Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin.

The long-term safety profile of simvastatin, established over 10 years of clinical use, is excellent. The principal adverse effect of all inhibitors of hydroxymethylglutarate co-enzyme A (HMG-CoA) reductase, myopathy, is infrequent. Simvastatin is a substrate for cytochrome P450 3A4 (CYP3A4). CYP3A4 inhibitors can elevate the plasma concentration of HMG-CoA reductase inhibitory activity derived from simvastatin. Clinical experience has shown that concomitant use of potent inhibitors of CYP3A4 increase the risk for myopathy. Evaluation of data from clinical trials and postmarketing surveillance allows assessment of whether concomitant use of weaker CYP3A4 inhibitors, as represented by calcium channel blockers, has any effect on the risk of myopathy. Cases of myopathy in long-term clinical megatrials and in analyses of postmarketing adverse event reports have been surveyed. In megatrials with simvastatin, the overall incidence of myopathy was 0.025%. The proportion of patients developing myopathy who were taking a calcium channel blocker with simvastatin (1 of 3) was similar to the proportion of patients taking a calcium channel blocker overall. Among marketed-use adverse event reports, concomitant medication with a potent CYP3A4 inhibitor was more frequent among reports of myopathy than among reports of nonmusculoskeletal adverse events. No excess use of calcium channel blockers among myopathy reports was observed. We conclude that the overall risk of myopathy during treatment with simvastatin is very low. Potent CYP3A4 inhibitors, especially cyclosporine, significantly increase the risk. There is no evidence that weaker CYP3A4 inhibitors such as calcium channel blockers increase the risk.

Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I.

A randomized, blinded, multicenter clinical trial was performed comparing low- and high-dose simvastatin (40 and 80 mg) with comparable doses of atorvastatin (20 and 40 mg) for effects on plasma concentrations of lipoproteins and apolipoprotein A-I over 12 weeks in 842 patients with elevated low-density lipoprotein cholesterol. The 2 agents reduced low-density lipoprotein cholesterol and triglycerides to a comparable degree, but simvastatin raised high-density lipoprotein cholesterol and apolipoprotein A-I more than atorvastatin, suggesting differences in metabolic effects of the 2 agents on plasma lipids and lipoproteins.

Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)

BACKGROUND: The Scandinavian Simvastatin Survival Study (4S) randomized 4444 patients with coronary heart disease (CHD) and serum cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with triglycerides < or =2.5 mmol/L (220 mg/dL) to simvastatin 20 to 40 mg or placebo once daily. Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction, P<.00001). Simvastatin produced substantial changes in several lipoprotein components, which we have attempted to relate to the beneficial effects observed. METHODS AND RESULTS: The Cox proportional hazards model was used to assess the relationship between lipid values (baseline, year 1, and percent change from baseline at year 1) and MCEs. The reduction in MCEs within the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total and LDL cholesterol, apolipoprotein B, and less so with HDL cholesterol, but there was no clear relationship with triglycerides. We estimate that each additional 1% reduction in LDL cholesterol reduces MCE risk by 1.7% (95% CI, 1.0% to 2.4%; P<.00001). CONCLUSIONS: These analyses suggest that the beneficial effect of simvastatin in individual patients in 4S was determined mainly by the magnitude of the change in LDL cholesterol, and they are consistent with current guidelines that emphasize aggressive reduction of this lipid in CHD patients.

Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S).

In patients participating in the Scandinavian Simvastatin Survival Study, cholesterol lowering with simvastatin reduced the incidence of carotid bruits and cerebrovascular events as well as new-onset or worsening of angina pectoris and intermittent claudication. These effects suggest that simvastatin may have a general antiatherosclerotic effect not limited to the coronary bed.

The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day.

The hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin is the most effective of the currently approved hypolipidemic drugs and has been shown to reduce mortality and coronary morbidity in patients with coronary artery disease. For these patients the United States National Cholesterol Education Program advocates reducing low-density lipoprotein (LDL) cholesterol to <100 mg/dl. However, in some patients this cannot be achieved using monotherapy with simvastatin 40 mg/day, the current maximal recommended dose. To evaluate the effectiveness of extending the dosage range, 156 subjects with LDL cholesterol >160 mg/dl and triglycerides (TG) <350 mg/dl were randomized to simvastatin at doses of 40, 80, and 160 mg/day in a 26 week, double-blind, 3-period, complete block crossover study. Each active treatment period was 6 weeks in duration with intervening 2 week washout periods. Median reductions from baseline in LDL cholesterol were 41%, 47%, and 53% in the 40-, 80-, and 160-mg groups, respectively. The corresponding reductions in plasma TG were 21%, 23%, and 33%. High-density lipoprotein (HDL) cholesterol increased by 6% to 8% in each group. One patient (0.7%) taking 160 mg developed myopathy; 1 patient (0.7%) taking 80 mg, and 3 (2.1%) taking 160 mg had transaminase elevations > 3 times the upper limit of normal. No new or unexpected adverse effects were observed. We conclude that simvastatin at doses of 80 and 160 mg/day provides additional efficacy with a low short-term incidence of adverse effects; our results support the continued investigation of simvastatin at these doses.

Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study.

BACKGROUND: Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. METHODS: The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). RESULTS: The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. CONCLUSION: The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.

Lipid-lowering therapy for patients with or at risk of coronary artery disease.

