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PubMed2001

STATT: a titrate-to-goal study of simvastatin in Asian patients with coronary heart disease. Simvastatin Treats Asians to Target.

BACKGROUND: Most published studies on the use of lipid-lowering agents to treat hypercholesterolemia have focused on Western populations, with few data on Asian populations. OBJECTIVE: The Simvastatin Treats Asians to Target (STATT) study used a titrate-to-goal protocol to evaluate the efficacy and tolerability of simvastatin 20 to 80 mg/d in the treatment of Asian patients with coronary heart disease. METHODS: This was a multicenter, open-label, uncontrolled, 14-week study in patients with coronary heart disease and serum low-density lipoprotein cholesterol (LDL-C) levels of 115-180 mg/dL and triglyceride levels of < or = 400 mg/dL. The dose of simvastatin was titrated from 20 to 80 mg/d to achieve the National Cholesterol Education Program (NCEP) LDL-C target of < or = 100 mg/dL. The primary efficacy measure was the percentage of patients achieving the NCEP target. Among secondary measures were the percentage of patients achieving European Society of Cardiology/European Atherosclerosis Society/European Society of Hypertension target LDL-C levels of < or = 115 mg/dL and the percentage change from baseline in lipid parameters. Tolerability was assessed in terms of the overall incidence of adverse experiences and the incidences of the most commonly reported adverse experiences. RESULTS: The intent-to-treat analysis included 133 Asian patients (93 men, 40 women; mean age, 59.5 years), of whom 125 completed 14 weeks of therapy. Their mean blood pressure was 130.2/79.4 mm Hg. Overall, 104 (78.2%) patients treated with simvastatin achieved LDL-C levels < or = 100 mg/dL at week 14, and 125 (94.0%) achieved this target at some point during the study. Similarly, 122 (91.7%) patients achieved an LDL-C level < or = 115 mg/dL at week 14, and 130 (97.7%) achieved this target at some point during the study. Treatment with simvastatin had favorable effects on the lipid profile, producing significant percentage changes from baseline in all parameters (P < 0.001). Simvastatin was well tolerated across the dose range. Overall, 40 patients (30.1%) had > or = 1 clinical adverse experience. Only 14 (10.5%) had adverse experiences that were possibly, probably, or definitely related to study drug; none of these experiences were considered serious. The most common adverse experiences (> or = 3% incidence) were abdominal pain (6%); chest pain (5%); dizziness (4%); and asthenia/fatigue, fibromyalgia, headache, insomnia, and upper respiratory tract infection (3% each). No new or unexpected adverse experiences were seen at the higher doses. CONCLUSIONS: Simvastatin was effective and well tolerated at doses of 20, 40, and 80 mg/d in Asian patients with coronary heart disease. Titration enabled the majority to achieve target LDL-C levels of < or = 100 mg/dL.

Aged↗
PubMed1999

Simvastatin in nephrotic syndrome. Simvastatin in Nephrotic Syndrome Study Group.

BACKGROUND: Hyperlipidemia of the nephrotic syndrome is a risk factor for the development of systemic atherosclerosis, but it also may aggravate glomerulosclerosis and enhance the progression of glomerular disease. HMG-CoA reductase inhibitors are effective in reducing cardiovascular morbidity and mortality. Whether they may influence the progression of glomerular disease is not clear. The Simvastatin in Nephrotic Syndrome Study addressed the question of whether or not cholesterol lowering by the HMG-CoA reductase inhibitor simvastatin was superior to placebo treatment in limiting the decline of GFR and reducing proteinuria in nephrotic patients with primary glomerulonephritis. METHODS: This was a prospective, two-year, double-blind trial that included 56 patients with primary glomerulonephritis, hypercholesterolemia due to the nephrotic syndrome (proteinuria > 3 g/24 hr), and a creatinine clearance > 40 ml/min/1.73 m2. They were randomly assigned to treatment with simvastatin or placebo targeted to achieve low density lipoprotein (LDL) cholesterol levels below 120 mg/dl. The objectives were to determine the efficacy and safety of simvastatin, the rate of GFR decline as measured by inulin clearance, and the change in proteinuria over a two-year treatment period. RESULTS: Simvastatin produced a mean change in cholesterol, LDL cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides of -39% -47%, +1%, and -30%, respectively. Serum lipoprotein(a) [Lp(a)] was not affected. No major simvastatin related events occurred. Minor events included elevations in serum creatine kinase without clinical symptoms. The course of renal function and of proteinuria during the study are still under evaluation and are not given here. CONCLUSIONS: Long-term treatment with simvastatin in nephrotic patients with hypercholesterolemia is effective and safe.

