Safety profile of atorvastatin-treated patients with low LDL-cholesterol levels.

Data pooled from 21 atorvastatin clinical trials have been analyzed to establish the safety of reducing low density lipoprotein cholesterol (LDL-C) levels below currently recommended minimum targets in hypercholesterolemic patients. Safety data for atorvastatin-treated patients with at least one LDL-C value < or =80 mg/dl (2.1 mmol/l) (n = 319) during treatment (mean LDL-C level throughout treatment was 91 mg/dl [2.4 mmol/l]) were compared to those from all atorvastatin-treated patients (n = 2502) and patients treated with lovastatin, simvastatin or pravastatin (n = 742). The frequency of treatment-associated adverse events (AEs) in the atorvastatin LDL-C < or =80 mg/dl (2.1 mmol/l) subgroup (24%) was comparable to the frequencies observed for all atorvastatin-treated patients (20%) and for patients receiving the other statins (24%). Patient withdrawals due to treatment-associated AEs (constipation, dyspepsia and flatulence being the most common) were consistent and low across treatment groups. No treatment-associated deaths occurred in any group. Safety data for 21 atorvastatin-treated patients with LDL-C < or =50 mg/dl (1.3 mmol/l) were also analyzed and found to be similar to all atorvastatin-treated patients and patients treated with the other statins. While recognizing the short-term nature of the data (all patients who received atorvastatin were treated for < or =1 year and approximately 30% were treated for < or =6 months), this analysis suggests that reducing LDL-C levels below 80 (2.1 mmol/l) or 50 mg/dl (1.3 mmol/l) with atorvastatin does not alter its safety profile, as measured by frequency of AEs, which remains similar to those of other statins.

An overview of the clinical safety profile of atorvastatin (lipitor), a new HMG-CoA reductase inhibitor.

BACKGROUND: Statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) have been used for a decade to lower low-density lipoprotein (LDL) cholesterol levels and to improve cardiovascular disease and clinical outcomes. OBJECTIVE: To evaluate the safety profile of atorvastatin (Lipitor). METHODS: Data were pooled for 21 completed (2502 patients) and 23 ongoing (1769 patients) clinical trials of atorvastatin conducted in US and international community- and university-based research centers. In these trials, patients with lipid disorders received atorvastatin at dosages of 10 to 80 mg/d. The majority of patients had moderate to severe hypercholesterolemia and were treated from 4 weeks to more than 24 months. MAIN OUTCOME MEASURES: Transaminase and creatine phosphokinase levels and adverse events were recorded. RESULTS: Atorvastatin was well tolerated; fewer than 2% of the atorvastatin-treated patients withdrew due to drug-attributable adverse events. The overall adverse event profile for atorvastatin was similar to that observed with other statins. The most common adverse events with atorvastatin as well as with other statins tested were constipation, flatulence, dyspepsia, and abdominal pain. Approximately 5% of atorvastatin-treated patients had serious adverse events; only 2 of these events were possibly associated with treatment. Thirty patients (0.7%) had confirmed transaminase elevations greater than 3 times the upper limit of the normal range. Most elevations occurred within 16 weeks of beginning treatment. No patients had a conclusive characterization of drug-induced myopathy. CONCLUSIONS: The safety profile of atorvastatin was consistent with that of all statins tested and was similar to that seen in all compounds of this class.

Effectiveness of atorvastatin for reducing low-density lipoprotein cholesterol to National Cholesterol Education Program treatment goals.

Atorvastatin is a highly efficacious hydroxymethylglutaryl-coenzyme A reductase inhibitor that has been shown to reduce low-density lipoprotein cholesterol by 40% to 60%. Monotherapy with atorvastatin (10 to 80 mg/day) is well-tolerated, convenient, and appears to be effective for achieving National Cholesterol Education Program treatment goals in most patients, regardless of risk status.

A brief review paper of the efficacy and safety of atorvastatin in early clinical trials.

Preclinical and clinical data on atorvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, indicate that it has superior activity in treating a variety of dyslipidemic disorders characterized by elevations in low-density lipoprotein cholesterol (LDL-C) and/or triglycerides. Results for patients randomized in early efficacy and safety studies were combined in one database and analyzed. This analysis included a total of 231 atorvastatin-treated patients (131 with hypercholesterolemia (HC), 63 with combined hyperlipidemia (CH), 36 with hypertriglyceridemia (HTG), and 1 with hyperchylomicronemia (Fredrickson Type V)). Patients were treated with a cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step 1 diet or a more rigorous diet) and either 2.5, 5, 10, 20, 40, or 80 mg/day of atorvastatin or placebo. Efficacy was based on percent change from baseline in total cholesterol, total triglycerides, LDL-C, very low-density lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apo B), and non-HDL-C/HDL-C. Safety was assessed in all randomized patients. Atorvastatin seemed to preferentially lower those lipid and lipoprotein component(s) most elevated within each dyslipidemic state: LDL-C in patients with HC, triglycerides and VLDL-C in patients with HTG, or all 3 in patients with CH. Atorvastatin was well-tolerated with a safety profile similar to other drugs in its class.

Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia.

