Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). 1998.
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Coronary Disease↗
Biomedical subjects
Jonathan A Tobert
Publications and source records attributed to Jonathan A Tobert.
Effects of simvastatin on the lipid profile and attainment of low-density lipoprotein cholesterol goals when added to thiazolidinedione therapy in patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, placebo-controlled trial.
BACKGROUND: Coronary heart disease is the major cause of mortality in individuals with diabetes mellitus (DM). Given the increasingly aggressive low-density lipoprotein cholesterol (LDL-C) goals for patients with DM set by the National Cholesterol Education Program Adult Treatment Panel III and the American Diabetes Association, many patients remain above target. Treatment with thiazolidinediones (TZDs) improves glycemic control but does not lower (and may raise) LDL-C concentrations. OBJECTIVE: This study assessed the lipid-modifying efficacy and tolerability of adding the hydroxymethylglutaryl coenzyme A-reductase inhibitor simvastatin to existing TZD therapy in patients with type 2 DM. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Patients with type 2 DM who were taking a stable dose of pioglitazone or rosiglitazone and had a glycosylated hemoglobin (HbA1c) value < or =9.0% and an LDL-C concentration > 100 mg/dL were randomized to receive simvastatin 40 mg (the recommended initial dose for patients with DM) or placebo for 24 weeks. The primary end point was the effect of treatment on LDL-C concentrations. Other lipid, lipoprotein, and safety measures were also assessed. RESULTS: Two hundred fifty-three patients (127 [50.2%] men, 126 [49.8%] women; mean age, 56 years) were randomized to treatment (123 simvastatin, 130 placebo). At the end of the study, mean LDL-C concentrations were reduced 34.)% from baseline (from 134.3 to 89.5 mg/dL) in the simvastatin group and were unchanged in the placebo group (P<0.001). Simvastatin produced significant reductions in concentrations of total cholesterol, triglycerides (TG), non-high-density lipoprotein cholesterol, and apolipoprotein (apo) B compared with placebo (all, P<0.001 ) and significant increases in concentrations of high-density lipoprotein cholesterol (HDL-C) ( P=0.002 ) and apo A-I ( P=0.006 ). In patients who had not attained target concentrations of LDL-C (<100 mg/dL), TG (<150 mg/dL), or HDL-C (>45 mg/dL) at baseline, significantly more simvastatin recipients had achieved these goals at the end of the study compared with placebo recipients (LDL-C: 67.3% vs 5.2%, respectively, P<0.001; HDL-C: 95.3% vs 83.6%, P<0.05; TG: 40.8% vs 11.0%, P<0.001 ). Simvastatin was well tolerated, and no clinically meaningful differences in the incidence of serious adverse events, treatment-related adverse events, or discontinuations due to adverse events were observed between groups. There were no significant between-group differences in glycemic control (HbA1c) or concentrations of fasting insulin, creatine phosphokinase, or hepatic transaminases. CONCLUSION: Simvastatin was an effective and generally well tolerated treatment for hyperlipidemia when used in combination with TZD therapy in this population of patients with type 2 DM.
Adult↗
Simvastatin: a review.
Simvastatin is a long-established hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, first introduced in 1988. At the maximal recommended dose of 80 mg/day, it produces an average reduction in low-density lipoprotein cholesterol (LDL-C) of 47%, accompanied by reductions in very LDL-C, triglycerides and apolipoprotein B, and a modest increase in high-density lipoprotein cholesterol. The only important, although rare, adverse effect of simvastatin is myopathy, an effect shared by all members of the class; when severe, this can take the form of rhabdomyolysis, which may lead to acute renal failure. The mechanism of the myopathy is not understood. The risk is increased by certain concomitant drugs, including gemfibrozil and potent inhibitors of cytochrome P450 3A4. Simvastatin has been studied in two large outcome trials, the Scandinavian Simvastatin Survival Study (4S), and the Heart Protection Study (HPS), both of which demonstrated strikingly beneficial effects on a variety of cardiovascular outcomes, with minimal adverse effects. 4S was the first study with a cholesterol-lowering agent to demonstrate an unequivocal reduction in all-cause mortality (30%; p = 0.0003). HPS showed that the beneficial effects of simvastatin were obtainable in a broad array of patients with, or at high risk of, coronary heart disease (CHD) in categories previously little studied, including women, the elderly, patients with diabetes without known CHD, and, perhaps most importantly, patients with LDL-C well below the UK population average. Simvastatin has recently become available in many countries as a combination product with the cholesterol absorption inhibitor, ezetimibe. Because of its long record of safety and demonstrated ability to reduce cardiovascular risk, simvastatin has recently become available without a prescription in the UK at the 10 mg dosage level.
Clinical Trials as Topic↗
Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors.
In the 1950s and 1960s, it became apparent that elevated concentrations of plasma cholesterol were a major risk factor for the development of coronary heart disease, which led to the search for drugs that could reduce plasma cholesterol. One possibility was to reduce cholesterol biosynthesis, and the rate-limiting enzyme in the cholesterol biosynthetic pathway, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, was a natural target. Here, I describe the discovery and development of lovastatin--the first approved inhibitor of HMG-CoA reductase--and the clinical trials that have provided the evidence for the ability of drugs in this class to reduce the morbidity and mortality associated with cardiovascular disease.
Animals↗