Adult↗
PubMed2003

Differences between lovastatin and simvastatin hydrolysis in healthy male and female volunteers:gut hydrolysis of lovastatin is twice that of simvastatin.

The aim of this pharmacokinetic evaluation was to show the effect of the extra methyl group in simvastatin on esterase hydrolysis between lovastatin and simvastatin in male and female volunteers. This study was based on the plasma concentration-time curves and the pharmacokinetics of lovastatin and simvastatin with its respective active metabolite statin-beta-hydroxy acid obtained from two different bioequivalence studies, each with 18 females and 18 males. Results were: The group of female volunteers showed a higher yield of the active metabolite beta-hydroxy acid than the group of males (p < 0.002) for both lovastatin and simvastatin. This difference was not related to the body weight of both groups. In the male/female groups, subject-dependent yield of active metabolite beta-hydroxy acid was demonstrated, which was independent of the formulation. The variation in plasma/liver hydrolysis resulted in a fan-shaped distribution of data points when the AUCt lovastatin was plotted vs. that of the beta-hydroxy acid metabolite. In the fan of data points, subgroups could be distinguished, each showing a different regression line and with a different Y-intercept (AUCtbeta-hydroxy acid). Lovastatin hydrolysis was higher than simvastatin hydrolysis. It was possible to discriminate between hydrolysis of both lovastatin and simvastatin by plasma/liver or tissue esterase activity. The three subgroups of subjects (males/females) showing different but high yield of statin beta-hydroxy acid can be explained by variable hydrolysis of plasma and hepatic microsomal and cytosolic carboxyesterase activity. This study showed clearly that despite the subject-dependent hydrolysis of lovastatin/simvastatin to the active metabolite, males tend to hydrolyse less than females. The extra methyl group in simvastatin results in less hydrolysis due to steric hindrance.

Adult↗
PubMed1994

Comparative efficacy and tolerability of 5 and 10 mg simvastatin and 10 mg pravastatin in moderate primary hypercholesterolemia. Simvastatin Pravastatin European Study Group.

Simvastatin and pravastatin, two 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, were compared in a multinational, randomized, double-blind trial. Patients demonstrating moderate hypercholesterolemia after 10 weeks on a lipid-lowering diet received 6 weeks of treatment with 5 mg/day simvastatin (n = 143) or 10 mg/day pravastatin (n = 138); the simvastatin dose was increased to 10 mg for an additional 6 weeks while the pravastatin dose remained at 10 mg. When administered at lower or equivalent daily doses, simvastatin was significantly more effective than pravastatin in reducing total and low-density lipoprotein (LDL) cholesterol. Reductions in plasma total and LDL cholesterol were significantly greater with 5 mg simvastatin (16 and 23%) compared to 10 mg pravastatin (12 and 18%; p < or = 0.01). The efficacy of 10 mg simvastatin in lowering these lipid parameters was also superior (19 vs. 11% and 27 vs. 17%, respectively; p < or = 0.01). At 6 and 12 weeks, a significantly higher percentage of simvastatin patients (45 and 59%, respectively) achieved a desirable LDL cholesterol level of < 130 mg/dl (< 3.4 mmol/l) compared to pravastatin patients (32-33%; p < or = 0.05). Both drugs were well tolerated and had comparable safety profiles.

Adult↗
PubMed2000

Lipid-altering efficacy and safety of simvastatin 80 mg/day: long-term experience in a large group of patients with hypercholesterolemia. World Wide Expanded Dose Simvastatin Study Group.

