This study evaluated the efficacy and tolerability of gemcabene, a new lipid-altering agent, in a double-blind, randomized, dose-response study of 161 patients with high-density lipoprotein (HDL) cholesterol of <35 mg/dl and serum triglyceride (TG) levels of either >/=200 (n = 94) or <200 mg/dl (n = 67). After a 6-week, placebo, dietary lead-in period, patients were administered either 150, 300, 600, or 900 mg of gemcabene or placebo once daily for 12 weeks. In the TG >/=200 mg/dl stratum, gemcabene significantly increased serum HDL cholesterol by 18% with corresponding significant increases of 6% in both apolipoprotein A-I and A-II levels at the 150-mg dose. HDL cholesterol levels also increased 12% at the 300-mg dose; however, this did not reach statistical significance. Also, in the TG >/=200 mg/dl stratum, serum TG levels were significantly reduced by 27% and 39% at the 150- and 300-mg doses of gemcabene, respectively. No significant differences were found in serum HDL cholesterol or TG levels in the TG >/=200 mg/dl groups that received 600 or 900 mg of gemcabene, or in TG <200 mg/dl groups administered any dose of gemcabene. However, at these higher 600- and 900-mg doses, gemcabene significantly reduced serum low-density lipoprotein (LDL) cholesterol levels by 15% to 25%, respectively, in both TG strata, with proportionate decreases in the levels of apolipoprotein B. Gemcabene was well tolerated with a frequency of adverse events similar to that of placebo. In conclusion, at the lower doses, gemcabene significantly increased HDL cholesterol and reduced TG serum levels in patients with low HDL cholesterol and TG >/=200 mg/dl. At the higher doses, gemcabene significantly reduced LDL cholesterol levels in all patients with low HDL cholesterol.

Background—Although effects of statins on cardiovascular outcomes are well established in men, fewer data exist for women. Furthermore, the effects of statins plus hormone replacement therapy (HRT) on cardiovascular outcomes are uncertain. Methods and Results—We examined statin use, cardiovascular events, and total mortality in the Heart and Estrogen/progestin Replacement Study (HERS), a randomized clinical trial of estrogen plus progestin versus placebo in postmenopausal women with heart disease (n=2763). A nonrandomized comparison of statin users and nonusers revealed lower rates of the primary outcome, nonfatal myocardial infarction or coronary heart disease death (relative hazard [RH]=0.79, 95% confidence intervals [CI] 0.63 to 0.99, P =0.04), and total mortality (RH=0.67, 95% CI 0.51 to 0.87, P =0.003). Rates of venous thromboembolic events were also lower among statin users (RH=0.45, 95% CI 0.23 to 0.88, P =0.02). HRT resulted in a significant increase in early risk for primary events in women who did not use statins (RH=1.75, 95% CI 1.02 to 3.03, P =0.04) but not in statin users (RH=1.34, 95% CI 0.63 to 2.86, P =0.45). Adjustment for postrandomization statin use showed no effect of HRT on risk for the primary outcome (RH=0.96, 95% CI 0.77 to 1.29;P =0.72). Conclusions—In HERS, statin use was associated with lower rates of cardiovascular events, venous thromboembolic events, and total mortality. These data provide strong support for statin use in eligible women with coronary disease.

Anew extended-release (XL) formulation of fluvastatin has been developed for once daily treatment of primary hypercholesterolaemia. This study was designed to determine the safety and effect of fluvastatin XL 80 mg on a range of lipid parameters compared with the immediate-release (IR) formulation of fluvastatin 40 mg. In a multicentre, double-blind study, 555 patients with primary hypercholesterolaemia (Fredrickson types IIa or IIb) were randomised to 24 weeks treatment with fluvastatin XL 80 mg or IR 40 mg, each given once daily at bedtime. The study found the least square mean reduction in LDL-C after 24 weeks treatment was 32.6% in the fluvastatin XL 80 mg group (n=312) and 23.9% in the fluvastatin IR 40 mg group (n=165), an 8.7% between-treatment difference (95% confidence interval: 6.5%, 10.9%) in favour of the XL formulation (p 35% reductions in low-density lipoprotein cholesterol (42.3% vs. 13.3%). High-density lipoprotein cholesterol levels were increased by 9.1% and 7.0%, respectively in the XL and IR groups; median triglyceride levels fell by 19% and 13%, respectively. Tolerability was comparable in the two groups, and there were no laboratory safety concerns. The study concluded that fluvastatin XL 80 mg once daily is safe as a starting dose and effectively lowers low-density lipoprotein cholesterol and triglyceride levels in patients with primary hypercholesterolaemia.

