Measurement of LDL-C after treatment with the CETP inhibitor anacetrapib.

Estimation of low-density lipoprotein cholesterol (LDL-C) using the Friedewald (FR) formula is often inaccurate when triglycerides are elevated or VLDL particle composition is altered. We hypothesized that LDL-C estimation by the FR formula and other measurement methods might also be inaccurate in individuals treated with a cholesteryl ester transfer protein (CETP) inhibitor. An assay comparison study was conducted using pre and posttreatment serum samples from 280 of the 811 patients treated with the CETP inhibitor anacetrapib in the DEFINE study (determining the efficacy and tolerability of CETP inhibition with anacetrapib). After 24 weeks of treatment with anacetrapib, mean LDL-C values by FR formula, Roche direct method (RDM) and Genzyme direct method (GDM) deviated from that measured by the ß-quantification (BQ) reference method by -12.2 ± 7.5, -10.2 ± 6.6, -10.8 ± 8.8 mg/dl, respectively. After treatment with anacetrapib, the FR formula and detergent-based direct methods provided lower LDL-C values than those obtained by the BQ reference method. The bias by the FR formula appeared to be due to an overestimation of VLDL-C by the TG/5 component of the formula. Evaluation of the clinical significance of these findings awaits comprehensive lipid and cardiovascular outcome data from ongoing Phase III clinical studies of anacetrapib.

Safety of anacetrapib in patients with or at high risk for coronary heart disease.

BACKGROUND: Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease or at high risk for coronary heart disease. Eligible patients who were taking a statin and who had an LDL cholesterol level that was consistent with that recommended in guidelines were assigned to receive 100 mg of anacetrapib or placebo daily for 18 months. The primary end points were the percent change from baseline in LDL cholesterol at 24 weeks (HDL cholesterol level was a secondary end point) and the safety and side-effect profile of anacetrapib through 76 weeks. Cardiovascular events and deaths were prospectively adjudicated. RESULTS: A total of 1623 patients underwent randomization. By 24 weeks, the LDL cholesterol level had been reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a reduction from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) in the placebo group (P<0.001)--a 39.8% reduction with anacetrapib beyond that seen with placebo. In addition, the HDL cholesterol level increased from 41 mg per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) in the anacetrapib group, as compared with an increase from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group (P<0.001)--a 138.1% increase with anacetrapib beyond that seen with placebo. Through 76 weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P = 0.40). The prespecified Bayesian analysis indicated that this event distribution provided a predictive probability (confidence) of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with torcetrapib. CONCLUSIONS: Treatment with anacetrapib had robust effects on LDL and HDL cholesterol, had an acceptable side-effect profile, and, within the limits of the power of this study, did not result in the adverse cardiovascular effects observed with torcetrapib. (Funded by Merck Research Laboratories; ClinicalTrials.gov number, NCT00685776.).

Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin.

CONTEXT: The level and duration of exposure to circulating low-density lipoprotein-cholesterol (LDL-C) are major contributors to coronary atherosclerosis. Therefore, optimal prevention will require long-term LDL-C reduction, making it important to select the most effective agent for each individual. OBJECTIVE: We tested the hypothesis that individuals with high fractional absorption of cholesterol respond better to the cholesterol absorption inhibitor ezetimibe than to simvastatin, whereas low absorbers, who have elevated rates of cholesterol synthesis, respond better to simvastatin. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled, crossover trial was performed in 215 African- and European-American men. INTERVENTION: Participants were randomized to placebo, ezetimibe (10 mg/d), simvastatin (10 mg/d), and both drugs for 6 wk each. MAIN OUTCOME: Plasma levels of LDL-C, surrogate markers for cholesterol absorption (campesterol) and synthesis (lathosterol), and proprotein convertase subtilisin-like kexin type 9 were measured at baseline and after treatment. RESULTS: LDL-C levels were reduced by 19% (ezetimibe), 25% (simvastatin), and 41% (ezetimibe+simvastatin) from a baseline of 146 +/- 20 mg/dl; results were similar between ethnic groups. Reduction in LDL-C correlated poorly with baseline levels of noncholesterol sterols and proprotein convertase subtilisin-like kexin type 9. Although individual responses varied widely, change in LDL-C on ezetimibe correlated with response to simvastatin (r = 0.46, P < 0.001). Combination therapy lowered LDL-C by 15% or greater in more than 95% of participants. CONCLUSIONS: Baseline cholesterol absorption and synthesis did not predict responsiveness to LDL-lowering drugs. Responsiveness to simvastatin and ezetimibe were highly correlated, suggesting that factors downstream of the primary sites of action of these drugs are a major determinant of response.