BACKGROUND: Elevated levels of low-density lipoprotein (LDL) cholesterol promote the development of atherosclerosis and coronary heart disease. HYPOTHESIS: Simvastatin 80 mg/day will be more effective than simvastatin 40 mg/day at reducing LDL cholesterol and will be well tolerated. METHODS: Two similar, randomized, multicenter, controlled, double-blind, parallel-group, 48-week studies were performed to evaluate the long-term lipid-altering efficacy and safety of simvastatin 80 mg/day in patients with hypercholesterolemia. One study conducted in the US enrolled patients meeting the National Cholesterol Education Program (NCEP) LDL cholesterol criteria for pharmacologic treatment. In the other multinational study, patients with LDL cholesterol levels > or = 4.2 mmol/l were enrolled. At 20 centers in the US and 19 countries world-wide, 1,105 hypercholesterolemic patients, while on a lipid-lowering diet, were randomly assigned at a ratio of 2:3 to receive simvastatin 40 mg (n = 436) or 80 mg (n = 669) once daily for 24 weeks. Those patients completing an initial 24-week base study were enrolled in a 24-week blinded extension. Patients who had started on the 80 mg dose in the base study continued on the same dose in the extension, while those who had started on the 40 mg dose were rerandomized at a 1:1 ratio to simvastatin 40 or 80 mg in the extension. RESULTS: There was a significant advantage in the LDL cholesterol-lowering effect of the 80 mg dose compared with that of the 40 mg dose, which was maintained over the 48 weeks of treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol for the 40 and 80 mg groups were 41% (42, 39) and 47% (48, 46), respectively, for the 24-week base study, and 41% (43, 39) and 46% (47, 45), respectively, after 48 weeks of treatment (p < 0.001 between groups). Larger reductions in total cholesterol and triglycerides were also observed with the 80 mg dose compared with the 40 mg dose at Weeks 24 and 48. Both doses were well tolerated, with close to 95% of patients enrolled completing the entire 48 weeks of treatment. Myopathy (muscle symptoms plus creatine kinase increase > 10 fold upper limit of normal) and clinically significant hepatic transaminase increases (> 3 times the upper limit of normal) occurred infrequently with both doses. There was no significant difference between the groups in the number of patients with such increases, although there were more cases for both with the 80 mg dose. CONCLUSIONS: Compared with the 40 mg dose, simvastatin 80 mg produced greater reductions in LDL cholesterol, total cholesterol, and triglycerides. Both doses were well tolerated.

Adult↗
PubMed1993

Comparison of the efficacy, safety and tolerability of simvastatin and pravastatin for hypercholesterolemia. The Simvastatin Pravastatin Study Group.

The efficacy and safety profile of simvastatin and pravastatin across their most commonly recommended dosage ranges were compared in a double-blind, parallel, multicenter study in 550 patients with primary hypercholesterolemia. The study consisted of a 6-week placebo period followed by 18 weeks of active treatment. Patients were randomized to 10 mg of simvastatin or pravastatin once in the evening; doses were titrated at 6-week intervals to a maximum of 40 mg/day if the low-density lipoprotein (LDL) cholesterol remained > or = 130 mg/dl (3.4 mmol/liter). Baseline characteristics were similar in both groups. At the end of the study with simvastatin and pravastatin, respectively, 30 and 14% continued to take the 10 mg dose and 48 and 66% were titrated to the maximal dose. After 18 weeks of treatment with simvastatin and pravastatin the mean percent decreases from baseline were, respectively, for total plasma cholesterol 27 and 19% (p < 0.01 between groups), for LDL cholesterol 38 and 26% (p < 0.01 between groups), for very low density lipoprotein cholesterol 30 and 16% (p < 0.01 between groups), and for triglycerides 18 and 14% (p < 0.05 between groups). The mean percent increase from baseline in high-density lipoprotein cholesterol was 15% with simvastatin compared to 12% with pravastatin (p < 0.05 between groups). The efficacy goal of LDL cholesterol < 130 mg/dl was achieved in 65% of the patients treated with simvastatin versus 39% of those treated with pravastatin (p < 0.001). There was no significant difference between groups in the frequency of drug-related adverse experiences.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Comparison of low-dose simvastatin and gemfibrozil in the treatment of elevated plasma cholesterol. A multicenter study. The Simvastatin Study Group.

