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PubMed1997

Efficacy of simvastatin and pumpkin-seed oil in the management of dietary-induced hypercholesterolemia.

Pumpkin-seed oil (PSO), a natural supplement rich with antioxidants and polyunsaturated fatty acids (PUFAs), was given in combination with simvastatin, as antihypercholesterolemic drug, to high cholesterol-fed rabbits, for three weeks. In comparison with normal rabbits, a significant increase of the aortic contractile response to norepinephrine was observed which could be attributed to endothelium dysfunction. In addition, serum levels of total lipids, triacylglycerols, total cholesterol and low density lipoprotein-cholesterol (LDL-C) were increased while phospholipids and high density lipoprotein-cholesterol (HDL-C) were decreased in hypercholesterolemic rabbits. These changes could be related to the predominance of LDL and oxidized-LDL particles caused by high levels of reactive oxygen species during hypercholesterolemia (HC). Treatment with simvastatin modulated most of the altered parameters affected during HC that might be, in part, due to inhibition of cholesterol biosynthesis. While concomitant administration of simvastatin and PSO succeeded to cause marked reduction of the aortic contractile response to norepinephrine and to normalize the most adverse effects observed during HC. These effects were explained by the potentiating effects of simvastatin with antioxidants and essential fatty acids in PSO. On the contrary, serum activities of aminotransferases and creatine phosphokinase were increased with simvastatin treatment but not with the combination therapy in hypercholesterolemic rabbits.

Adrenergic alpha-Agonists↗
PubMed2001

The influence of simvastatin on lipase and cholesterol esterase activity in the serum of men with coronary heart disease.

Several studies have demonstrated that any beneficial effects of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), of which simvastatin (Merck Sharp & Dohme) is an example, on coronary events are linked to their hypocholesterolemic properties. The in vivo effects of simvastatin treatment on lipase (GEH = glycerol ester hydrolase) and cholesterol esterase (CEase) activity in the serum of men with coronary heart disease (CHD) were examined. GEH and CEase activity in the serum of men with CHD, before simvastatin treatment, was lower than in the control subjects. In our study we have provided evidence that simvastatin increases GEH activity in a time-dependent manner, but has no effect on CEase activity. This suggests that simvastatin can directly affect acylglycerol metabolism by an increase in GEH activity and may therefore be suitable for the treatment of combined lipoprotein disorders characterized by elevation of triacylglycerols.

Adult↗
PubMed1992

Effect of simvastatin on high density lipoprotein subfractions and apolipoproteins in type IIa hypercholesterolemia.

Changes in plasma concentrations of high density lipoproteins (HDL) and triglycerides may partly explain the ability of cholesterol-lowering drugs to decrease the incidence of coronary heart disease. We measured the response of fasting plasma lipids, lipoproteins, and apolipoproteins in 46 subjects with Type IIa hypercholesterolemia treated with simvastatin for 3 months. The initial dose of simvastatin (10 mg/day) was subsequently increased up to 40 mg/day if the plasma cholesterol concentration had not fallen below 5.2 mmol/l. Plasma concentrations of HDL cholesterol and of the apolipoproteins AI and AII were increased by simvastatin. The increase in HDL cholesterol (9%) was due to increases in both subfractions (HDL2 17%; HDL3 7%), changes that would be consistent with a beneficial effect on cardiovascular risk. Simvastatin decreased plasma triglyceride concentrations by 25%. Plasma total cholesterol concentrations fell by 35% after 3 months of treatment; this fall was proportional to the initial concentration and was due almost entirely to a 45% fall in low density lipoprotein cholesterol. In contrast, plasma concentrations of lipoprotein Lp(a) were not affected by simvastatin.

Anticholesteremic Agents↗
PubMed1988

Simvastatin and bezafibrate: effects on serum lipoproteins and lecithin: cholesterol acyltransferase activity in familial hypercholesterolaemia.

