Sukrut Shah

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.).

Inhibition of Intestinal Cholesterol Absorption by Ezetimibe in Humans

Background—Ezetimibe has been shown to inhibit cholesterol absorption in animal models, but studies on cholesterol absorption in humans have not been performed thus far. Methods and Results—The effect of ezetimibe (10 mg/d) on cholesterol absorption and synthesis, sterol excretion, and plasma concentrations of cholesterol and noncholesterol sterols was investigated in a randomized, double-blind, placebo-controlled, crossover study in 18 patients with mild to moderate hypercholesterolemia. Treatment periods lasted 2 weeks with an intervening 2-week washout period. Fractional cholesterol absorption rates averaged 49.8±13.8% on placebo and 22.7±25.8% on ezetimibe, indicating a reduction of 54% (geometric mean ratio;P < 0.001). Cholesterol synthesis increased by 89% from 931±1027 mg/d on placebo to 1763±1098 mg/d on ezetimibe (P <0.001), while the ratio of lathosterol-to-cholesterol, an indirect marker of cholesterol synthesis, was increased by 72% (P <0.001). Bile acid synthesis was insignificantly increased (placebo: 264±209 mg/d, ezetimibe: 308±184 mg/d;P =0.068). Mean percent changes from baseline for LDL and total cholesterol after ezetimibe treatment were −20.4% and −15.1%, respectively (P <0.001 for both), whereas campesterol and sitosterol were decreased by −48% and − 41%, respectively. Conclusion—In humans, ezetimibe inhibits cholesterol absorption and promotes a compensatory increase of cholesterol synthesis, followed by clinically relevant reductions in LDL and total cholesterol concentrations. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols sitosterol and campesterol, suggesting an effect on the absorption of these compounds as well.

Effects of an 11β‐hydroxysteroid dehydrogenase type 1 inhibitor, MK‐0916, in patients with type 2 diabetes mellitus and metabolic syndrome

Aim: We examined the effects of the 11β‐hydroxysteroid dehydrogenase type 1 (HSD1) inhibitor, MK‐0916, on the multiple components of the metabolic syndrome (MetS) in patients with type 2 diabetes (T2DM) and MetS.

Long-term 6-year experience with finasteride in patients with benign prostatic hyperplasia

OBJECTIVES To summarize the 6-year clinical trial data with finasteride. Benign prostatic hyperplasia is a chronic and progressive disease and therefore assessment of long-term safety and efficacy is important. METHODS The North American and International Phase III Finasteride trials enrolled symptomatic men with enlarged prostate glands. The initial 1-year placebo-controlled study was followed by a 5-year open-label extension. In total, 6-year finasteride data were available in 487 patients originally randomized to finasteride, and 5-year data were available on 238 patients originally randomized to placebo. RESULTS After 6 years of treatment with finasteride 5 mg, the mean quasi-American Urological Association Symptom Score improved by 4.0 points, the median prostate volume decreased by 24%, and the mean maximal urinary flow rate increased by 2.9 mL/s (P <0.001 for all parameters). Long-term finasteride treatment was well tolerated, with a low incidence of drug-related sexual adverse events occurring during the first year and even fewer occurrences during the 5-year open extension. CONCLUSIONS Treatment with finasteride leads to durable improvement in urinary tract symptoms, flow rate, and prostate volume, with no increase in the prevalence of drug-related adverse events over time.

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.

Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study

BACKGROUND Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease. We aimed to investigate the safety and efficacy of anacetrapib, a cholesteryl ester transfer protein inhibitor, in patients with heterozygous familial hypercholesterolaemia. METHODS In this multicentre, randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18-80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia, on optimum lipid-lowering treatment for at least 6 weeks, and with an LDL-C concentration of 2·59 mmol/L or higher without cardiovascular disease or 1·81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible. We randomly allocated participants with a computer-generated allocation schedule (2:1; block size of six; no stratification) to oral anacetrapib 100 mg or placebo for 52 weeks, with a 12 week post-treatment follow-up afterwards. We masked patients, care providers, and those assessing outcomes to treatment groups throughout the study. The primary outcome was percentage change from baseline in LDL-C concentration. We did analysis using a constrained longitudinal repeated measures model. This trial is registered with ClinicalTrials.gov, number NCT01524289. FINDINGS Between Feb 10, 2012, and Feb 12, 2014, we randomly allocated 204 patients to anacetrapib and 102 to placebo. One patient in the anacetrapib group did not receive the drug. At week 52, anacetrapib reduced mean LDL-C concentration from 3·3 mmol/L (SD 0·8) to 2·1 mmol/L (0·8; percentage change 36·0% [95% CI -39·5 to -32·5] compared with an increase with placebo from 3·4 mmol/L (1·2) to 3·5 mmol/L (1·6; percentage change 3·7% [-1·2 to 8·6], with a difference in percentage change between anacetrapib and placebo of -39·7% (95% CI -45·7 to -33·7; p<0·0001). The number of cardiovascular events was increased in patients given anacetrapib compared with those given placebo (4 [2%] of 203 vs none [0%] of 102; p=0·1544), but the proportion with adverse events leading to discontinuation was similar (12 [6%] of 203 vs five [5%] of 102). INTERPRETATION In patients with heterozygous familial hypercholesterolaemia, treatment with anacetrapib for 1 year was well tolerated and resulted in substantial reductions in LDL-C concentration. Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study. FUNDING Merck & Co, Inc.