Plasma cholesterol and other lipoproteins play a significant role in the development of atherosclerosis and subsequent coronary heart disease (CHD). This 1 year study was designed to confirm the efficacy and safety of atorvastatin (Lipitor) compared to pravastatin, a marketed agent for low density lipoprotein cholesterol (LDL-C) reduction in hypercholesterolemic patients. Patients were recruited at 26 centers in six European countries. After a 6 week placebo baseline phase, patients were randomized to receive atorvastatin 10 mg or pravastatin 20 mg daily. The dose could be doubled at week 16, if LDL-C levels remained > or = 3.4 mmol/l (135 mg/dl). Atorvastatin significantly lowered LDL-C from baseline by 35% compared with 23% for pravastatin (P < 0.05). A total of 72% of atorvastatin patients attained the LDL-C target level of < 3.4 mmol/l, compared to 26% of pravastatin patients. Atorvastatin also significantly reduced TC, TG and apo B (P < 0.05). Safety was assessed by recording adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. Atorvastatin 10 and 20 mg once daily is superior to pravastatin 20 and 40 mg once daily in treating patients with hypercholesterolemia.

A study to determine the response of coronary atherosclerosis to raising low high density lipoprotein cholesterol with a fibric-acid derivative in men after coronary bypass surgery. The rationale, design, and baseline characteristics of the LOCAT Study. Lopid Coronary Angiography Trial.

Several clinical trials have shown that reducing serum cholesterol levels retards the progression of coronary atherosclerosis assessed by serial angiography. By contrast, as yet no studies have addressed the impact of increasing high density lipoprotein (HDL) cholesterol levels on progression of coronary artery disease (CAD). As HDL cholesterol is inversely related to the risk of CAD, we hypothesize that an intervention that raises low HDL cholesterol concentrations may have a beneficial effect on the course of CAD. Lopid Coronary Angiography Trial (LOCAT) was designed to test this hypothesis. Three hundred and ninety-five men, aged < or = 70 years, all of whom had previously undergone coronary bypass surgery, were randomly assigned to receive either slow-release gemfibrozil, 1200 mg once daily, or a matching placebo for on average 2 1/2 years. The lipid inclusion criteria were HDL cholesterol concentration < or = 1.1 mmol/L, low density lipoprotein (LDL) cholesterol < or = 4.5 mmol/L, and serum triglyceride < or = 4.0 mmol/L. Subjects were not accepted if they had manifest diabetes, body mass index > 30 kg/m2, uncontrolled hypertension, or if they were regular smokers. All randomized subjects underwent baseline coronary angiography, which will be repeated at the end of the study. The angiograms will be analyzed using the Cardiovascular Measurement System, a validated computer-assisted image-analysis and quantitation package. The primary endpoints are the changes in the per-patient mean of 1) the average diameter of evaluable native coronary segments, and 2) the minimal luminal diameter of evaluable stenoses, and 3) the appearance of new lesions. Extensive lipoprotein and other metabolic studies and analyses of genetic polymorphisms are carried out to study the determinants of CAD progression. At baseline, the study subjects were 59.1 +/- 6.8 (mean +/- standard deviation) years old, had a body mass index 26.4 +/- 2.2 kg/m2, and serum triglyceride, serum cholesterol, HDL cholesterol, and LDL cholesterol concentrations 1.64 +/- 0.64, 5.17 +/- 0.64, 0.82 +/- 0.14, and 3.61 +/- 0.53 mmol/L, respectively.

Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor.

This 6-week, double-blind clinical trial evaluated lipid parameter responses to different dosages of atorvastatin in patients with primary hypercholesterolemia. Atorvastatin is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor under development. After completing an 8-week placebo-baseline dietary phase, 81 patients were randomly assigned to receive either placebo or 2.5, 5, 10, 20, 40, or 80 mg atorvastatin once daily for 6 weeks. Plasma LDL cholesterol reductions from baseline were dose related, with 25% to 61% reduction from the minimum dose to the maximum dose of 80 mg atorvastatin once a day. Plasma total cholesterol and apo B reductions were also dose related. Previously, reductions in LDL cholesterol of the magnitude observed in this study have been seen only with combination drug therapy. In this study, atorvastatin was well tolerated by hyperlipidemic patients, had an acceptable safety profile, and provided greater reduction in cholesterol than other previously reported HMG-CoA reductase inhibitors.

Some comparative effects of gemfibrozil, clofibrate, bezafibrate, cholestyramine and compactin on sterol metabolism in rats.

Liver cholesterogenesis in rats was measured by giving [l-14C]octanoate i.p.; 1 h later digitonin-precipitable sterols were isolated and counted. In rats fed normal chow and given 7 daily p.o. doses of compounds and then fasted, at 20 h after the last dose, clofibrate or bezafibrate had no effect at lower doses or inhibited incorporation at higher doses, while compactin or gemfibrozil caused increases; cholestyramine added to the diet also caused marked increases. When rats were fed chow containing 0.1% cholesterol and 5.5% peanut oil, again at 20 h following the last of 7 daily doses, gemfibrozil caused increases of incorporation which diminished at higher levels of dosage, while clofibrate caused only inhibition. A single dose of gemfibrozil caused inhibition at 3 h postdose followed by increases over control at 36 and 48 h; a single dose of compactin caused inhibition at 3 h but not subsequent increase, and a single dose of clofibrate had no effect over the entire period. In rats fed chow containing 1.5% cholesterol and 5.5% peanut oil, gemfibrozil given orally or cholestyramine in the diet prevented the diet-induced decreases of plasma HDL cholesterol and increases of liver cholesterol content, while bezafibrate treatment did not have those effects. The effects of cholestyramine rapidly disappeared when it was withdrawn from the diet, while the effects of gemfibrozil persisted after dosage was stopped. These results suggest that some of the actions of gemfibrozil on rat sterol metabolism are quantitatively different from those of the other agents tested.