Sixteen subjects with familial hypercholesterolaemia were randomly assigned to treatment with simvastatin 20-40 mg/day (an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase) or with bezafibrate 600 mg/day (a clofibrate analogue) for 12 weeks. Both drugs produced significant reductions in serum and LDL cholesterol; mean percentage fall -30.5% and -38.1% (simvastatin) and -17.8% and -20.6% (bezafibrate), respectively. Both drugs also caused a decrease in VLDL cholesterol, while only bezafibrate decreased the serum and VLDL triglyceride levels and increased HDL cholesterol and serum apolipoprotein A-I and A-II levels. Serum apolipoprotein B fell by 33.3% (simvastatin) and 15.7% (bezafibrate). Simvastatin and bezafibrate produced significant increases in the mean fractional esterification rate of LCAT, by +124.1% and +20.6%, respectively. Thus simvastatin was clearly more effective than bezafibrate in lowering LDL by enhancing its turnover, but bezafibrate had specific effects on VLDL and HDL that might be favourable in combined treatment regimens.

Adult↗
PubMedDate not supplied

Effects of fluvastatin slow-release (XL 80 mg) versus simvastatin (20 mg) on the lipid triad in patients with type 2 diabetes.

The lipid triad is the association of small, dense (sd) low-density lipoprotein (LDL), low high-density lipoprotein (HDL), and hypertriglyceridemia, all of which play a role in coronary artery disease in patients with type 2 diabetes. Although statins have demonstrated clear positive effects on cardiovascular morbidity/mortality in patients with diabetes and on single components of the lipid triad, it remains controversial whether they affect all components of the triad in these patients. Therefore, we performed a single-center, parallel-group, prospective, randomized, open-label, blinded-endpoint (PROBE)-type comparison of fluvastatin extended-release (XL) 80 mg (n=48) and simvastatin 20 mg (n=46), each given once daily for 2 months to patients with type 2 diabetes with the lipid triad, who were enrolled after a 1-month lifestyle modification and dietary intervention program. After fluvastatin therapy, LDL (-51%; P<.01), apolipoprotein B (ApoB; -33%; P<.01), intermediate-density LDL (idLDL) (-14.3%; P<.05), sdLDL (-45%; P<.01), and triglycerides (-38%; P<.01) were significantly decreased, and HDL (+14.3%; P<.05) and apolipoprotein A-I (ApoA-I; +7%; P<.05) were increased; large buoyant (lb) LDL did not change (P=NS). Simvastatin therapy decreased LDL (-55.1%; P<.01), ApoB (-46%; P<.01), lbLDL (-33.3%; P<.05), idLDL (-22.7%; P<.05), sdLDL (-33.3%; P<.05), and triglycerides (-47.9%; P<.01); HDL was not changed (P=NS) after simvastatin, but ApoA-I was increased (+11.3%; P<.01). HDL increases (P<.01) and sdLDL decreases (P<.01) were significantly greater after fluvastatin compared with simvastatin therapy; LDL, triglycerides, ApoB, and idLDL changes were similar after both therapies (P=NS), and lbLDL decreases were greater with simvastatin therapy (P<.05). With both treatments, classic mean LDL and ApoB target levels were achieved in most patients. We conclude that the lipid triad can be controlled with fluvastatin XL 80 mg in patients with type 2 diabetes.

Aged↗
PubMed1994

Effects of long-term simvastatin treatment on testicular and adrenal steroidogenesis in hypercholesterolemic patients.

Simvastatin is an inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, the key enzyme in the synthesis of cholesterol, recently introduced in the therapy of hypercholesterolemic patients. Cholesterol is the precursor of the biosynthesis of steroid hormones; thus, a reduction of the availability of cholesterol in the adrenal and testicular cells may reduce the synthesis of corticosteroids and androgens. To establish whether chronic therapy with simvastatin interferes with the integrity of the hypothalamic-pituitary-adrenal axis and with the adrenal and testicular reserve, we administered simvastatin orally in a single-day 10 mg dose for 6 months in 8 mildly hypercholesterolemic male patients. At weeks 0, 6 and 24 of treatment we evaluated the lipids, the activity of the hypothalamic-pituitary-adrenal axis by means of the Corticotropin-Releasing Hormone (CRH) test, the adrenal reserve by means of the Corticotropin rapid test and, finally, the testicular reserve by means of the Human Chorionic Gonadotropin (HCG) test. Total cholesterol and LDL-cholesterol were significantly reduced by Simvastatin, while the HDL-cholesterol and triglycerides did not change significantly. The hormonal responses to CRH, ACTH and HCG tests at weeks 6 and 24 of treatment were comparable to those obtained in basal conditions. We conclude that Simvastatin, while effective in reducing total and LDL-cholesterol in hypercholesterolemic male patients, did not interfere with hypothalamic-pituitary-adrenal axis activity or with basal and stimulated adrenal and testicular steroidogenesis.