A 12-week, randomized, double-blind, multicenter study was undertaken to compare the efficacy, tolerability, and safety of simvastatin and gemfibrozil in 290 patients with primary hypercholesterolemia. Patients in stratum I (initial low-density lipoprotein cholesterol level less than 195 mg/dl) received simvastatin 5 to 10 mg once every afternoon; patients in stratum II (initial low-density lipoprotein cholesterol level at least 195 mg/dl) received 10 to 20 mg once every afternoon. Gemfibrozil was given in a constant dosage of 600 mg twice daily in both strata. Simvastatin reduced low-density lipoprotein cholesterol levels by 26 and 34 percent in strata I and II, respectively. The corresponding reductions brought about by gemfibrozil were 18 and 17 percent. High-density lipoprotein cholesterol was increased by 7 and 9 percent by simvastatin and by 17 and 16 percent by gemfibrozil in strata I and II, respectively. Ratios of low-density to high-density lipoprotein cholesterol were reduced by approximately 25 percent by simvastatin 5 to 10 mg once every afternoon and gemfibrozil 600 mg twice daily, but were reduced by 37 percent by simvastatin 10 to 20 mg once every afternoon. Both drugs reduced plasma triglyceride levels, but gemfibrozil was much more effective. The short-term tolerability and safety of both drugs appeared to be good during the 12-week study. The results suggest that both drugs have useful but distinctly different lipid-modifying properties.

Anticholesteremic Agents↗
PubMedDate not supplied

Effects of low-dose simvastatin therapy on serum lipid levels in patients with moderate hypercholesterolemia: a 12-month study. The Simvastatin Study Group.

The aim of this study was to investigate the safety and long-term effects on serum lipid levels of low-dose simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in Japanese patients with moderate primary hypercholesterolemia. We assigned 201 patients (68 men and 133 women; mean +/- SD age, 61.3 +/- 10.2 years) with serum total cholesterol levels > or = 220 mg/dL to receive simvastatin 5 mg each evening; the treatment period was 1 year. Serum total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol levels decreased significantly in response to simvastatin therapy, and the changes were maintained throughout the treatment period. Mean total cholesterol decreased from 269.9 +/- 35.4 mg/dL to 215.2 +/- 34.5 mg/dL (20.3%), triglycerides decreased from 183.0 +/- 110.2 mg/dL to 155.5 +/- 88.5 mg/dL (15.0%), and LDL cholesterol decreased from 180.0 +/- 33.1 mg/dL to 130.1 +/- 35.1 mg/dL (27.7%). Total cholesterol, triglycerides, and LDL cholesterol tended to decline when the pretreatment values were higher; the critical values and the bidirectional changes of the serum lipid levels were 188.1, 109.5, and 91.6 mg/dL, respectively. Although the serum level of high-density lipoprotein cholesterol did not change significantly, it tended to increase more when the pretreatment values were lower; the "critical value" was 70 mg/dL. Nine patients experienced mild adverse events, but none discontinued simvastatin during the 12-month treatment period. We found that low-dose simvastatin therapy is effective in achieving long-term decreases in serum lipid levels and is well tolerated by patients with moderate hypercholesterolemia. Simvastatin therapy may result in normalization of serum lipid levels.

Adult↗
PubMed1997

Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S)

