Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616.

BACKGROUND: MK-0616 is an oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) in development for the treatment of hypercholesterolemia. OBJECTIVES: This Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial aimed to evaluate the efficacy and safety of MK-0616 in participants with hypercholesterolemia. METHODS: This trial was planned to include 375 adult participants with a wide range of atherosclerotic cardiovascular disease risk. Participants were assigned randomly (1:1:1:1:1 ratio) to MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo. The primary endpoints included percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) at Week 8 and the proportion of participants with adverse events (AEs) and study intervention discontinuations due to AEs; participants were monitored for AEs for an additional 8 weeks after the 8-week treatment period. RESULTS: Of the 381 participants randomized, 49% were female, and the median age was 62 years. Among 380 treated participants, all doses of MK-0616 demonstrated statistically significant (P < 0.001) differences in least squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). AEs occurred in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group. CONCLUSIONS: MK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 of up to 60.9% from baseline and was well tolerated during 8 weeks of treatment and an additional 8 weeks of follow-up. (A Study of the Efficacy and Safety of MK-0616 [Oral PCSK9 Inhibitor] in Adults With Hypercholesterolemia [MK-0616-008]; NCT05261126).

A Multiregional, Randomized Evaluation of the Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients With Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol.

This phase 3, multiregional, randomized, double-blind, placebo-controlled study assessed the efficacy/safety profile of anacetrapib added to ongoing therapy with statin ± other lipid-modifying therapies in patients with hypercholesterolemia who were not at their low-density lipoprotein (LDL-C) goal (as per the National Cholesterol Education Program Adult Treatment Panel III guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of statin ± other lipid-modifying therapies and with LDL-C ≥70 to <115, ≥100 to <145, ≥130, or ≥160 mg/dl for very high, high, moderate, or low CHD risk or at LDL-C goal (per CHD risk category) with HDL-C ≤40 mg/dl were randomized in a ratio of 1:1 to anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks, followed by a 12-week off-drug phase. The co-primary end points were % change from baseline in LDL-C and HDL-C and the safety profile of anacetrapib. Treatment with anacetrapib reduced LDL-C (BQ) by 37% (95% confidence interval -42.5, -31.0) and increased HDL-C by 118% (95% confidence interval 110.6, 125.7) relative to placebo (p <0.001 for both). Anacetrapib also reduced non-HDL-C, apolipoprotein B, and lipoprotein a and increased apolipoprotein AI versus placebo (p <0.001 for all). There were no clinically meaningful differences between the anacetrapib and placebo groups in the % patients who discontinued drug due to an adverse event or in abnormalities in liver enzymes, creatine kinase, blood pressure, electrolytes, or adjudicated cardiovascular events. Treatment with anacetrapib substantially reduced LDL-C and also increased HDL-C and was well tolerated over 24 weeks in statin-treated patients with hypercholesterolemia or low HDL-C.

Atherothrombotic Risk Stratification and Ezetimibe for Secondary Prevention.

BACKGROUND: Ezetimibe improves cardiovascular (CV) outcomes in patients stabilized after acute coronary syndrome (ACS) when added to statin therapy. After ACS, patients vary considerably in their risk for recurrent CV events. OBJECTIVES: This study tested the hypothesis that atherothrombotic risk stratification may be useful to identify post-ACS patients who have the greatest potential for benefit from the addition of ezetimibe to statin therapy. METHODS: The TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention (TRS 2°P) is a simple 9-point risk stratification tool, previously developed in a large population with atherothrombosis to predict CV death, myocardial infarction (MI), and ischemic stroke (CV death/MI/ischemic cerebrovascular accident [iCVA]). The current study applied this tool prospectively to 17,717 post-ACS patients randomized either to ezetimibe and simvastatin or to placebo and simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Treatment efficacy was assessed by baseline risk for CV death/MI/iCVA, the IMPROVE-IT composite endpoints (CE), and individual component endpoints at 7 years. RESULTS: All 9 clinical variables in the TRS 2°P were independent risk indicators for CV death/MI/iCVA (p < 0.001). The integer-based scheme showed a strong graded relationship with the rate of CV death/MI/iCVA, the trial CE, and the individual components (p trend <0.0001 for each). High-risk patients (n = 4,393; 25%), defined by ≥3 risk indicators, had a 6.3% (95% confidence interval: 2.9% to 9.7%) absolute risk reduction in CV death/MI/iCVA at 7 years with ezetimibe/simvastatin, thus translating to a number-needed-to-treat of 16. Intermediate-risk patients (2 risk indicators; n = 5,292; 30%) had a 2.2% (95% confidence interval: -0.3% to 4.6%) absolute risk reduction. Low-risk patients (0 to 1 risk indicators; n = 8,032; 45%) did not appear to derive benefit from the addition of ezetimibe (p interaction = 0.010). Similar findings were observed for the IMPROVE-IT primary CE. CONCLUSIONS: Atherothrombotic risk stratification using the TRS 2°P identifies high-risk patients who derive greatest benefit from the addition of ezetimibe to statin therapy for secondary prevention after ACS. (Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878).

Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients with Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol.

To assess the effects of anacetrapib added to statin ± other lipid-modifying therapies in patients with hypercholesterolemia and not at their low-density lipoprotein cholesterol (LDL-C) goal (as per National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of moderate/high-intensity statin ± other lipid-modifying therapies with LDL-C ≥70, ≥100, ≥130, or ≥160 mg/dl for very high, high, moderate, and low coronary heart disease risk, respectively, or at LDL-C goal with HDL-C ≤40 mg/dl, were randomized 1:1:1, stratified by background therapy use, to anacetrapib 100 mg (n = 153), anacetrapib 25 mg (n = 152), or placebo (n = 154) for 24 weeks, followed by a 12-week off-drug reversal phase. The primary end points were percent change from baseline in LDL-C (beta-quantification method) and HDL-C, as well as the safety profile of anacetrapib. Both doses of anacetrapib reduced LDL-C, non-HDL-C, apolipoprotein (Apo) B, and lipoprotein a and increased HDL-C and Apo AI versus placebo (p <0.001 for all). There were no meaningful differences between the anacetrapib 25 mg, 100 mg, and placebo groups in the proportions of discontinuations due to drug-related adverse events (0.7%, 1.3% vs 1.3%) or in abnormalities in liver enzymes (0%, 0% vs 0.7%), creatine kinase elevations overall (0%, 0.7% vs 0%) or with muscle symptoms (none seen), blood pressure, electrolytes, or adjudicated cardiovascular events (0.7%, 0.7% vs 1.3%). In conclusion, treatment with anacetrapib resulted in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated.

Effects of extended-release niacin/laropiprant on correlations between apolipoprotein B, LDL-cholesterol and non-HDL-cholesterol in patients with type 2 diabetes.

BACKGROUND: LDL-C, non-HDL-C and ApoB levels are inter-correlated and all predict risk of atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes mellitus (T2DM) and/or high TG. These levels are lowered by extended-release niacin (ERN), and changes in the ratios of these levels may affect ASCVD risk. This analysis examined the effects of extended-release niacin/laropiprant (ERN/LRPT) on the relationships between apoB:LDL-C and apoB:non-HDL-C in patients with T2DM. METHODS: T2DM patients (n = 796) had LDL-C ≥1.55 and <2.97 mmol/L and TG <5.65 mmol/L following a 4-week, lipid-modifying run-in (~78 % taking statins). ApoB:LDL-C and apoB:non-HDL-C correlations were assessed after randomized (4:3), double-blind ERN/LRPT or placebo for 12 weeks. Pearson correlation coefficients between apoB:LDL-C and apoB:non-HDL-C were computed and simple linear regression models were fitted for apoB:LDL-C and apoB:non-HDL-C at baseline and Week 12, and the correlations between measured apoB and measured vs predicted values of LDL-C and non-HDL-C were studied. RESULTS: LDL-C and especially non-HDL-C were well correlated with apoB at baseline, and treatment with ERN/LRPT increased these correlations, especially between LDL-C and apoB. Despite the tighter correlations, many patients who achieved non-HDL-C goal, and especially LDL-C goal, remained above apoB goal. There was a trend towards greater increases in these correlations in the higher TG subgroup, non-significant possibly due to the small number of subjects. CONCLUSIONS: ERN/LRPT treatment increased association of apoB with LDL-C and non-HDL-C in patients with T2DM. Lowering LDL-C, non-HDL-C and apoB with niacin has the potential to reduce coronary risk in patients with T2DM.

Safety and tolerability of extended-release niacin-laropiprant: Pooled analyses for 11,310 patients in 12 controlled clinical trials.

