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PubMed2005

Treatment with high-dose simvastatin reduces secretion of apolipoprotein B-lipoproteins in patients with diabetic dyslipidemia.

HMG-CoA reductase inhibitors (statins) are effective lipid-altering drugs for the treatment of dyslipidemia in patients with type 2 diabetes mellitus. We conducted a randomized, double-blind, placebo-controlled, crossover design trial to determine the effects of simvastatin, 80 mg/day, on plasma lipid and lipoprotein levels and on the metabolism of apolipoprotein B (apoB) in VLDL, intermediate density lipoprotein (IDL), and LDL and of triglycerides (TGs) in VLDL. Simvastatin therapy decreased TG, cholesterol, and apoB significantly in VLDL, IDL, and LDL. These effects were associated with reduced production of LDL-apoB, mainly as a result of reduced secretion of apoB-lipoproteins directly into the LDL density range. Statin therapy also reduced hepatic production of VLDL-TG. There were no effects of simvastatin on the fractional catabolic rates of VLDL-apoB or -TG or LDL-apoB. The basis for decreased VLDL-TG secretion during simvastatin treatment is not clear, but recent studies suggest that statins may activate peroxisomal proliferator-activated receptor alpha (PPARalpha). Activation of PPARalpha could lead to increased hepatic oxidation of fatty acids and less synthesis of TG for VLDL assembly.

Aged↗
PubMed2006

Effects of simvastatin and oral contraceptive agent on polycystic ovary syndrome: prospective, randomized, crossover trial.

CONTEXT: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and cardiovascular risks including dyslipidemia and systemic inflammation. In vitro, statins decrease proliferation and steroidogenesis of ovarian theca-interstitial cells. OBJECTIVE: The study objective was to compare effects of two treatments of PCOS: simvastatin plus oral contraceptive pill (OCP) vs. OCP alone. DESIGN: In a prospective, crossover trial, 48 women with PCOS were randomized to either simvastatin plus OCP for 12 wk followed by OCP alone for an additional 12 wk, or to OCP alone for 12 wk and, subsequently, simvastatin plus OCP for an additional 12 wk. Evaluations were performed at baseline, after 12 wk (crossover), and after 24 wk. Data were analyzed using a random effects model. SETTING: The study was conducted in an academic medical center. PRIMARY OUTCOME: Serum total testosterone was the primary outcome measure. RESULTS: Total testosterone decreased by 38% after Statin + OCP, whereas OCP alone led to a 26% decrease; the statin-attributable effect was significant (P < 0.004). Free testosterone declined by 58% after Statin + OCP, significantly more than the 35% decline after OCP alone (P = 0.006). Hirsutism decreased by 8.1% after Statin + OCP, a greater effect than the 4.7% decrease after OCP alone (P = 0.02). Statin decreased LH, but not FSH or prolactin. Statin + OCP decreased total and low-density lipoprotein cholesterol by 7.5% and 20%, respectively. OCP alone led to a 5% increase of total cholesterol without effect on low-density lipoprotein cholesterol. Statin prevented OCP induced increase of triglycerides. C-reactive protein decreased by 45% after Statin + OCP, a significantly different effect (P = 0.006) than a 6% increase after OCP alone. Soluble vascular cell adhesion molecule 1 decreased by 18% after Statin + OCP, a greater decline than the 10% decrease after OCP alone (P = 0.01). CONCLUSIONS: Simvastatin improved endocrine/clinical aspects of PCOS and had beneficial effects on lipid profile and markers of systemic inflammation.

Adult↗
PubMed2001

Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol.