Adrenocorticotropic Hormone↗
PubMed2004

Losartan and simvastatin inhibit platelet activation in hypertensive patients.

BACKGROUND: Diabetic patients also show hypercoagulability and platelet hyperaggregability, with increased levels of platelet activation-markers such as P-selectin (CD62P) and platelet-derived microparticles. We investigated the effects of losartan and simvastatin on circulating levels of platelet activation markers, microparticles, soluble selectins, and soluble cell adhesion molecules in hypertensive and hyperlipidemic patients with or without Type 2 diabetes. METHODS: The subjects included 25 normotensive healthy controls and 41 hypertensive patients. The 41 hypertensive patients were divided into three groups: group A had hypertension and hyperlipidemia (n = 11), group B had hypertension and Type 2 diabetes (n = 14), and group C had hypertension, hyperlipidemia, and diabetes (n = 16). Losartan was administered to all of the patients at a dose of 50 mg/day for 24 weeks. In addition, simvastatin was administered to the hyperlipidemic patients at a dose of 10 mg/day for 24 weeks. RESULTS: There were significant differences in the levels of CD62P, CD63, PAC-1, platelet microparticles, endothelial microparticles, sE-selectin, and sVCAM-1 between the hypertensive patients and healthy controls. These markers were all significantly increased in hypertensive and hyperlipidemic patients with Type 2 diabetes. In hypertensive patients with diabetes, CD62P, CD63, PAC-1, platelet and endothelial microparticles, and soluble adhesion markers were all decreased by losartan monotherapy. The decrease of each marker in hypertensive and hyperlipidemic patients given combined therapy with losartan plus simvastatin was greater among those with than without Type 2 diabetes. Low-density lipoprotein was decreased significantly by simvastatin and was correlated with CD62P or platelet microparticles in all of the patients. CONCLUSION: Administration of losartan plus simvastatin to hypertensive and hyperlipidemic patients with Type 2 diabetes may prevent the development of cardiovascular complications caused by activated platelets and microparticles via another mechanism in addition to reduction of the blood pressure or lipid levels.

Aged↗
PubMed1992

Efficacy and tolerability of simvastatin and pravastatin in patients with primary hypercholesterolemia (multicountry comparative study). The European Study Group.

A total of 291 patients with primary hypercholesterolemia [total plasma cholesterol > or = 6.20 mmol/liter (> or = 240 mg/dl)] were enrolled in an open, randomized, parallel, comparative study of simvstatin and pravastatin. All patients started or continued a standard lipid-lowering diet for > or = 6 weeks before entry into the 4-week placebo baseline period. There were 145 patients who received simvastatin and 146 patients who received pravastatin, both at the commonly recommended starting dose of 10 mg once daily, for a treatment period of 6 weeks. Concentrations of total cholesterol in plasma were reduced by 23% with simvastatin, and by 16% with pravastatin. Concentrations of low-density lipoprotein cholesterol in plasma were reduced by 32 and 22%, and high-density lipoprotein cholesterol concentrations were increased by 7 and 5% with simvastatin and pravastatin, respectively. Plasma triglyceride concentrations were reduced by 13% with simvastatin and by 6% with pravastatin. Adverse experiences were similar between treatment groups and both drugs were well tolerated. In each treatment group, 3 patients were withdrawn from the study for clinical adverse experiences; 1 patient in the pravastatin group required a reduction in dose to 5 mg/day because of insomnia. At the commonly recommended starting dose for each, simvastatin had a significantly greater lipid-lowering effect than pravastatin. Both drugs were well tolerated.