Several studies have shown that effective lipid-lowering therapy slows the progression of atherosclerotic lesions in the coronary and carotid arteries. Recent clinical trials have confirmed and extended previous work showing that lowering cholesterol reduces the risk of coronary events. A clear reduction in major coronary events during treatment for 5 years with the hydroxymethylglutaryl-coenzyme A reductase inhibitor pravastatin was observed in the West of Scotland study and in the preliminary results of the Cholesterol and Recurrent Events study. The Scandinavian Simvastatin Survival Study has provided the first unequivocal demonstration of improved survival as a result of lipid-lowering therapy. These three trials, which together included over 15,000 patients studied for 5 years, have provided good evidence that noncardiovascular mortality is not affected by substantial reductions in blood cholesterol.

Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: a reappraisal.

Although several cholesterol-lowering interventions have reduced coronary heart disease (CHD) events in clinical trials, drug therapy for hypercholesterolaemia has not been as widely used as the US and European guidelines recommend, mainly because until recently there was insufficient clinical trial evidence for improved survival. The Scandinavian Simvastatin Survival Study (4S) is the first trial of lipid-lowering therapy to demonstrate an unequivocal reduction in total mortality. Largely as a result of this study, there is now little disagreement on the necessity to reduce low density lipoprotein (LDL) cholesterol effectively in hypercholesterolaemic patients with CHD. Many physicians believe it is also important to reduce elevated levels of LDL cholesterol in patients without overt coronary disease, but more clinical trial evidence will be required before this is universally accepted. Inhibitors of HMG-CoA reductase are the most effective class of agents for this purpose, and have become widely used. It is likely that the magnitude of risk reduction produced by lipid-lowering therapy is proportional to the degree of cholesterol lowering achieved, which is an important consideration when selecting an agent and deciding the dosage to use. The results of several multicentre comparative trials have clearly established that the 4 members of the class are not all equipotent on a mg basis in terms of their effects on lowering LDL cholesterol. They have shown that the hypolipidaemic effect of simvastatin 5 mg approximately equals that of pravastatin 15 mg and lovastatin 15 mg and that of fluvastatin 40 mg, all given once daily. The tolerability profiles of HMG-CoA reductase inhibitors are excellent. Five-year data are available for simvastatin and lovastatin, and to date there is no good evidence for important differences in safety or tolerability among the class.

A review of clinical trials comparing HMG-CoA reductase inhibitors.

Four drugs that act as specific inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase--lovastatin, pravastatin, simvastatin, and, most recently, fluvastatin--have been approved by regulatory authorities throughout the world. In the present review, we have critically assessed the comparative hypocholesterolemic effects of these four drugs based on direct comparative studies, which were randomized, double-blind, and included more than 25 patients per treatment group. All studies were conducted in patients with primary hypercholesterolemia and the major end point of efficacy was reduction in the plasma concentrations of low-density lipoprotein (LDL)-cholesterol. Eight comparative trials have evaluated the efficacy and safety of lovastatin, simvastatin, or pravastatin, and one recently completed trial has compared lovastatin and fluvastatin. These trials confirm the log-linear dose response curves for all four of these drugs but indicate that on a milligram-for-milligram basis, lovastatin and pravastatin are approximately equipotent, whereas simvastatin is at least twice as effective per milligram of drug administered as lovastatin and pravastatin. Lovastatin at doses of 20 and 40 mg/d was of similar efficacy to fluvastatin at doses of 40 and 80 mg/d and would suggest that on a milligram-for-milligram basis, fluvastatin is half as potent as lovastatin. The side-effect profiles of all four drugs appeared similar, and earlier reports that suggested a higher incidence of sleep disorders in patients treated with the more lipophilic drugs, lovastatin and simvastatin, as compared with pravastatin, are not supported by more recent, controlled clinical trials. We conclude that although the currently available HMG-CoA reductase inhibitors differ in their relative hypolipidemic effects, as a class they constitute the most effective agents available to maximally reduce elevated concentrations of LDL-cholesterol.

The efficacy of intensive dietary therapy alone or combined with lovastatin in outpatients with hypercholesterolemia.

BACKGROUND: A diet low in saturated fat and cholesterol is the standard initial treatment for hypercholesterolemia. However, little quantitative information is available about the efficacy of dietary therapy in clinical practice or about the combined effects of diet and drug therapy. METHODS: One hundred eleven outpatients with moderate hypercholesterolemia were treated at five lipid clinics with the National Cholesterol Education Program Step 2 diet (which is low in fat and cholesterol) and lovastatin (20 mg once daily), both alone and together. A diet high in fat and cholesterol and a placebo identical in appearance to the lovastatin were used as the respective controls. Each of the 97 patients completing the study (58 men and 39 women) underwent four consecutive nine-week periods of treatment according to a randomized, balanced design: a high-fat diet-placebo period, a low-fat diet-placebo period, a high-fat diet-lovastatin period, and a low-fat diet-lovastatin period. RESULTS: The level of low-density lipoprotein (LDL) cholesterol was a mean of 5 percent (95 percent confidence interval, 3 to 7 percent) lower during the low-fat diet than during the high-fat diet (P < 0.001). With lovastatin therapy as compared with placebo, the reduction was 27 percent. Together, the low-fat diet and lovastatin led to a mean reduction of 32 percent in the level of LDL cholesterol. The level of high-density lipoprotein (HDL) cholesterol fell by 6 percent (95 percent confidence interval, 4 to 8 percent) during the low-fat diet (P < 0.001) and rose by 4 percent during treatment with lovastatin (P < 0.001). The ratio of LDL to HDL cholesterol and the level of total triglycerides were reduced by lovastatin (P < 0.001), but not by the low-fat diet. CONCLUSIONS: The effects of the low-fat-low-cholesterol diet and lovastatin on lipoprotein levels were independent and additive. However, the reduction in LDL cholesterol produced by the diet was small, and its benefit was possibly offset by the accompanying reduction in the level of HDL cholesterol.