The aims of this study were to examine the presence of mutations in the low-density lipoprotein receptor gene among subjects clinically diagnosed with familial hypercholesterolemia and to analyze whether the molecular diagnosis helps to predict the response to simvastatin treatment in our familial hypercholesterolemia population. Fifty-five probands and 128 related subjects with familial hypercholesterolemia were studied. Genetic diagnosis was carried out following a three-step protocol based on Southern blot and PCR-single strand conformational polymorphism analysis. A randomized clinical trial with simvastatin was conducted in 42 genetically diagnosed subjects with familial hypercholesterolemia classified as carriers of null mutations (n = 22) and of defective mutations (n = 20). A mutation-causing familial hypercholesterolemia was identified in 46 probands (84%). In 41 of them (89%), a total of 28 point mutations were detected, 13 of which have not been previously described. The remaining five probands (11%) were carriers of large rearrangements. Familial hypercholesterolemia with null mutations showed a poor response to simvastatin treatment. The mean percentage reduction of plasma total and low-density lipoprotein cholesterol levels in these subjects were significantly lower (24.8 +/- 10.3 vs. 34.8 +/- 10.9, P = 0.04 and 30.0 +/- 39.8 vs. 46.1 +/- 18.2, P = 0.02, respectively) than in subjects with defective mutations. Baseline and posttreatment high-density lipoprotein cholesterol plasma values were significantly lower in subjects with familial hypercholesterolemia with null mutations (P < 0.001). In an outbreed Caucasian population, a three-step protocol for genetic screening detected a mutation in the low-density lipoprotein receptor gene in a high percentage (84%) of subjects with familial hypercholesterolemia. Subjects with familial hypercholesterolemia with null mutations (class I) showed lower plasma high-density lipoprotein cholesterol values and a poor low-density lipoprotein cholesterol response to simvastatin treatment.

Adult↗
PubMed2002

Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia.

Hyperlipidemia is a well-established risk factor for primary coronary heart disease (CHD). Although simvastatin is known to lower serum lipid concentrations, the protective effect of such lipid-lowering therapy against primary CHD has not been established in Japanese patients with hypercholesterolemia. The Japan Lipid Intervention Trial was a 6-year, nationwide cohort study of 47,294 patients treated with open-labeled simvastatin (5-10 mg/day) and monitored by physicians under standard clinical conditions. The aim of the study was to determine the relationship between the occurrence of CHD and the serum lipid concentrations during low-dose simvastatin treatment. Simvastatin reduced serum concentrations of total cholesterol (TC), low-density lipoprotein- cholesterol (LDL-C) and triglyceride (TG), by 18.4%, 26.8% and 16.1% on average, respectively, during the treatment period. The risk of coronary events was higher when the average TC concentration was > or =240 mg/dl and the average LDL-C concentration was > or =160 mg/dl. The incidence of coronary events increased in the patients with TG concentration > or =300 mg/dl compared with patients with TG concentration <150 mg/dl. The high-density lipoprotein cholesterol (HDL-C) inversely correlated with the risk of coronary events. The J-curve association was observed between average TC or LDL-C concentrations and total mortality. Malignancy was the most prevalent cause of death. The health of patients should be monitored closely when there is a remarkable decrease in TC and LDL-C concentrations with low-dose statin. A reasonable strategy to prevent coronary events in Japanese hypercholesterolemic patients without prior CHD under low-dose statin treatment might be regulating the serum lipid concentrations to at least <240 mg/dl for TC, <160 mg/dl for LDL-C, <300 mg/dl for TG, and >40 mg/dl for HDL-C.

Adult↗
PubMed2001

Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin.