Adolescent↗
PubMed1992

Long-term therapy with high-dose simvastatin does not affect adrenocortical and gonadal hormones in hypercholesterolemic patients.

Simvastatin is an effective hypocholesterolemic drug that inhibits cholesterol synthesis selectively in the liver, but could have potential side effects on the adrenal gland, ovary, and testis, as these three glands use cholesterol for their hormonal biosynthesis. In this report, we examined adrenal and sex steroids in 10 type IIA hypercholesterolemic patients (three with familial [FH] and seven with polygenic hypercholesterolemia) over a period of 1 year on simvastatin therapy in order to confirm in vivo its selective action. Furthermore, we evaluated the adrenal reserve by a corticotropin rapid test, before starting treatment and again at the end of the third month on 20 mg of simvastatin per day, then at the sixth and 12th month on 40 mg/d. There was a significant lowering of total cholesterol (TC) (-31%), low-density lipoprotein cholesterol (LDL-C) (-39%), and apolipoprotein (apo) B (-39%); no statistically significant differences were seen in cortisol response to the corticotropin test between baseline and simvastatin-treated patients. No variation of any sex steroid was observed in patients of either gender. We conclude that long-term therapy with high-dose simvastatin does not interfere with either adrenocortical function or sex hormone production.

Adrenal Cortex Hormones↗
PubMed1992

A multicenter comparison of the effects of simvastatin and fenofibrate therapy in severe primary hypercholesterolemia, with particular emphasis on lipoproteins defined by their apolipoprotein composition.

This multicenter, double-blind, randomized study was designed to compare the effects of simvastatin (20 mg/d and 40 mg/d) and fenofibrate (400 mg/d) on plasma lipids, lipoproteins, apolipoproteins (apo), and lipoprotein particles defined by their apo composition (Lp A-I, Lp A-II:A-I, Lp E:B, Lp C-III:B) in primary hypercholesterolemia. After 6 and 10 weeks of therapy, both drugs lowered plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and apo B. The effect on LDL and apo B was significantly more pronounced for simvastatin (P = .01). Simvastatin increased Lp A-I, but did not change Lp A-II:A-I, while fenofibrate decreased Lp A-I and increased Lp A-II:A-I. Lp E:B and Lp C-III:B were decreased with both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin. This study demonstrates that both drugs have beneficial effects on the parameters positively or negatively correlated with the atherosclerotic risk, with simvastatin being more effective in reducing some of them. These results suggest that the drugs led to different structural modifications of the lipoproteins, which would not be revealed by examination of lipoprotein density classes. These differences are probably related to the different mechanisms of action of the agents.

Adolescent↗
PubMed1995

A comparison between the effects of gemfibrozil and simvastatin on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus and hyperlipoproteinemia.

In a double-blind, randomized crossover study, 29 patients with non-insulin-dependent diabetes mellitus (NIDDM) and hyperlipoproteinemia were treated with gemfibrozil (1,200 mg/d) or simvastatin (10 mg/d) for 4 months. After gemfibrozil treatment, the insulin concentration was increased during the major part of the intravenous glucose tolerance test (IVGTT) and during the hyperinsulinemic euglycemic clamp. Similar but less pronounced elevations were caused by simvastatin. Insulin sensitivity decreased by 27% and 28% during gemfibrozil and simvastatin treatment, respectively. Low-density lipoprotein (LDL) cholesterol was decreased with simvastatin treatment by 24%. The LDL cholesterol level was not changed by gemfibrozil, but very-low-density lipoprotein (VLDL) cholesterol was reduced by 40%. The VLDL triglyceride concentration was reduced to a significantly greater extent by gemfibrozil. After gemfibrozil treatment, lipoprotein(a) [Lp(a)] was decreased by 24%, and the plasma free fatty acid (FFA) concentration was increased by 20% and skeletal muscle lipoprotein lipase activity (LPLA) by 37%. Although simvastatin more effectively decreased LDL cholesterol levels and the LDL to high-density lipoprotein (HDL) ratio, it cannot be claimed unreservedly that this drug is necessarily preferable in NIDDM patients. Gemfibrozil improved triglyceride removal and decreased VLDL concentrations, with qualitative changes in LDL. The apparent effects on insulin sensitivity are difficult to evaluate and need further study.