Although acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been shown to reduce lipid levels in several animal models, the safety and lipid modifying activity of any single agent in this class has not been demonstrated in humans. The safety and efficacy of avasimibe (CI-1011), a new, unique, wholly synthetic ACAT inhibitor, was evaluated in the treatment of 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia (low levels of high-density lipoprotein cholesterol [HDL-C]). Following an 8-week placebo and dietary-controlled baseline period, patients were randomly assigned to double-blind treatment with placebo, 50, 125, 250, or 500 mg avasimibe administered as capsules once daily for 8 weeks. At all evaluated doses, avasimibe treatment resulted in prompt and significant reductions (P<0.05) in plasma levels of total triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C) with mean reductions of up to 23% and 30% respectively, apparently independent of dose. No statistically significant changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C or apolipoprotein (apo) B were detected. ApoAI levels were also unchanged on all doses of avasimibe apart from the 500 mg dosage, which was associated with a significant decrease in plasma apoAI. The relevance of this latter finding in only one dosage group is not known. All doses of avasimibe were well tolerated with no resulting significant abnormalities of biochemical, hematological, or clinical parameters.

BACKGROUND AND AIM:Clinical data suggesting that larger decreases in low density lipoprotein cholesterol (LDL-C) result in greater reductions in coronary heart disease events have led to the establishment of aggressive LDL-C targets for the treatment of hypercholesterolemia. In view of this, the efficacy and safety of a new maximum dose of simvastatin, 80 mg, were evaluated in 9 studies involving 2819 hypercholesterolemic patients. This report focuses on the combined results from the 4 main or Pivotal studies in which a total of 1936 patients received simvastatin 40 or 80 mg for 36 to 48 weeks. METHODS AND RESULTS:The Pivotal studies had similar randomized, multicenter, controlled, double-blind, parallel-group designs. Their combined results demonstrated a significant advantage in the LDL-C-lowering effect for the 80 mg dose. At week 24, the mean percentage reductions (95% confidence intervals) from baseline in LDL-C for the 40 and 80 mg groups were -39.8% (-40.9, -38.7) and -45.7% (-46.5, -45.0) respectively (p < 0.001, between groups), and larger reductions in total cholesterol and triglycerides were also observed in the 80 mg group. Both doses were well tolerated. No new or unexpected adverse events were observed and the overall clinical event profiles were similar in the two groups. Clinically significant hepatic transaminase increases (> 3 times the upper limit of normal/ULN) and myopathy (muscle symptoms plus creatine kinase increase > 10 times ULN) occurred infrequently with both doses. Simvastatin 80 mg had a comparable efficacy and safety profile in women and men as well as in non-elderly and elderly patients. CONCLUSIONS:Simvastatin 80 mg provides additional LDL-C and triglyceride reductions compared to the 40 mg dose and has an excellent safety and tolerability profile.

The Friedewald equation is often used to estimate low-density lipoprotein cholesterol (LDL-C). Hormone therapy is known to raise triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) and alter lipid contents of lipoproteins. We compared Friedewald estimated LDL-C to measured LDL-C in PEPI participants on placebo or four different hormone treatment groups. At baseline, the 0.2 coefficient for triglyceride (TG) was accurate for all five treatment groups. Among women who took >80% of their pills and whose TG was <4.5 mmol/l (400 mg/dl), LDL-C was underestimated for 69–82% of the participants in the active treatment groups, compared to 50% in the placebo group. After 3 years of therapy, the TG coefficient that offered a better fit of the Friedewald equation in the active treatment groups was 0.39 for the equation in mmol/l (0.17 for the equation in mg/dl). Using this coefficient is clearly warranted for greater accuracy in research studies.