OBJECTIVE: To report a case of rhabdomyolysis resulting from concomitant use of clarithromycin and simvastatin. CASE SUMMARY: A 64-year-old African-American man was admitted to the hospital for worsening renal failure, elevated creatine phosphokinase, diffuse muscle pain, and severe muscle weakness. About three weeks prior to admission, the patient was started on clarithromycin for sinusitis. The patient had been receiving simvastatin for approximately six months. He was treated aggressively with intravenous hydration, sodium bicarbonate, and hemodialysis. A muscle biopsy revealed necrotizing myopathy secondary to a toxin. The patient continued to receive intermittent hemodialysis until his death from infectious complications that occurred three months after admission. There were several factors that could have increased his risk for developing rhabdomyolysis, including chronic renal failure. DISCUSSION: Clarithromycin is a potent inhibitor of CYP3A4, the major enzyme responsible for simvastatin metabolism. The concomitant administration of macrolide antibiotics and other hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have resulted in previous reports of rhabdomyolysis. Other factors may increase the risk of this drug interaction, including the administration of other medications that are associated with myopathy, underlying renal insufficiency, and administration of high doses of HMG-CoA reductase inhibitors. CONCLUSIONS: Macrolide antibiotics inhibit the metabolism of HMG-CoA reductase inhibitors that are metabolized by CYP3A4 (i.e., atorvastatin, cerivastatin, lovastatin, simvastatin). This interaction may result in myopathy and rhabdomyolysis, particularly in patients with renal insufficiency or those who are concurrently taking medications associated with myopathy.

Anti-Bacterial Agents↗
PubMedDate not supplied

Simvastatin-fluconazole causing rhabdomyolysis.

OBJECTIVE: To report a case of rhabdomyolysis after concomitant use of simvastatin, a commonly used hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and fluconazole, an azole antifungal agent. CASE SUMMARY: An 83-year-old white man with a history of congestive heart failure and hyperlipidemia presented to the hospital 1 week following the addition of fluconazole to a medication regimen that included simvastatin 40 mg once daily. The patient had severe muscle weakness and a markedly elevated serum creatine kinase activity, which resolved following discontinuation of simvastatin and fluconazole. DISCUSSION: Rhabdomyolysis is a recognized adverse effect of HMG-CoA reductase inhibitors (statins), commonly caused by their interaction with other drugs, such as azole antifungals, that inhibit the cytochrome P450 isoenzyme family. An objective causality assessment revealed that the adverse drug event was probable. Although drug interactions have been described for combinations of other HMG-CoA reductase inhibitors and azole antifungals, rhabdomyolysis likely caused by the interaction between simvastatin and fluconazole has not yet been reported. This case reinforces the importance of being vigilant for drug interactions, particularly in connection with commonly prescribed medications such as statins. CONCLUSIONS: Patients receiving statins who have cancer may receive azole antifungals and other drugs that inhibit CYP3A4 during treatment, predisposing them to toxicity. These patients should therefore be monitored closely for drug interactions.

Aged↗
PubMed1996

Effects of simvastatin on the number and composition of apoproteinB-containing lipoproteins in hypercholesterolemia: analysis of apoproteinB in each lipoprotein fraction by highly sensitive latex method.

We investigated the effects of simvastatin on the number and composition of apoproteinB (apoB)-containing lipoproteins in thirteen patients with hypercholesterolemia type IIa or IIb by measuring apoB by a highly sensitive latex method. Patients received simvastatin 5-10 mg (7.7 +/- 0.7 mg, mean +/- SEM) daily for 83-218 days (131 +/- 13 days). In both types of patients, treatment with simvastatin significantly reduced plasma cholesterol levels (mean +/- SEM mg/dl: in type IIa from 234.4 +/- 5.4 to 171.4 +/- 7.8, in type IIb from 242.4 +/- 11.6 to 178.8 +/- 9.6), low density lipoprotein (LDL) cholesterol levels (from 122.6 +/- 5.2 to 68.5 +/- 4.6, and from 115.6 +/- 14.0 to 70.4 +/- 11.6 in the two types, respectively) and LDL apoB levels (from 94.5 +/- 6.6 to 60.6 +/- 7.0, and from 85.0 +/- 8.4 to 56.6 +/- 6.2, respectively). There was no significant change in cholesterol, triglyceride (TG) or apoB in very low density lipoprotein (VLDL). High density lipoprotein (HDL) cholesterol did not change in this study. With respect to lipoprotein composition, the ratio of either cholesterol or TG to apoB in VLDL, intermediate density lipoprotein (IDL) and LDL did not change significantly, but that of TG to apoB in the IDL fraction increased in type IIa. Simvastatin promotes more effective reduction in cholesterol and apoB in LDL than in VLDL, probably by increasing the hepatic LDL receptor which preferentially binds LDL.