Aged↗
PubMed1994

Simvastatin in non-insulin-dependent diabetes mellitus: effect on serum lipids, lipoproteins and haemostatic measures.

The clinical efficacy of the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMGCoA) reductase inhibitor simvastatin in the treatment of hypercholesterolaemia in non-insulin-dependent diabetes (NIDDM), was examined in a double-blind placebo-controlled study of 6 months in 70 patients with NIDDM (age 25-70 years), of whom 57 were randomised to placebo (29 patients) or simvastatin for 6 months, following a 3-month run-in on diet. Patients were hypercholesterolaemic (7.8 (7.6-8.0) (mean (95% confidence intervals)) mmol/l simvastatin vs. 8.0 (7.7-8.5) mmol/l placebo) and mildly hypertriglyceridaemic (2.6 (2.2-3.0) simvastatin vs. 2.9 (2.3-3.5) placebo). Other lipid measures and estimates of glycaemic control and haemostasis were similar in both groups. There were no significant changes in lipids, haemostatic factors, or measures of glycaemic control in the placebo treatment group. Conversely by the end of 24 weeks, simvastatin produced a 28% reduction in cholesterol (to 5.6 (5.0-6.2) mmol/l (P < 0.001)), a 38% reduction in LDL cholesterol (from 5.5 (5.4-5.6) mmol/l to 3.4 (2.8-4.0) mmol/l, P < 0.001), a 15% reduction in triglyceride (to 2.2 (1.8-2.6) mmol/l, P < 0.05, and a 9% rise in HDL (from 1.16 (1.07-1.25) to 1.23 (1.14-1.32) mmol/l, P < 0.05). Improvements in apolipoprotein B (apo B) (-28%, P < 0.001), the LDL cholesterol to apo B ratio (-20%, P < 0.001), and apo A1 (+15%, P < 0.001) were recorded. There were no effects upon fibrinogen, factor VII activity, factor VIII activity, or measures of glycaemic control (fasting glucose, insulin, C-peptide, or HbA1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention.

BACKGROUND: The relative efficacy of different statins for long-term cardiovascular prevention remains largely undetermined. METHODS: Using adjusted indirect comparison, we compared 3 statins (pravastatin, simvastatin, and atorvastatin) based on published randomized placebo-controlled trials for long-term cardiovascular prevention. A systematic literature search between 1980 and 2004 was conducted. Randomized placebo-controlled trials of the 3 statins, which studied cardiovascular diseases or death as the outcome, enrolled > or = 1000 participants, and had > or = 1-year follow-up, were included. Trials were grouped according to the statin under study. A pooled relative risk (RR) was derived from each set of trials using a random-effects model. Adjusted indirect comparisons using pooled RRs were made between statins with regard to prespecified clinical outcomes. RESULTS: Eight placebo-controlled trials met the inclusion criteria, including 4 pravastatin trials (n = 25,572), 2 simvastatin trials (n = 24,980), and 2 atorvastatin trials (n = 13,143). All trials had a similar degree of lipid reduction. Graphical and statistical assessments showed minimal heterogeneity in the trials' effect sizes. Adjusted indirect comparisons did not reveal a statistically significant difference between statins in reducing fatal coronary heart disease and nonfatal myocardial infarctions (simvastatin vs pravastatin: RR 0.93 [95% CI 0.84-1.03]; atorvastatin vs simvastatin: RR 0.84 [95% CI 0.66-1.08]; atorvastatin vs pravastatin: RR 0.79 [95% CI 0.61-1.02]). We were unable to detect differences either in outcomes for fatal and nonfatal strokes, all cardiovascular deaths, and all-cause mortality. CONCLUSION: Evidence from published statin randomized placebo-controlled trials suggests that pravastatin, simvastatin, and atorvastatin, when used at their standard dosages, show no statistically significant difference in their effect on long-term cardiovascular prevention.

