia and dyslipidemia
Lipitor (atorvastatin calcium) is a synthetic lipid-lowering agent. It is an inhibitor of the enzyme HMG-CoA reductase. By blocking or inhibiting the action of HMG-CoA reductase, a link is broken in the chain of reactions that produces cholesterol. When less cholesterol is produced, the liver takes up more cholesterol from the bloodstream, which results in lower levels of cholesterol circulating in the blood.
Lipitor is specifically indicated for the prevention of cardiovascular disease, including myocardial infarction and stroke, and for primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.
Lipitor is supplied as a tablet for oral administration. The recommended initial dose of Lipitor is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of Lipitor is 10 to 80 mg once daily, based on patient characteristics such as goal of therapy and response.
The FDA approval of Lipitor for the prevention of cardiovascular disease was based on four clinical trials.
The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was a double-blind, placebo-controlled study evaluating the effect of Lipitor on fatal and non-fatal coronary heart disease. The trial enrolled 10,305 hypertensive subjects 40 to 80 years of age without a previous myocardial infarction and with TC levels ≤251 mg/dL (6.5 mmol/L) and with certain cardiovascular risk factors. The subjects received anti-hypertensive therapy and allocated to either Lipitor 10 mg daily or placebo, according to their baseline characteristics. Lipitor significantly reduced the rate of coronary events, both fatal coronary heart disease (46 events in the placebo group vs. 40 events in the Lipitor group) and non-fatal MI (108 events in the placebo group vs. 60 events in the Lipitor group), with a relative risk reduction of 36% (based on incidences of 1.9% for Lipitor vs. 3.0% for placebo) (p=0.0005). Lipitor also significantly decreased the relative risk for revascularization procedures by 42%. Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for Lipitor and 2.3% for placebo).
The Collaborative Atorvastatin Diabetes Study (CARDS) was a multicenter, placebo-controlled, double-blind study evaluating the effect of Lipitor on cardiovascular disease (CVD) endpoints. The trial enrolled 2,838 subjects, ages 40 to 75, with type II diabetes, without prior history of cardiovascular disease and with LDL ≤160 mg/dL and TG ≤600 mg/dL. In addition to diabetes, subjects had 1 or more risk factors. The subjects were randomly allocated to either Lipitor 10 mg daily or placebo and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. Lipitor significantly reduced the rate of major cardiovascular events (83 events in the Lipitor group vs. 127 events in the placebo group) with a relative risk reduction of 37% (p=0.001). Lipitor significantly reduced the risk of stroke by 48% (21 events in the Lipitor group vs. 39 events in the placebo group; p=0.016) and reduced the risk of MI by 42% (38 events in the Lipitor group vs. 64 events in the placebo group; p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death.
The Treating to New Targets (TNT) study evaluated the effect of Lipitor 80 mg/day vs. Lipitor 10 mg/day on the reduction in cardiovascular events. The trial enrolled 10,001 subjects with clinically evident coronary heart disease who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label, run-in period with Lipitor 10 mg/day. The subjects received either 10 mg/day or 80 mg/day of Lipitor and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. Treatment with Lipitor 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22% (p=0.0002). Of the events that comprised the primary efficacy endpoint, treatment with Lipitor 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest.
The Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL) study evaluated Lipitor 80 mg/day compared to simvastatin 20 to 40 mg/day in 8,888 subjects up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved. The subjects subjects were followed for a median duration of 4.8 years. There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary event (fatal CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the Lipitor 80 mg/day group vs. 463 (10.4%) in the simvastatin 20 to 40 mg/day group (p=0.07). There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the Lipitor 80 mg/day group vs. 374 (8.4%) in the simvastatin 20 to 40 mg/day group.
The FDA approval of Lipitor for hyperlipidemia (Heterozygous Familial and Nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb) was based on a variety of clincal tials. In two multicenter, placebo-controlled, dose-response studies Lipitorwas given as a single dose over six weeks. Lipitor significantly reduced total-C, LDL-C, apo B, and TG. Twenty four (24) controlled trials enrolled subjects with Fredrickson Types IIa and IIb hyperlipoproteinemia. The median (25th and 75th percentile) percent changes from baseline in HDL-C for Lipitor 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Analysis of the pooled data also demonstrated consistent and significant decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.
The FDA approval of Lipitor for Hypertriglyceridemia (Fredrickson Type IV) and Dysbetalipoproteinemia (Fredrickson Type III) were also positive.
The FDA approval of Lipitor for Homozygous Familial Hypercholesterolemia was based on a trial in 29 subjects ages 6 to 37 years with homozygous FH received maximum daily doses of 20 to 80 mg of Lipitor. The mean LDL-C reduction in this study was 18%. Twenty-five subjects with a reduction in LDL-C had a mean response of 20%; the remaining four subjects had 7% to 24% increases in LDL-C. Five of the 29 subjects had absent LDL-receptor function. Of these, 2 subjects also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative subjects had a mean LDL-C reduction of 22%.
The FDA approval of Lipitor for Heterozygous Familial Hypercholesterolemia in pediatrics was based on a double-blind, placebo-controlled study, which was followed by an open-label phase. The study enrolled 187 boys and postmenarchal girls 10-17 years of age. with heterozygous FH or severe hypercholesterolemia. The subejcts were randomized to Lipitor or placebo for 26 weeks and then all received Lipitor for 26 weeks. The mean baseline LDL-C value was 218.6 mg/dL in the Lipitor arm compared to 230.0 mg/dL in the placebo arm. The dosage of Lipitor (once daily) was 10 mg for the first four weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. Lipitor significantly decreased plasma levels of LDL-C. The mean achieved LDL-C value was 130.7 mg/dL in the Lipitor group compared to 228.5 mg/dL in the placebo group during the 26-week double-blind phase.
Adverse reactions associated with the use of Lipitor may include, but are not limited to, the following:
- pain in extremity
- urinary tract infection
Mechanism of Action
Lipitor (atorvastatin calcium) is a synthetic lipid-lowering agent. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. By blocking or inhibiting the action of HMG-CoA reductase, a link is broken in the chain of reactions that produces cholesterol. When less cholesterol is produced, the liver takes up more cholesterol from the bloodstream, which results in lower levels of cholesterol circulating in the blood.
For additional information regarding Lipitor or cardiovascular disease, hyperlipidemia and dyslipidemia, please visit the Lipitor web page.