Adult↗
PubMedDate not supplied

Endothelium modulates contractile response to simvastatin in rat aorta.

Simvastatin is an inhibitor of HMG-CoA reductase used in the treatment of hypercholesterolemia. In the present study simvastatin-induced contraction was observed in rat aortic thoracic rings, this effect increased when the endothelium was removed and when NO synthase was blocked by L-NOARG (3 x 10(-5) M). The contractile effect of simvastatin on intact aortic rings diminished when cyclo-oxygenase was inhibited with indomethacin (10(-5) M). Also in the presence of endothelium, pretreatment with mevalonate (1 mM), the product of HMG-CoA reductase activity, significantly inhibited the contraction. In other experiments carried out on endothelium-removed preparations and in medium containing the calcium antagonist, diltiazem (10(-5) and 10(-6) M), the contraction dose-response curves were significantly reduced and the same happened in the presence of the inhibitor of sarcoplasmic reticulum Ca-2+-ATPase, cyclopiazonic acid (CPA) (3 x 10(-6) M). The results suggest that simvastatin might increase intracellular calcium concentration. This effect could lead to an activation of NO synthase and cyclooxygenase pathways in endothelial cells and to contraction in vascular smooth muscle cells. This rise in Ca2+ concentration could be due to an inhibition of isoprenoid synthesis prevented by mevalonate.

Animals↗
PubMed2002

Daily dosing versus alternate-day dosing of simvastatin in patients with hypercholesterolemia.

STUDY OBJECTIVE: To compare the efficacy of daily simvastatin administration with that of alternate-day therapy at double the daily dose. DESIGN: Nonrandomized, before-after comparison trial. SETTING: Outpatient clinic of a Veterans Affairs medical center. PATIENTS: Fifteen men with hyperlipidemia. INTERVENTION: The simvastatin regimen for patients with a low-density lipoprotein cholesterol (LDL) level at their established National Cholesterol Education Program goal was converted from daily dosing to double the daily dose given every other day for 8 weeks. MEASUREMENTS AND MAIN RESULTS: Baseline laboratory values were obtained for patients receiving daily simvastatin therapy After 8 weeks of alternate-day therapy, follow-up laboratory values were obtained and assessed for efficacy and toxicity. The LDL-lowering effect of the daily dosing regimen was compared with that of the alternate-day dosing regimen. Paired t tests were computed to compare LDL concentrations before and after the study using a 95% confidence interval. No statistically significant difference was observed. CONCLUSION: Alternate-day dosing of simvastatin may be an effective alternative to daily dosing.

Aged↗
PubMedDate not supplied

Cost-effectiveness analysis of simvastatin and lovastatin/extended- release niacin to achieve LDL and HDL goal using NHANES data.

OBJECTIVE: The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Adult Treatment Panel III (ATP III) encouraged reduced low-density lipoprotein (LDL) cholesterol levels for a greater number of patients and reemphasized the benefits of high-density lipoprotein (HDL) cholesterol. The purpose of this study was to compare 2 regimens achieving simultaneous LDL and HDL goals. METHODS: A decision-analytic model compared the cost-effectiveness of simvastatin and lovastatin/extended-release niacin. The perspective of the analysis was that of a health system. Product labeling was used to determine changes in cholesterol concentrations and frequencies of clinically important adverse events. The Third National Health and Nutrition Examination Survey (NHANES III) adult data were used for baseline cholesterol levels. Each product was titrated to achieve LDL and HDL goals unless an adverse effect occurred. Direct medical costs were determined for each treatment to determine cost-effectiveness. RESULTS: For both the 130 mg/dL and 100 mg/dL LDL goal analyses (and HDL e40 mg/dL), lovastatin/extended-release niacin had higher success rates and lower estimated direct-medical costs than simvastatin. Simvastatin had the highest success rate in achieving LDL level <160 mg/dL and HDL e40 mg/dL; however, its estimated direct-medical cost was approximately twice that of lovastatin/extended-release niacin (665 US dollars versus 333 US dollars). CONCLUSION: For the LDL goals <130 mg/dL and <100 mg/dL (and HDL e40 mg/dL) required of the majority of U.S. residents, lovastatin/extended-release niacin was both more successful and less costly than simvastatin.

