D. Plotkin

Effect of Cholesterol-Lowering Therapy on Coronary Endothelial Vasomotor Function in Patients With Coronary Artery Disease

BACKGROUND Improved endothelial function may contribute to the beneficial effects of cholesterol-lowering therapy. METHODS AND RESULTS In this randomized, double-blind study, we compared the effect of 6 months of simvastatin (40 mg/d) treatment with that of placebo on coronary endothelial vasomotor function in 60 patients with coronary artery disease. Simvastatin lowered LDL-cholesterol by 40+/-12% from 130+/-28 mg/dL (P<0.001). Peak intracoronary acetylcholine infusion produced epicardial coronary constriction at baseline in both the simvastatin (-17+/-13%) and placebo (-24+/-16%) groups. After treatment, acetylcholine produced less constriction in both groups (-12+/-19% and -15+/-14%, respectively, P=0.97). The increase in coronary blood flow during infusion of the peak dose of substance P was blunted at baseline in both the simvastatin (42+/-50%) and placebo (55+/-71%) groups, reflecting impaired endothelium-dependent dilation of coronary microvessels. After treatment, the flow increase was 82+/-81% in the simvastatin group and 63+/-53% in the placebo group (P=0.16). CONCLUSIONS Six months of cholesterol-lowering therapy has no significant effect on coronary endothelial vasomotor function in the study population of patients with coronary artery disease and mildly elevated cholesterol levels. These findings suggest that the effects of cholesterol lowering on endothelial function are more complex than previously thought.

Efficacy and safety of ezetimibe co‐administered with simvastatin in thiazolidinedione‐treated type 2 diabetic patients

Aim:  In patients with type 2 diabetes mellitus (T2DM), combination therapy is usually required to optimize glucose metabolism as well as to help patients achieve aggressive targets for low‐density lipoprotein cholesterol (LDL‐C) and other lipid parameters associated with cardiovascular risk. The thiazolidinediones (TZDs) are increasingly being used for both their blood glucose‐lowering properties and their modest beneficial effects on triglycerides (TG) and high‐density lipoprotein cholesterol (HDL‐C). Ezetimibe, an intestinal cholesterol absorption inhibitor, has a mechanism of action that differs from that of statins, which inhibit hepatic cholesterol synthesis. We compared the lipid‐modifying efficacy and safety of adding ezetimibe to simvastatin, vs. doubling the dose of simvastatin, in TZD‐treated T2DM patients.

Effects of simvastatin (40 and 80 mg/day) in patients with mixed hyperlipidemia.

Mixed hyperlipidemia is characterized by both elevated total cholesterol and triglycerides. It is estimated to account for 10% to 20% of patients with dyslipidemia. This study assessed the lipid-altering efficacy and tolerability of simvastatin 40 and 80 mg/day as monotherapy. One hundred thirty patients (62 women [48%], 24 [16%] with type 2 diabetes mellitus, mean age 53 years) with mixed hyperlipidemia (baseline low-density lipoprotein [LDL] cholesterol 156 mg/dl [mean], and triglycerides 391 mg/dl [median) were randomized in a multicenter, double-masked, placebo-controlled, 3-period, 22-week, balanced crossover study, and received placebo, and simvastatin 40 and 80 mg/day each for 6 weeks. Compared with placebo, simvastatin produced significant (p <0.01) and dose-dependent changes in all lipid and lipoprotein parameters (LDL cholesterol 2.1%, -28.9%, and -35.5%; triglycerides -3.5%, -27.8%, and -33.0%; high-density lipoprotein cholesterol 3.3%, 13.1%, and 15. 7%; apolipoprotein B 3.8%, -23.1%, and -30.6%; and apolipoprotein A-I 4.0%, 8.2%, and 10.5% with placebo, and simvastatin 40 and 80 mg/day, respectively). The changes were consistent in patients with diabetes mellitus. One patient taking simvastatin 80 mg/day had an asymptomatic and reversible increase in hepatic transaminases 3 times above the upper limit of normal. Simvastatin 40 and 80 mg/day is effective in patients with mixed hyperlipidemia across the entire lipid and lipoprotein profile. The reductions in LDL cholesterol and triglycerides are large, significant, and dose dependent. The increase in high-density lipoprotein cholesterol was greater than that observed in patients with hypercholesterolemia, and appears dose dependent.

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.

Long Term Experience with Simvastatin

SummarySimvastatin is a potent lipid-lowering agent that has proven highly effective in the treatment of primary hypercholesterolaemia. This report extends the data on controlled clinical trials, involving 2423 patients receiving simvastatin. The mean duration of treatment was 1.5 years, and some patients were followed up for a period of up to 4.3 years. This cohort had a mean age of 50 years, with males comprising 61% of the population. Because of the severity of lipid abnormalities treated in this population, simvastatin was titrated to the maximum daily dose of 40mg each evening in over half the population. An evaluation of long term efficacy indicates that improvements in the lipid/lipoprotein profile observed initially in patients were maintained over 3 years of treatment with chronic administration. The improvements in plasma levels included reductions in total and low-density lipoprotein cholesterol, decreases in triglyceride and increases in high-density lipoprotein cholesterol plasma levels. The profile of adverse events remained unchanged since the initial controlled clinical studies, with no reports of new or unexpected adverse effects. The most commonly reported drug-related clinical adverse experiences were gastrointestinal in nature, including constipation (in 2.5% of the patient population), abdominal pain (2.5%), flatulence (2.0%) and nausea (1.2%). Persistent elevations in levels of serum transaminases > 3 times the upper limit of normal were observed in 1.2% of the population, but rarely required discontinuation of therapy. Elevations in levels of creatine Phosphokinase (CPK) > 10 times the upper limit of normal were infrequent (0.7%), and reports of myopathy were rare (0.08%). Elderly patients (aged ⩾ 65 years) had a clinical and laboratory tolerability profile comparable to the nonelderly population. The long term clinical experience with simvastatin confirms its efficacy and tolerability profile for the treatment of hypercholesterolaemia.

1084-169 Efficacy and safety of ezetimibe coadministered with simvastatin versus simvastatin alone in thiazolidinedione-treated patients with type 2 diabetes mellitus

Vacular Diase, Hypension, nd Prention then increased at 24 h along with an increase in FXR. Geranylgeraniol abolished the effects of pitavastatin on apo A-I, PPARα, and FXR, but enhanced the induction of CYP7A1 mRNA by pitavastatin, suggesting the existence of factors that regulate CYP7A1 in the non-sterol/geranylgeranyl diphosphate (GGpp) pathway. However, the inhibition of Rho-kinase by Y27632 enhanced the effects of pitavastatin on the induction of mRNA levels of apo A-I, PPARα, and FXR, but not that of CYP7A1, suggesting that PPARα may not be a major factor that regulates CYP7A1. Conclusions: Pitavastatin increases CYP7A1 mRNA levels in HepG2 cells, suggesting that increased conversion of cholesterol into bile acids may be a mechanism for the potent LDL-C-lowering effects of pitavastatin. Increased CYP7A1 mRNA levels by pitavastatin are the net effect of the induction of CYP7A1 by the inhibition of cholesterol synthesis and the suppression of CYP7A1 by inhibition of the non-sterol /GGpp pathway.