Objective.-To report the histological findings of the endometrium of postmenopausal women who were randomized to receive placebo, estrogen only, or one of three estrogen plus progestin (EI-P) regimens in the Postmenopausal Estrogen/ Progestin Interventions (PEPI) Trial.Design.-A 3-year multicenter, randomized, double-masked, placebo-controlled trial.Participants-A total of 596 postmenopausal women aged 45 through 64 years without contraindication to hormone therapy.Intervention.-Participants were randomized and stratified in equal numbers to one of the following treatments in 28-day cycles: placebo, 0.625 mg/d of conjugated equine estrogens (GEE), 0.625 mg/d of CEE plus 10 mg/d of medroxyprogesterone acetate (MPA)for the first 12 days, 0.625 mg/d of CEE plus 2.5 mg/d of MPA, or 0.625 mg/d of CEE plus 200 mg/d of micronized progesterone (MP) for the first 12 days.Outcome Measure.-Histology of endometrium collected at baseline, annual, or unscheduled Visits by biopsy, curettage, or hysterectomy.Analysis.-Intention to treat.Results.-During follow-up women assigned to estrogen atone were more likely to develop simple (cystic), complex (adenomatous), or atypical hyperplasia than those given placebo (27.7% vs 0.8%, 22.7% vs 0.8%, and 11.8% vs 0%, respectively) for the same types of hyperplasia (P<.001). Participants administered one of the three E+P regimens had similar rates of hyperplasia as those given placebo (P=.16). The occurrence of hyperplasia was distributed evenly across the 3 years of the trial. Women taking estrogens alone also had more unscheduled biopsies (66.4% vs 8.4%; P<.001) and curettages (17.6% vs 0.8%; P<.001) than women receiving placebo. The number of surgical procedures was similar for women receiving placebo and women receiving the E+P regimens (P=.38). Of the 45 women with complex (adenomatous) or atypical hyperplasia, study medications were discontinued in all, and the biopsy results of 34 (94%) of 36 women with hyperplasia reverted to normal with progestin therapy. The remainder had dilatation and curettage (n=2) or hysterectomy with (n=2) or without (n=6) prior medical therapy, or refused further biopsies (n=1). One woman developed adenocarcinoma of the endometrium while receiving placebo.Conclusions.-At a dosage of 0.625 mg, the daily administration of CEE enhanced the development of endometrial hyperplasia. Combining CEE with cyclic or continuous MPA or cyclic MP protected the endometrium from hyperplastic changes associated with estrogen-only therapy.

OBJECTIVE Little is known about the covariates of hyperglycemia and hyperinsulinemia. We examined candidate factors in postmenopausal women. RESEARCH DESIGN AND METHODS We determined the cross-sectional associations of sociodemographic, body-size, lifestyle, reproductive, and menopausal factors with pretrial fasting and postchallenge glucose and insulin levels in 869 postmenopausal women aged 45-65 years. Women were participants in the Postmenopausal Estrogen/Progestin Interventions study who were not taking estrogen or insulin. RESULTS Plasma glucose levels increased significantly with age; serum insulin levels did not. BMI and waist-to-hip ratio (WHR) each showed graded positive and independent associations with glucose and insulin levels. Alcohol intake, cigarette smoking, physical activity, parity, education, and income were also associated with insulin or glucose in age-adjusted models. In multivariable models, BMI and WHR explained 18% of the variability in fasting glucose, 16% in postchallenge glucose, 28% in fasting insulin, and 17% in postchallenge insulin. Age and all other factors combined accounted for <6% of the variance in glucose or insulin. In multiply adjusted models, African-American and Hispanic women had higher fasting and 2-h insulin levels than non-Hispanic white women. CONCLUSIONS Most of the variance in glycemia and insulin is unexplained. Measures of obesity and fat distribution account for nearly all the explained variance.

OBJECTIVE To assess pairwise differences between placebo, unopposed estrogen, and each of three estrogen/progestin regimens on selected heart disease risk factors in healthy postmenopausal women. DESIGN A 3-year, multicenter, randomized, double-blind, placebo-controlled trial. PARTICIPANTS A total of 875 healthy postmenopausal women aged 45 to 64 years who had no known contraindication to hormone therapy. INTERVENTION Participants were randomly assigned in equal numbers to the following groups: (1) placebo; (2) conjugated equine estrogen (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus cyclic medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus consecutive MPA, 2.5 mg/d; or (5) CEE, 0.625 mg/d plus cyclic micronized progesterone (MP), 200 mg/d for 12 d/mo. PRIMARY ENDPOINTS: Four endpoints were chosen to represent four biological systems related to the risk of cardiovascular disease: (1) high-density lipoprotein cholesterol (HDL-C), (2) systolic blood pressure, (3) serum insulin, and (4) fibrinogen. ANALYSIS Analyses presented are by intention to treat. P values for primary endpoints are adjusted for multiple comparisons; 95% confidence intervals around estimated effects were calculated without this adjustment. RESULTS Mean changes in HDL-C segregated treatment regimens into three statistically distinct groups: (1) placebo (decrease of 0.03 mmol/L [1.2 mg/dL]); (2) MPA regimens (increases of 0.03 to 0.04 mmol/L [1.2 to 1.6 mg/dL]); and (3) CEE with cyclic MP (increase of 0.11 mmol/L [4.1 mg/dL]) and CEE alone (increase of 0.14 mmol/L [5.6 mg/dL]). Active treatments decreased mean low-density lipoprotein cholesterol (0.37 to 0.46 mmol/L [14.5 to 17.7 mg/dL]) and increased mean triglyceride (0.13 to 0.15 mmol/L [11.4 to 13.7 mg/dL]) compared with placebo. Placebo was associated with a significantly greater increase in mean fibrinogen than any active treatment (0.10 g/L compared with -0.02 to 0.06 g/L); differences among active treatments were not significant. Systolic blood pressure increased and postchallenge insulin levels decreased during the trial, but neither varied significantly by treatment assignment. Compared with other active treatments, unopposed estrogen was associated with a significantly increased risk of adenomatous or atypical hyperplasia (34% vs 1%) and of hysterectomy (6% vs 1%). No other adverse effect differed by treatment assignment or hysterectomy status. CONCLUSIONS Estrogen alone or in combination with a progestin improves lipoproteins and lowers fibrinogen levels without detectable effects on postchallenge insulin or blood pressure. Unopposed estrogen is the optimal regimen for elevation of HDL-C, but the high rate of endometrial hyperplasia restricts use to women without a uterus. In women with a uterus, CEE with cyclic MP has the most favorable effect on HDL-C and no excess risk of endometrial hyperplasia.