Atorvastatin↗
PubMed2004

Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects.

The effects of atorvastatin at 20, 40, and 80 mg/day on plasma lipoprotein subspecies were examined in a randomized, placebo-controlled fashion over 36 weeks in 97 patients with coronary heart disease (CHD) with low-density lipoprotein (LDL) cholesterol levels of >130 mg/dl and compared directly with the effects of fluvastatin (n = 28), pravastatin (n = 22), lovastatin (n = 24), and simvastatin (n = 25). The effects of placebo and 40 mg/day of each statin were also examined in subjects with CHD with subjects in the fasting state and in the fed state 4 hours after a meal rich in saturated fat and cholesterol and compared with results in age- and gender-matched control subjects. At all doses tested in the fasting and fed states, atorvastatin was significantly (p <0.01) more effective in lowering LDL cholesterol and non-high-density lipoprotein (HDL) cholesterol than all other statins, and significantly (p <0.05) more effective than all statins, except for simvastatin, in lowering triglyceride and remnant lipoprotein (RLP) cholesterol. At 40 mg/day in the fasting state, atorvastatin was significantly (p <0.01) more effective than all statins, except for lovastatin and simvastatin, in lowering cholesterol levels in small LDL, and was significantly (p <0.05) more effective than all statins, except for simvastatin, in increasing cholesterol in large HDL and in lowering LDL particle numbers. Our data indicate that atorvastatin was the most effective statin tested in lowering cholesterol in LDL, non-HDL, and RLP in the fasting and fed states, and getting patients with CHD to established goals, with fluvastatin, pravastatin, lovastatin, and simvastatin having about 33%, 50%, 60%, and 85% of the efficacy of atorvastatin, respectively, at the same dose in the same patients.

Anticholesteremic Agents↗
PubMed2004

Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (The HDL Atherosclerosis Treatment Study).

The high-density lipoprotein (HDL)-Atherosclerosis Treatment Study showed that simvastatin plus niacin (mean daily dose 13 mg and 2.4 g, respectively) halt angiographic atherosclerosis progression and reduce major clinical events by 60% in patients with coronary artery disease (CAD) who have low HDL, in comparison with placebos, over 3 years. How safe and well-tolerated is this combination? One hundred sixty patients with CAD, including 25 with diabetes mellitus, with mean low-density lipoprotein cholesterol of 128 mg/dl, HDL cholesterol of < or =35 mg/dl (mean 31), and mean triglycerides of 217 mg/dl were randomized to 4 factorial combinations of antioxidant vitamins or their placebos and simvastatin plus niacin or their placebos. Patients were examined monthly or bimonthly for 38 months; side effects (gastrointestinal upset, nausea, anorexia, vision, skin, and energy problems, or muscle aches) were directly queried and recorded. Aspartate aminotransferase, creatine phosphokinase (CPK), uric acid, homocysteine, and fasting glucose levels were regularly monitored. A safety monitor reviewed all side effects and adjusted drug dosages accordingly. Patients who received simvastatin plus niacin and those on placebo had similar frequencies of clinical or laboratory side effects: any degree of flushing (30% vs 23%, p = NS), symptoms of fatigue, nausea, and/or muscle aches (9% vs 5%, p = NS), aspartate aminotransferase (SGOT) > or =3 times upper limit of normal (3% vs 1%, p = NS), CPK > or =2 times upper limit of normal (3% vs 4%, p = NS), CPK > or =5 times upper limit of normal, new onset of uric acid > or =7.5 mg/dl (18% vs 15%, p = NS), and homocysteine > or =15 micromol/L (9% vs 4%, p = NS). Glycemic control among diabetics declined mildly in the simvastatin-niacin group but returned to pretreatment levels at 8 months and remained stable for rest of the study. This combination regimen was repeatedly described by 91% of treated patients and 86% of placebo subjects as "very easy" or "fairly easy" to take. Thus, the simvastatin plus niacin regimen is effective, safe, and well tolerated in patients with or without diabetes mellitus.

Blood Glucose↗
PubMed2004

Reclassification of simvastatin to over-the-counter status in the United Kingdom: a primary prevention strategy.