Efficacy and safety of ezetimibe co‐administered with simvastatin in thiazolidinedione‐treated type 2 diabetic patients

Aim:  In patients with type 2 diabetes mellitus (T2DM), combination therapy is usually required to optimize glucose metabolism as well as to help patients achieve aggressive targets for low‐density lipoprotein cholesterol (LDL‐C) and other lipid parameters associated with cardiovascular risk. The thiazolidinediones (TZDs) are increasingly being used for both their blood glucose‐lowering properties and their modest beneficial effects on triglycerides (TG) and high‐density lipoprotein cholesterol (HDL‐C). Ezetimibe, an intestinal cholesterol absorption inhibitor, has a mechanism of action that differs from that of statins, which inhibit hepatic cholesterol synthesis. We compared the lipid‐modifying efficacy and safety of adding ezetimibe to simvastatin, vs. doubling the dose of simvastatin, in TZD‐treated T2DM patients.

Efficacy and safety of the selective 11β-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be involved in several abnormalities associated with the metabolic syndrome. This study evaluated the antihypertensive efficacy and safety of two 11β-HSD1 inhibitors, MK-0736 and MK-0916, in overweight-to-obese hypertensive patients. Patients aged 18-75 years with sitting diastolic blood pressure (SiDBP) 90-104 mm Hg, systolic BP <160 mm Hg (after washout of prior antihypertensive medications), and BMI ≥27 to <41 kg/m(2) were randomized to receive 2 or 7 mg/d MK-0736, 6 mg/d MK-0916, or placebo for 12 weeks (n = 51-54/group). Patients with BMI ≥20 to <27 kg/m(2) received 6 mg/d MK-0916 or placebo for 24 weeks (n = 19/group). The primary endpoint was placebo-adjusted change from baseline in trough SiDBP in patients treated for 12 weeks with 7 mg/d MK-0736. The primary endpoint was not met (placebo-adjusted reduction = 2.2 mm Hg; P = .157). With 7 mg/d MK-0736, placebo-adjusted LDL-C decreased by 12.3%, high-density lipoprotein cholesterol by 6.3%, and body weight by 1.4 kg. Both 11β-HSD1 inhibitors were generally well tolerated. In overweight-to-obese patients with hypertension, reduction in SiDBP with MK-0736 was not statistically significant. Nonetheless, MK-0736 was well tolerated and did appear to modestly improve other BP endpoints, LDL-C, and body weight.

Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease.

The aim of this study was to assess the effects on lipids and safety during a 12-week reversal period after 18 months of treatment with anacetrapib. The cholesteryl ester transfer protein inhibitor anacetrapib was previously shown to reduce low-density lipoprotein cholesterol by 39.8% (estimated using the Friedewald equation) and increase high-density lipoprotein (HDL) cholesterol by 138.1%, with an acceptable side-effect profile, in patients with or at high risk for coronary heart disease in the Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial. A total of 1,398 patients entered the 12-week reversal-phase study, either after completion of the active-treatment phase or after early discontinuation of the study medication. In patients allocated to anacetrapib, placebo-adjusted mean percentage decreases from baseline were observed at 12 weeks off the study drug for Friedewald-calculated low-density lipoprotein cholesterol (18.6%), non-HDL cholesterol (17.6%), and apolipoprotein B (10.2%); placebo-adjusted mean percentage increases were observed for HDL cholesterol (73.0%) and apolipoprotein A-I (24.5%). Residual plasma anacetrapib levels (about 40% of on-treatment apparent steady-state trough levels) were also detected 12 weeks after cessation of anacetrapib. No clinically important elevations in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the reversal phase. Preliminary data from a small cohort (n = 30) revealed the presence of low concentrations of anacetrapib in plasma 2.5 to 4 years after the last anacetrapib dose. In conclusion, after the cessation of active treatment, anacetrapib plasma lipid changes and drug levels decreased to approximately 40% of on-treatment trough levels at 12 weeks after dosing, but modest HDL cholesterol elevations and low drug concentrations were still detectable 2 to 4 years after the last dosing.

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 ef ficacy and tolerability of CETP in hibition with anac e trapib). 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 β-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.