OBJECTIVE: To assess in diabetic patients with coronary heart disease (CHD) the effect of cholesterol lowering with simvastatin on mortality and the risk of CHD and other atherosclerotic events. RESEARCH DESIGN AND METHODS: A post hoc subgroup analysis was carried out on data from 202 diabetic patients and 4,242 nondiabetic patients with previous myocardial infarction or angina pectoris, serum total cholesterol 5.5-8.0 mmol/l, and serum triglycerides < or = 2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S). Participants in the 4S were randomly assigned to double-blind treatment with simvastatin, 20 mg daily, with blinded dosage titration up to 40 mg daily, according to cholesterol response during the first 6-18 weeks, or placebo. Endpoints were 1) total mortality, 2) major CHD events (CHD death or nonfatal myocardial infarction), 3) other acute atherosclerotic events, 4) myocardial revascularization procedures. RESULTS: Over the 5.4-year median follow-up period, simvastatin treatment produced mean changes in serum lipids in diabetic patients similar to those observed in nondiabetic patients. The relative risks (RRs) of main endpoints in simvastatin-treated diabetic patients were as follows: total mortality 0.57 (95% CI, 0.30-1.08; P = 0.087), major CHD events 0.45 (95% CI, 0.27-0.74; P = 0.002), and any atherosclerotic event 0.63 (95% CI, 0.43-0.92; P = 0.018). The corresponding RRs in nondiabetic patients were the following: 0.71 (95% CI, 0.58-0.87; P = 0.001), 0.68 (95% CI, 0.60-0.77; P < 0.0001), and 0.74 (95% CI, 0.68-0.82; P < 0.0001). CONCLUSIONS: The results strongly suggest that cholesterol lowering with simvastatin improves the prognosis of diabetic patients with CHD. The absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with CHD because diabetic patients have a higher absolute risk of recurrent CHD events and other atherosclerotic events.

Anticholesteremic Agents↗
PubMed2004

Reduction of cardiovascular events by simvastatin in nondiabetic coronary heart disease patients with and without the metabolic syndrome: subgroup analyses of the Scandinavian Simvastatin Survival Study (4S).

OBJECTIVE: To assess the effect of simvastatin treatment on the risk of cardiovascular events in nondiabetic patients with coronary heart disease (CHD) with and without the metabolic syndrome, as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III). RESEARCH DESIGN AND METHODS: Subgroup analyses were performed on data from 3933 nondiabetic patients with clinically established CHD, serum total cholesterol level 5.5-8.0 mmol/l, and serum triglyceride level <or=2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S), a randomized, placebo-controlled trial. End points were total mortality, coronary mortality, major CHD event, myocardial revascularization, any CHD event, stroke, and any atherosclerotic event. RESULTS: Over the 5.4-year median follow-up period, simvastatin produced similar changes in serum lipid levels in 893 patients with the metabolic syndrome and in 3040 patients without the metabolic syndrome. The relative risks of main end points in simvastatin-treated patients compared with placebo-treated patients with the metabolic syndrome were as follows: total mortality 0.54 (95% CI 0.36-0.82), coronary mortality 0.39 (0.23-0.65), major CHD event 0.59 (0.45-0.77), and any atherosclerotic event 0.69 (0.56-0.84). The corresponding RRs in patients without the metabolic syndrome were 0.72 (0.56-0.91), 0.62 (0.45-0.84), 0.71 (0.61-0.82), and 0.76 (0.68-0.85). CONCLUSIONS: Nondiabetic CHD patients with or without the metabolic syndrome realize from simvastatin treatment a similar, substantial relative reduction in the risk of cardiovascular events. The absolute benefit may be greater in patients with the metabolic syndrome because they are at a higher absolute risk.

Cardiovascular Diseases↗
PubMed1997

Cost effectiveness of simvastatin treatment to lower cholesterol levels in patients with coronary heart disease. Scandinavian Simvastatin Survival Study Group.

BACKGROUND: The Scandinavian Simvastatin Survival Study (4S) showed that lowering cholesterol levels with simvastatin reduces mortality and morbidity in patients with angina pectoris or previous acute myocardial infarction. Before the widespread use of cholesterol-lowering drugs in such patients is recommended, its cost effectiveness should be demonstrated. We estimated the cost effectiveness of simvastatin treatment to lower cholesterol levels in relation to the age, sex, and cholesterol level before treatment of patients with coronary heart disease. METHODS: We estimated the cost per year of life gained with simvastatin therapy. To model the increased life expectancy, hazard functions from 4S were used. The costs studied included those of the intervention and the direct and indirect costs associated with morbidity from coronary causes. We prepared separate estimates for men and women at various ages (from 35 to 70 years) and total cholesterol levels before treatment (213 to 309 mg per deciliter). RESULTS: In the analysis limited to direct costs, the cost of each year of life gained ranged from $3,800 for 70-year-old men with 309 mg of cholesterol per deciliter to $27,400 for 35-year-old women with 213 mg of cholesterol per deciliter. When we included indirect costs, the results ranged from a savings in the youngest patients to a cost of $13,300 per year of life gained in 70-year-old women with 213 mg of cholesterol per deciliter. CONCLUSIONS: In patients with coronary heart disease, simvastatin therapy is cost effective among both men and women at the ages and cholesterol levels studied.