Simvastatin (10-mg tablet) has been reclassified for sale as a pharmacy-only over-the-counter medicine in the United Kingdom. It is designed to be a primary prevention agent targeting that segment of the population having a moderate risk of coronary artery disease (CAD). The anticipated effect is a reduction of risk of a first major coronary event (nonfatal myocardial infarction or CAD death). Simvastatin is a component of the Heart Health Programme, which also addresses other modifiable risk factors such as diet, exercise, and smoking. Men >/=55 years of age, men aged 45 to 54 years with >/=1 risk factor, and women aged >/=55 years with >/=1 risk factor have a moderate (10% to 15%) 10-year risk of developing CAD. Risk factors include having a first-degree relative with a history of early family CAD, smoking, being overweight, and South Asian ethnicity. Simvastatin 10 mg lowers low-density lipoprotein cholesterol levels by approximately 30%, with a resultant 33% reduction in risk of a major CAD event after 3 years. After the patient completes a check-box questionnaire regarding his or her medical history and other specific risk factors, the pharmacist performs a few simple physical measurements and makes a decision as to CAD risk and simvastatin eligibility. After 1 month of simvastatin therapy, cholesterol testing is highly recommended to patients, and a kit is made available that permits home blood collection and analysis at a central laboratory.

Anticholesteremic Agents↗
PubMed2006

Comparison of effects of high (80 mg) versus low (20 mg) dose of simvastatin on C-reactive protein and lipoproteins in patients with angiographic evidence of coronary arterial narrowing.

Although previous studies have demonstrated that various "statins" decrease levels of high-sensitivity C-reactive protein (hs-CRP), the dose-response relation for lowering hs-CRP by the clinically important drug simvastatin compared with lipid lowering is unclear. A 16-week, randomized, double-blind study was performed in patients with stable coronary artery disease and high hs-CRP levels (>3 mg/L). Subjects were randomized to placebo, 20 mg of simvastatin, or 80 mg of simvastatin for 12 weeks. Those currently on a statin first underwent a 4-week washout. Of the 107 total patients randomized, 96 completed the trial, and 89 were able to be evaluated for efficacy. Changes in hs-CRP differed across simvastatin and placebo groups (change score +1.6 vs -0.6 mg/L, p = 0.004), but no dose response was observed when comparing 80 with 20 mg/day (-0.6 vs -0.5 mg/L, respectively). A strong dose response was observed for changes in total (p <0.01) and low-density lipoprotein (p <0.001) cholesterol. hs-CRP changes did not correlate with low-density lipoprotein changes. In conclusion, this randomized trial in patients with chronic stable coronary artery disease showed a strong dose response for simvastatin for total and low-density lipoprotein cholesterol lowering but not for hs-CRP.

Aged↗
PubMed2005

Simvastatin induces impairment in skeletal muscle while heart is protected.

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are widely used to reduce plasma cholesterol concentration. However, statins are also known to induce various forms of muscular toxicity. We have previously shown that acute application of simvastatin on human skeletal muscle samples induced a cascade of cellular events originating from mitochondria and resulting in a global alteration of Ca2+ homeostasis. The present study was designed to further define the origin of the mitochondria impairment and to understand the apparent lack of deleterious effect on the heart. Using fluorescence imaging analysis and oxygraphy on human and rat skinned skeletal muscle samples, we show that the simvastatin-induced mitochondria impairment results from inhibition of the complex I of respiratory chain. Similar simvastatin-induced mitochondria impairment and alteration of Ca2+ homeostasis occur in permeabilized but not in intact ventricular rat cardiomyocytes. In intact rat skeletal muscle fibers from the flexor digitorum brevis muscle, the simvastatin-induced alteration of Ca2+ homeostasis is abolished when monocarboxylate transporter (MCT4) is inhibited. The impairment of complex I by simvastatin might be the primary step of its cellular deleterious effects leading to muscle fiber death. This mechanism is seen specifically in skeletal muscles. This specificity should be in part attributed to a preferential uptake of statins by MCT4 that is not expressed in cardiomyocytes.

Animals↗