Design of the DEFINE trial: determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib.

BACKGROUND: Residual cardiovascular (CV) risk often remains high despite statin therapy to lower low-density lipoprotein cholesterol (LDL-C). New therapies to raise high-density lipoprotein cholesterol (HDL-C) are currently being investigated. Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that raises HDL-C and reduces LDL-C when administered alone or with a statin. Adverse effects on blood pressure, electrolytes, and aldosterone levels, seen with another drug in this class, have not been noted in studies of anacetrapib to date. METHODS: Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib (DEFINE) is a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease (CHD) or CHD risk equivalents (clinical trials.gov NCT00685776). Eligible patients at National Cholesterol Education Program-Adult Treatment Panel III LDL-C treatment goal on a statin, with or without other lipid-modifying medications, are treated with anacetrapib, 100 mg, or placebo for 18 months, followed by a 3-month, poststudy follow-up. The primary end points are percent change from baseline in LDL-C and the safety and tolerability of anacetrapib. Comprehensive preplanned interim safety analyses will be performed at the 6- and 12-month time points to examine treatment effects on key safety end points, including blood pressure and electrolytes. A preplanned Bayesian analysis will be performed to interpret the CV event distribution, given the limited number of events expected in this study. RESULTS: A total of 2,757 patients were screened at 153 centers in 20 countries, and 1,623 patients were randomized into the trial. Lipid results, clinical CV events, and safety outcomes from this trial are anticipated in 2010.

Striated muscle safety of ezetimibe/simvastatin (Vytorin).

Despite the excellent benefit/risk profile of statins, their use is limited by a dose-related risk of adverse events, particularly those related to muscle toxicity. Ezetimibe/simvastatin (Vytorin) is a cholesterol-lowering therapy that inhibits the intestinal absorption (ezetimibe) and synthesis (simvastatin) of cholesterol. This analysis compared the muscle safety profiles of ezetimibe/simvastatin and simvastatin monotherapy. We reviewed muscle-related adverse event (AE) data from 17 randomized, blinded clinical trials (13 base and 4 extension studies), in which ezetimibe and simvastatin were either co-administered as separate entities or given as a combination tablet to 4,558 patients. The following AE categories were summarized: incidence of musculoskeletal or connective-tissue AEs (all and drug related); discontinuations due to musculoskeletal or connective-tissue AEs (all and drug related); incidence of AEs reported under the term "myalgia" (all and drug related); discontinuation due to myalgia (all and drug related); incidence of "myopathy" (all and drug related); increases in creatine kinase to 3 to < 5, 5 to < 10, and > or = 10 times the upper limit of normal. For all AE categories examined, the incidence of muscle-related clinical and laboratory AEs or discontinuations due to muscle-related AEs was no more common in patients taking ezetimibe/simvastatin than in those taking simvastatin alone. Thus, the clinical trial experience with ezetimibe/simvastatin suggests that ezetimibe does not enhance or aggravate the muscle effects of simvastatin.

Pregnancy outcomes after maternal exposure to simvastatin and lovastatin.