Aged↗
PubMed1988

Clinical experience with simvastatin compared with cholestyramine.

Simvastatin (MK733), derived from lovastatin by substituting CH3 for H at the 2' position, is a potent hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor. Its cholesterol-lowering effect in 40 patients with heterozygous familial hypercholesterolaemia was more pronounced (an LDL-cholesterol reduction of 43%) than that of cholestyramine monotherapy in a matched group of 20 patients (30% reduction). The combination of the 2 drugs for 50 patients who tolerated cholestyramine was even more effective (a 54% reduction of LDL-cholesterol). The other changes were as follows: total cholesterol (simvastatin [S] -36%, cholestyramine [C] -23%, both drugs in combination [S + C] -45%); HDL-cholesterol (S +16%, C +9%, S + C +20%); triglyceride (S -21%, C +11%, S + C -17%); and the apolipoprotein B/apolipoprotein A ratio (S -51%, C -39%, S + C -67%). Cholestyramine caused more gastrointestinal adverse effects (12 of 20 patients), whereas a transaminase increase was seen both with cholestyramine (2 of 20 patients) and simvastatin (3 of 40 patients) and with the combination (6 of 50 patients). Treatment with simvastatin decreases the atherogenic potential of plasma more than cholestyramine monotherapy and causes fewer adverse effects. For those patients who tolerate cholestyramine, the combination of the drugs is even more potent.

Adult↗
PubMed2006

Different effects of simvastatin and losartan on cytokine levels in coronary artery disease.

BACKGROUND AND OBJECTIVE: Use of HMG-CoA reductase inhibitors (statins) and angiotensin II type 1 (AT(1)) receptor antagonists reduces the incidence of cardiovascular events. The cytokines macrophage colony-stimulating factor (M-CSF) and transforming growth factor (TGF)-beta may exert proatherogenic and antiatherogenic effects, respectively. In this study, we examined whether treatment with a statin or an AT(1) receptor antagonist alters M-CSF and TGF-beta levels in patients with coronary artery disease. METHODS: Twenty-seven consecutive patients with coronary artery disease were randomly assigned to the following three treatment groups for 8 weeks: simvastatin 5 mg/day (n = 10); losartan 50 mg/day (n = 9); or control (usual treatment; n = 8). Blood samples were collected before and after treatment. RESULTS: Clinical characteristics and baseline cytokine levels were comparable among the three groups. Serum levels of M-CSF were significantly decreased only in the simvastatin group (from 403 +/- 71 to 303 +/- 116 pg/mL; p = 0.009). Plasma levels of TGF-beta were significantly increased only in the losartan group (from 5.01 +/- 1.13 to 7.50 +/- 3.83 ng/mL; p = 0.021). Simvastatin decreased serum M-CSF levels independently of changes in total cholesterol or low-density lipoprotein-cholesterol. CONCLUSIONS: The results of this study indicate that simvastatin decreases serum levels of M-CSF while losartan increases plasma levels of TGF-beta, suggesting that the two drugs may have different anti-atherosclerotic properties.

Aged↗
PubMed2004

Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment.