Adult↗
PubMed1990

Safety, tolerability, and efficacy of simvastatin and fenofibrate--a multicenter study. Simvastatin-Fenofibrate Study Group.

Five centers participated in a double-blind, randomized, active-drug controlled study. The selected patients had a diagnosis of primary hypercholesterolemia (phenotype IIa or IIb, total cholesterol [TC] greater than 300 mg/dl, low-density lipoprotein [LDL] cholesterol greater than 195 mg/dl, triglycerides [TG] less than 350 mg/dl). Throughout the study the patients observed a lipid-lowering diet (American Heart Association). After a baseline placebo period (4 weeks), the patients were randomly assigned to simvastatin 20 mg q.p.m. or fenofibrate 200 mg b.i.d. If after 6 weeks of treatment the LDL cholesterol level remained over 140 mg/dl the dose of simvastatin was doubled. The total duration of treatment was 10 weeks. One hundred eighty-four patients completed the study; age ranged from 17 to 72 years (mean 46; 129 men, 55 women). Seventy-nine patients had ischemic heart diseases. Simvastatin significantly reduces TC, LDL, and apolipoprotein (apo) B (30%, 35%, and 27%, respectively). These effects are larger than those of fenofibrate (19%, 22%, and 14%, respectively). Fenofibrate decreased very-low-density lipoprotein and TG, and increased high-density lipoprotein and apo A1, to a larger extent than simvastatin. However, the difference reached statistical significance only for TG (29% versus 17%). Both drugs were well tolerated. Clinical adverse experiences occurred with a low frequency, and few of these were considered drug related (6 and 8% in the simvastatin and fenofibrate groups, respectively). Only two patients had serious laboratory adverse experiences considered drug related or possibly drug related (one in each treatment group with increased SGPT, gamma-GT, and/or creatine phosphokinase).

Adolescent↗
PubMed2002

A randomized crossover study to evaluate LDL-cholesterol lowering effect of a generic product of simvastatin (Unison Company) compared to simvastatin (Zocor) in hypercholesterolemic subjects.

It is agreed that people with a high blood LDL-cholesterol level will have a higher risk of coronary heart disease (CAD) than those with low blood LDL-cholesterol level. Because of the present National Drug Strategy of Thailand, the promotion of "in-country production" of a generic drug has been established. Simvastatin is one of the drugs in this strategy. In this, the primary report of a randomized crossover study with washout period for a cholesterol lowering effect in a generic product of simvastatin (Unison company) which was compared to the original simvastatin (Zocor) hypercholesterolemic to the subjects were presented. Simvastatin used in this study were derived from two sources. The first group was the original product (Zocor), dosage 10 mg, Lot No IC4/36(N) from Merck Sharp & Dohme Company and the second group was a generic product, dosage 10 mg, Lot No T05/080 and T06/109 from Unison Company. All simvastatin tablets from the first and second sources were inserted into closed capsule of the same shape and called drug A and drug B, respectively. Both the physician in-charge and the subjects in this study were blinded for the content inside the capsule (Double blind). Thirty drug capsules were put into a sachet and distributed to the subject at each visit. The interval between each visit was 4 weeks. All subjects were asked to bring back the residual capsule within the sachet to the researcher at each visit in order to evaluate the subject's compliance. All subjects had physical examination and blood tests at each visit. Furthermore, all subjects were advised to practice diet control and regular in-take of the drug capsule daily after their evening meal. All 48 subjects were randomly allocated into 2 groups. This study was run as a randomized crossover study. After taking the drugs for the first 8 weeks, no statistically significant difference of blood LDL-cholesterol between the first and second group was detected. After a 4 week washout period, crossover and taking the drugs for the last 8 weeks, no statistically significant difference of blood LDL-cholesterol between the first and second group was detected. At the end of this study, comparing both groups by ANOVA crossover test, no statistically significant difference of blood LDL-cholesterol between the first and second group was detected.