A total of 96 patients with moderate elevations of low-density lipoprotein (LDL) cholesterol were randomly assigned to 4 different double-blind treatment regimens: placebo; colestipol 5 g and lovastatin 20 mg/day (C5 + L20); colestipol 10 g and lovastatin 20 mg/day (C10 + L20); and lovastatin 40 mg/day (L40). During 12 weeks of therapy, C10 + L20 achieved the greatest reduction in total cholesterol (-32%) and LDL cholesterol (-48%) levels from baseline. This combination also exhibited significantly greater reductions in LDL cholesterol levels than the C5 + L20 and L40 groups (p < 0.01). The differences in total and LDL cholesterol reduction between the C5 + L20 and L40 groups were not significant. Similar changes and differences between treatments were seen in apolipoprotein B levels. Whereas mean total apolipoprotein A-I levels increased with all treatments (p < 0.05), lipoprotein particles A-I were significantly increased in the C10 + L20 group (p < 0.01) only. Results demonstrate that the combination of low-dose lovastatin (20 mg/day) with low-dose colestipol (5 or 10 g/day) produces LDL cholesterol reductions equal to or greater than higher doses of lovastatin (40 mg/day). In addition, low-dose combinations are > 25% more cost-effective than high-dose monotherapy.

In 875 predominantly white (89%), postmenopausal women, aged 45–-65 years, enrolled in the Postmenopausal Estrogen/Progestin Interventions Trial, univariate analysis showed that mean total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglyceride (TG) levels were positively associated with age (p < 0.01) across 5-year age groups, whereas high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I did not vary by age. HDL-C levels were positively associated with leisure time exercise level (p < 0.01), income (p < 0.01), alcohol intake (p < 0.01), and education level (p < 0.05). Current smokers have lower HDL-C levels than former smokers and those who never smoked (p < 0.01). TG levels were negatively associated with leisure time exercise (p < 0.01) and education (p < 0.01), and higher TG levels occurred in current smokers compared with former smokers and those who never smoked (p < 0.05). LDL-C showed no significant associations with these lifestyle variables. Increased adiposity, as determined by body mass index (BMI) or in body fat distribution as defined by waist/hip ratio (WHR), was significantly negatively associated with HDL-C levels and positively associated with total cholesterol, LDL-C, and TG. Multivariate models showed that 27% of the variance of log triglyceride was explained by WHR, BMI, and smoking, and 31% of the variance of HDL-C was explained by these factors plus alcohol and leisure time exercise.

This 8-week multicenter, placebo-controlled trial compared the efficacy and safety of the HMG-CoA reductase inhibitor, pravastatin, when administered either as single doses of 40 mg in the morning (AM) or evening (PM) or 20 mg twice daily (bid) in 196 diet-stabilized outpatients with primary type II hypercholesterolemia. Mean reductions in total and low-density lipoprotein (LDL) cholesterol concentrations were observed in all pravastatin groups after 1 week and were sustained throughout the study (P less-than-or-equal-to 0.001 versus baseline and placebo). At week 8, mean reductions from baseline in the pravastatin treatment groups were 23-27% for total cholesterol and 30-34% for LDL cholesterol. LDL cholesterol was reduced greater-than-or-equal-to 15% by pravastatin in all patients in the group treated with 40 mg PM and in 88 and 96% in those receiving 20 mg bid and 40 mg AM, respectively. High density lipoprotein cholesterol was elevated (up to 8%) and triglycerides were reduced (up to 25%) by all pravastatin regimens (P less-than-or-equal-to 0.05). Pravastatin was well tolerated and was associated with a low incidence of adverse events. No patient withdrew from the study due to a pravastatin-related adverse event. Once-daily pravastatin is a safe and effective treatment for patients with primary hypercholesterolemia and has a favorable safety profile.