Adhesion molecules, particularly intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin, have been associated with cardiovascular disease. Elevated levels of these molecules have been reported in diabetic patients. Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease, and evidence suggests that postprandial hypertriglyceridemia and hyperglycemia may induce an increase in circulating adhesion molecules. However, the distinct role of these two factors is a matter of debate. Thirty type 2 diabetic patients and 20 normal subjects ate three different meals: a high-fat meal, 75 g of glucose alone, and a high-fat meal plus glucose. Glycemia, triglyceridemia, plasma nitrotyrosine, ICAM-1, VCAM-1, and E-selectin were assayed during the tests. Subsequently, diabetic subjects took simvastatin 40 mg/day or placebo for 12 weeks. The three tests were performed again at baseline, between 3 and 6 days after starting the study, and at the end of each study. High-fat load and glucose alone produced an increase of nitrotyrosine, ICAM-1, VCAM-1, and E-selectin plasma levels in normal and diabetic subjects. These effects were more pronounced when high fat and glucose were combined. Short-term simvastatin treatment had no effect on lipid parameters, but reduced the effect on adhesion molecules and nitrotyrosine, which was observed during every different test. Long-term simvastatin treatment was accompanied by a lower increase in postprandial triglycerides, which was followed by smaller variations in ICAM-1, VCAM-1, E-selectin, and nitrotyrosine during the tests. This study shows an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on ICAM-1, VCAM-1, and E-selectin plasma levels, suggesting oxidative stress as a common mediator of such effects. Simvastatin shows a beneficial effect on oxidative stress and the plasma levels of adhesion molecules, which may be ascribed to a direct effect in addition to the lipid-lowering action of the drug.

Body Mass Index↗
PubMed1997

Reduction of albumin excretion rate in normotensive microalbuminuric type 2 diabetic patients during long-term simvastatin treatment.

OBJECTIVE: To study the long-term effects of simvastatin on urinary albumin excretion rate (AER) in normotensive microalbuminuric type 2 diabetic patients with hypercholesterolemia. RESEARCH DESIGN AND METHODS: A total of 19 normotensive microalbuminuric hypercholesterolemic type 2 diabetic patients entered a double-blind crossover study for 2 years, receiving either simvastatin (20 mg/day) or placebo (each treatment for 1 year). RESULTS: Simvastatin significantly decreased plasma cholesterol (total and LDL) after 52 weeks of treatment. A concomitant significant decrease of AER (25% from basal) with no significant changes in creatinine clearance was observed during the same period. CONCLUSIONS: Our data are in keeping with the hypothesis that simvastatin might be used as an additional means to preserve renal function in microalbuminuric hypercholesterolemic type 2 diabetic patients.

Adult↗
PubMed2003

A novel anti-inflammatory role for simvastatin in inflammatory arthritis.

3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-gamma release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.

Animals↗
PubMed1998

Simvastatin, a potent HMG-CoA reductase inhibitor, inhibits the proliferation of human and bovine endothelial cells in vitro.

We investigated in vitro effect of simvastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the proliferation of human and bovine endothelial cells (EC) compared to that of bovine smooth muscle cells (SMC). Cells were cultured in a medium supplemented with 10% normal serum (FBS). Simvastatin at concentrations ranging from 0.1 microg/ml to 10 microg/ml were used. In each kind of cells the proliferation was markedly reduced at 1 microg/ml of simvastatin (P<0.01) which was accompanied by morphological changes in the cell shape. We conclude that simvastatin inhibits the proliferation of not only the smooth muscle cells but also the endothelial cells.

Animals↗
PubMed1992

Successful management of primary hypercholesterolaemia with simvastatin and low-dose colestipol.