BACKGROUND: Our objective was to determine the frequency of adverse outcomes after maternal exposure to simvastatin and/or lovastatin during pregnancy in postmarketing experience. METHODS: We reviewed the Merck & Co., Inc. (West Point, PA) pharmacovigilance database for reports of exposure to simvastatin or lovastatin during pregnancy. The reports were classified as prospective (reported prior to pregnancy outcome) or retrospective (reported after pregnancy outcome) and were evaluated for timing of exposure, outcome, congenital anomalies, and other events. Outcome rates were calculated for prospective pregnancies. RESULTS: We identified 477 reports (386 prospective and 91 retrospective) with 225 prospective outcomes reported: 154 live born infants, 49 elective abortions, 18 spontaneous abortions, and 4 fetal deaths. Six congenital anomalies were reported: chromosomal translocation, trisomy 18, hypospadias, duodenal atresia, cleft lip, and skin tag. The rate of congenital anomalies (congenital anomalies/live births plus fetal deaths) was 3.8%, which is similar to the background population rate (3.2%; relative ratio, 1.21; 95% 1-sided upper confidence interval [CI], 2.02). There were 13 retrospective reports describing a range of congenital anomalies. No specific pattern of anomalies was identified in either the prospective or retrospective reports. Rates for other outcomes were similar to background rates. CONCLUSIONS: Although the number of reports was relatively small, there was no evidence of a notable increase in congenital anomalies in women exposed to simvastatin or lovastatin versus the general population. Greater reporting of congenital abnormalities in the retrospective cohort is not unexpected and may reflect a reporting bias. Drugs should be used during pregnancy only if the benefits outweigh the risks. Simvastatin and lovastatin remain contraindicated during pregnancy.

Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin.

BACKGROUND: A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate LDL cholesterol-lowering efficacy, overall safety, and tolerability and the influence on growth and pubertal development of simvastatin in a large cohort of boys and girls with heterozygous familial hypercholesterolemia (heFH). METHODS AND RESULTS: A total of 173 heFH children (98 boys and 75 girls) were included in this study. After a 4-week diet/placebo run-in period, children with heFH were randomized to either simvastatin or placebo in a ratio of 3:2. Simvastatin was started at 10 mg/d and titrated at 8-week intervals to 20 and then 40 mg/d. During a 24-week extension period, the patients continued to receive simvastatin (40 mg) or placebo according to their assignment. After 48 weeks of simvastatin therapy, there were significant reductions of LDL cholesterol (-41%), total cholesterol (-31%), apolipoprotein B (-34%), VLDL cholesterol (-21%), and triglyceride (-9%) levels. HDL cholesterol and apolipoprotein A-I levels were increased by 3.3% and 10.4%, respectively (not significant). No safety issues became evident. Except for small decreases in dehydroepiandrosterone sulfate compared with placebo, there were no significant changes from baseline in adrenal, gonadal, and pituitary hormones in either treatment group. CONCLUSIONS: Simvastatin significantly reduced LDL cholesterol, total cholesterol, triglyceride, VLDL cholesterol, and apolipoprotein B levels and was well tolerated in children with heFH. There was no evidence of any adverse effect of simvastatin on growth and pubertal development. Therefore, simvastatin at doses up to 40 mg is a well-tolerated and effective therapy for heFH children.

The effect of rizatriptan, ergotamine, and their combination on human peripheral arteries: a double-blind, placebo-controlled, crossover study in normal subjects.

AIMS: To compare the peripheral vasoconstrictor effects of ergotamine, rizatriptan, and their combination, in normal subjects. METHODS: This was a double-blind, four-way, crossover study. Sixteen young male volunteers, selected as responders to the vasoconstrictor effect of 0.5 mg ergotamine i.v., were administered 10 mg oral rizatriptan, 0.25 mg i.v. ergotamine, 10 mg oral rizatriptan+0.25 mg i.v. ergotamine, and placebo. The vasoconstrictor effect on peripheral arteries was measured with strain gauge plethysmography up to 8 h after dosing. The 8 h assessment period was divided into two 4 h intervals to assess the immediate (0-4 h) vs sustained effect (4-8 h) of treatment. RESULTS: For the 0-4 h interval, the decreases in peripheral systolic blood pressure gradients were: placebo (-1 mmHg [95% CI: -3, 1])