Adult↗
PubMed1996

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.

Adult↗
PubMed2002

Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain.

BACKGROUND: Previous studies have shown that patients with early onset of Alzheimer disease and vascular dementia have higher levels of circulating brain-derived 24S-hydroxycholesterol (cerebrosterol). Two recent epidemiological studies indicated that treatment with inhibitors of cholesterol synthesis (statins) reduces the incidence of Alzheimer disease. OBJECTIVE: To test the hypothesis that treatment with high-dosage simvastatin reduces circulating levels of 24S-hydroxycholesterol. DESIGN: Prospective, 24-week treatment trial for lowering of cholesterol levels. We conducted assessments at baseline, week 6, and week 24. SETTING: An academic outpatient clinical study. PATIENTS: Eighteen patients who met the criteria for hypercholesterolemia. INTERVENTION: Treatment with 80 mg/d of simvastatin at night. MAIN OUTCOME MEASURES: Plasma lipoprotein levels were measured enzymatically; lathosterol, by means of gas chromatography; and 24S-hydroxycholesterol, by means of gas chromatography-mass spectrometry. RESULTS: Simvastatin reduced total plasma cholesterol levels by 36% and 35% after 6 and 24 weeks, respectively (P<.001). Lathosterol levels were reduced by 74% and 72%, respectively, and the ratio of lathosterol to cholesterol, an indicator of whole-body cholesterol synthesis, was reduced by 60% and 61%, respectively (P<.001). Plasma 24S-hydroxycholesterol levels were lowered by 45% and 53%, respectively (P<.001). The ratio of 24S-hydroxycholesterol to cholesterol also decreased significantly (-12% [P=.01] and -23% [P<.002], respectively). The further reduction of 24S-hydroxycholesterol levels and its ratio to cholesterol from weeks 6 to 24 was also significant (P=.02 for both). CONCLUSIONS: The greater reduction of plasma concentrations of 24S-hydroxycholesterol compared with cholesterol indicates that simvastatin in a dosage of 80 mg/d reduces cholesterol turnover in the brain. The present results might describe a possible mechanism of how long-term treatment with statins could reduce the incidence of Alzheimer disease.

Administration, Oral↗
PubMed1998

Efficacy and safety of simvastatin 80 mg/day in hypercholesterolemic patients. The Expanded Dose Simvastatin U.S. Study Group.

This randomized, multicenter, double-blind parallel-group study was performed to evaluate the lipid-altering efficacy and safety of simvastatin 80 mg/day, a dose twice the current maximum recommended dose. At 20 centers in the United States, 521 male and female hypercholesterolemic patients were randomly assigned in a ratio of 2:3 to receive simvastatin 40 or 80 mg once daily, respectively, for 24 weeks in conjunction with a lipid-lowering diet. Patients met National Cholesterol Education Program (NCEP) low-density lipoprotein (LDL) cholesterol criteria for pharmacologic treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol averaged at weeks 18 and 24 were 38% (-40 to -36) and 46% (-47 to -45) for the 40- and 80-mg groups, respectively (p <0.001 between groups). One third of patients on the 40- and 80-mg doses achieved an LDL cholesterol reduction of 46% and > or = 53%, respectively. Decreases in apolipoprotein B, total cholesterol, and triglycerides were also significantly greater among patients receiving 80 mg/day. Simvastatin was well tolerated in both groups. Two patients (0.6%) in the 80-mg group developed myopathy. Consecutive, clinically significant hepatic transaminase elevations occurred in 3 (1.0%) and 6 (1.9%) patients in the 40- and 80-mg groups, respectively (p= 0.486). In conclusion, simvastatin 80 mg/day provided substantial reductions in LDL cholesterol, allowing most patients to reach their NCEP target levels; it also had an excellent safety and tolerability profile.