OBJECTIVE: To examine whether a small dose of bile acid sequestrant used in combination with a hydroxymethylglutaryl coenzyme A reductase inhibitor is more effective in reducing serum and low-density lipoprotein (LDL) cholesterol levels than inhibitor used alone. DESIGN: A randomised, double-blind study. SETTING: Subjects receiving tertiary care at a hospital lipid clinic. PATIENTS: Subjects with severe primary hypercholesterolaemia (types IIa and IIb), already stabilised on a cholesterol-lowering diet, with serum cholesterol levels of 7.0 mmol/L or more and triglyceride levels of 6.0 mmol/L or less. Sixty-four subjects were randomly assigned to the treatment groups; three withdrew before any outcome observations; 61 completed the trial and their results were analysed. INTERVENTIONS: Subjects were randomly assigned to receive either colestipol placebo or colestipol 5 g or 10 g each morning in fixed dosage for 18 weeks. They simultaneously received incremental doses of simvastatin: placebo for six weeks, then 20 mg/night for six weeks, then 40 mg/night for a final six weeks. MAIN OUTCOME MEASURES: Lipids, lipoproteins, and haematological and biochemical safety parameters were measured at the end of each treatment period. Adverse events were monitored. RESULTS: Respective maximum reductions (95% confidence intervals) in serum cholesterol, LDL cholesterol and apolipoprotein B (apo-B) values in subjects taking combination therapy were 41% (38%-45%), 50% (46%-53%) and 43% (39%-46%), compared with lesser reductions of 32% (26%-37%), 38% (31%-45%) and 37% (32%-41%) in those taking simvastatin monotherapy. The percentage changes in LDL cholesterol with combination therapy were independent of baseline cholesterol level or lipid phenotype. Combination therapy reduced serum triglyceride levels by up to 24% (15%-32%) and increased high-density lipoprotein (HDL) cholesterol levels by up to 9% (3%-15%). Three subjects withdrew within a few weeks because of severe gastrointestinal side effects related to colestipol; 19 experienced milder gastrointestinal side effects, 15 were taking combination therapy. CONCLUSIONS: A combination of low-dose colestipol and simvastatin was found to be more effective in reducing serum and LDL cholesterol than simvastatin used alone. Such combination therapy offers the possibility of improved cholesterol lowering without the need for full dosage of either drug.

Anticholesteremic Agents↗
PubMed1998

Hormone replacement and simvastatin in the therapy of hypercholesterolemic postmenopausal women.

OBJECTIVES: To prospectively investigate the effect of cholesterol lowering diet, hormone replacement therapy and simvastatin on plasma lipid levels using a 3-month stepwise protocol. METHODS: Participants were postmenopausal women under the age of 60 with hypercholesterolemia (plasma total cholesterol > 240 mg/dl). The study started with 3 months of Step-One diet (phase I) followed by 3 months of diet and hormone replacement therapy (0.625 mg conjugated estrogens daily combined with 5 mg medroxyprogesterone acetate at days 13-25 of each cycle) (phase II). In women whose total cholesterol remained above 240 mg/dl or LDL-cholesterol above 160 mg/dl by the end of phase II, simvastatin at 10 mg daily was added (phase III). Plasma cholesterol levels as well as safety measurements were closely monitored. RESULTS: Sixteen (21%) of 75 patients who entered the study had satisfactory cholesterol levels by the end of 6 months. Another 25 patients (33%) dropped out of the study for various reasons by that time. In the 34 patients who started simvastatin, plasma total cholesterol levels did not significantly change during phase I and II, however, LDL-cholesterol significantly decreased (204 +/- 31 to 187 +/- 26 mg/dl, p = 0.04) and HDL increased (53 +/- 12 to 62 +/- 16 mg/dl, p = 0.04). A dramatic decrease occurred in both total and LDL-cholesterol levels after one month of phase III (281 +/- 26 to 213 +/- 30 mg/dl 187 +/- 26 to 122 +/- 30 mg/dl respectively, p < 0.0001), with no further changes during the rest of the study period. No significant changes occurred in HDL-cholesterol and triglyceride plasma levels at this phase. Adverse effects were few and minor throughout the study. CONCLUSIONS: Some of the hypercholesterolemic postmenopausal women will benefit from hormone replacement therapy as a single cholesterol lowering treatment in addition to diet (21% in our series). Nevertheless, combination therapy of estrogens and low dose simvastatin proved to be extremely effective in lowering cholesterol levels with no significant side effects. Such therapeutic regimen may also have a synergistic anti-atherogenic effect.

Anticholesteremic Agents↗