Adult↗
PubMed2004

A randomized, open-label, comparative study of simvastatin plus diet versus diet alone on angiographic retardation of coronary atherosclerosis in adult Japanese patients: Japanese utilization of simvastatin therapy (JUST) study.

BACKGROUND: Cholesterol-lowering therapy reduces the risk of cardiovascular events by slowing the progression or enhancing the regression of coronary atherosclerosis. OBJECTIVE: This study assessed the effects of simvastatin 10 mg/d on progressive coronary atherosclerosis in Japanese patients with coronary artery disease and mild to moderate hypercholesterolemia. METHODS: In a 2-year, open-label comparative study, patients with coronary atherosclerotic lesions (> or =50% diameter stenosis) and serum total cholesterol levels > or =200 and < or =280 mg/dL were randomly assigned to 2 groups: 1 group received simvastatin 10 mg/d taken orally with diet (S-D) and the other group was assigned to diet alone (D). Atherosclerotic progression in coronary segments was compared in the 2 groups using quantitative coronary angiography (QCA). QCA measurements were done under blinded conditions. The study's primary end point was the comparison of mean changes in each segment's minimum obstruction diameter (MOD) or mean segment diameter (MSD) between the S-D group and the D group. RESULTS: A total of 299 patients were randomized, 146 to the S-D group and 153 to the D group. Mean (SD) age was 58.7 (8.0) years and mean (SD) total cholesterol level was 232.6 (21.6) mg/dL at baseline. After 2 years, serum low-density lipoprotein cholesterol levels decreased by 31.9% in the S-D group and by 2.0% in the D group. QCA showed significant stenotic progression in the D group, with reductions in MOD and MSD both by per-segment-based (P < 0.001 and P = 0.004, respectively) and per-patient-based (both P = 0.004) analyses. Although simvastatin treatment suppressed atherosclerotic progression in both per-segment- and per-patient-based analyses, significant reductions were found only in MOD values with per-segment-based analyses (P = 0.034). In a categorical approach, progression was found in significantly fewer segments in the S-D group compared with the D group (MOD, P = 0.014; MSD, P = 0.003), with odds ratios (S-D) group/D group) of 0.571 for MOD and 0.390 for MSD. Significantly fewer patients with angiographic progression were observed in the S-D group (23.3%) compared with the D group (39.4%) with respect to MSD (P = 0.02). CONCLUSION: Two years of treatment with simvastatin 10 mg/d improved patients' lipid profile and retarded coronary atherosclerotic progression in Japanese patients with coronary artery disease and mild to moderate hypercholesterolemia

Anticholesteremic Agents↗
PubMed1995

Long-term effects of simvastatin in hypercholesterolemic patients with NIDDM and additional atherosclerotic risk factors. Hyogo Simvastatin Study Group.

Effects of 12 months of simvastatin treatment were examined in 48 NIDDM patients with total serum cholesterol levels exceeding 220 mg/dl and were compared with those in 35 nondiabetic patients with hypercholesterolemia. In the diabetic group, 5-10 mg of simvastatin given once daily at bedtime significantly lowered total cholesterol (21%). LDL cholesterol (28%), apoB (15%) and triglycerides (8%) levels. These changes were identical to those in the nondiabetic group, except for triglycerides which did not change significantly. HDL cholesterol increased significantly in the nondiabetic group but not in the diabetic group. The reductions in LDL cholesterol and apoB in hypercholesterolemic patients with NIDDM were not influenced by gender, age, glycemic control, the presence or absence of systemic hypertension, obesity and overt proteinuria. In addition, the decrease in LDL cholesterol was not affected by the number of risk factors per patient. Simvastatin did not significantly alter hemoglobin A1c or fasting plasma glucose and was well tolerated in both groups. Simvastatin produced beneficial effects on serum lipids and apolipoproteins and neutral effects on glycemic control in hypercholesterolemic patients with NIDDM, whether or not they had an additional atherosclerotic risk factor.

Anticholesteremic Agents↗