BACKGROUND: The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) showed that adding extended-release niacin-laropiprant (ERN-LRPT) to statin provided no incremental cardiovascular benefit vs placebo (PBO). ERN-LRPT was also associated with an excess of serious adverse experiences (AEs), some of which were unexpected (infections and bleeding). These findings led to the withdrawal of ERN-LRPT from all markets. OBJECTIVE: We examined the safety profile of ERN-LRPT vs the comparators ERN alone and statins in the ERN-LRPT development program to assess whether similar safety signals were observed to those seen in HPS-THRIVE and whether these might be attributed to ERN or LRPT. METHODS: Postrandomization safety data from 12 clinical studies, 12 to 52 weeks in duration and involving 11,310 patients, were analyzed across 3 treatments: (1) ERN-LRPT; (2) ERN-NSP (ERN, Merck & Co, Inc or Niaspan [NSP], Abbott Laboratories); and (3) statin-PBO (statin or PBO). RESULTS: The safety profiles of ERN-LRPT and ERN-NSP were similar, except for less flushing with ERN-LRPT. Nonflushing AEs reported more frequently with ERN-LRPT or ERN-NSP than with statin-PBO were mostly nonserious and typical of niacin (nausea, diarrhea, and increased blood glucose). There was no evidence for an increased risk of serious AEs related to diabetes, muscle, infection, or bleeding. CONCLUSIONS: Pooled data from 11,310 patients revealed that, except for reduced flushing, the safety profile of ERN-LRPT was similar to that of ERN-NSP; LRPT did not appear to adversely affect the side-effect profile of ERN. The inability to replicate the unexpected AE findings in HPS2-THRIVE could be because of the smaller sample size and substantially shorter duration of these studies.

Extended-release niacin/laropiprant significantly improves lipid levels in type 2 diabetes mellitus irrespective of baseline glycemic control.

BACKGROUND: The degree of glycemic control in patients with type 2 diabetes mellitus (T2DM) may alter lipid levels and may alter the efficacy of lipid-modifying agents. OBJECTIVE: Evaluate the lipid-modifying efficacy of extended-release niacin/laropiprant (ERN/LRPT) in subgroups of patients with T2DM with better or poorer glycemic control. METHODS: Post hoc analysis of clinical trial data from patients with T2DM who were randomized 4:3 to double-blind ERN/LRPT or placebo (n=796), examining the lipid-modifying effects of ERN/LRPT in patients with glycosylated hemoglobin or fasting plasma glucose levels above and below median baseline levels. RESULTS: At Week 12 of treatment, ERN/LRPT significantly improved low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol, triglycerides, and lipoprotein (a), compared with placebo, with equal efficacy in patients above or below median baseline glycemic control. Compared with placebo, over 36 weeks of treatment more patients treated with ERN/LRPT had worsening of their diabetes and required intensification of antihyperglycemic medication, irrespective of baseline glycemic control. Incidences of other adverse experiences were generally low in all treatment groups. CONCLUSION: The lipid-modifying effects of ERN/LRPT are independent of the degree of baseline glycemic control in patients with T2DM (NCT00485758).

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.

Effects of anacetrapib on plasma lipids in specific patient subgroups in the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) trial.

BACKGROUND: In the Determining the Efficacy and Tolerability of cholesteryl ester transfer protein (CETP) INhibition with AnacEtrapib (DEFINE) trial, anacetrapib added to statin produced robust low-density lipoprotein cholesterol (LDL-C)-lowering and high-density lipoprotein cholesterol (HDL-C)-raising vs placebo in patients with coronary heart disease (CHD). Predictors of the degree of LDL-C and HDL-C responses to anacetrapib, however, are poorly understood. OBJECTIVE: Lipid effects of anacetrapib in patient subgroups within the DEFINE trial (clinicaltrials.gov: NCT00685776) are reported. METHODS: The percent of placebo-corrected changes from baseline for LDL-C (estimated by Friedewald calculation [Fc-LDL-C]) and HDL-C after 24 weeks of anacetrapib 100 mg/day were compared among patients by age, gender, race, diabetes status, type of concomitant statin with or without other lipid therapies, and baseline HDL-C, Fc-LDL-C, and triglyceride (TG) levels. RESULTS: Percent decreases in Fc-LDL-C and increases in HDL-C with anacetrapib were similar (magnitude of difference generally <1/5 of the overall treatment effect) across subgroups by age, gender, diabetes status, lipid-modifying regimen, and baseline Fc-LDL-C, HDL-C, or TG. On the other hand, anacetrapib effects on Fc-LDL-C (-24% vs -41%) and HDL-C (+75% vs +139%) appeared to be less in black vs white patients, respectively. CONCLUSION: Effects of anacetrapib on Fc-LDL-C and HDL-C were generally comparable across subgroups, including being relatively independent of baseline Fc-LDL-C, HDL-C, or TG levels. The clinical impact of the lipid-modifying effects of anacetrapib is being evaluated in the cardiovascular disease outcomes trial, Randomized EValuation of the Effects of Anacetrapib though Lipid-modification (REVEAL).

Effects of extended-release niacin/laropiprant, simvastatin, and the combination on correlations between apolipoprotein B, LDL cholesterol, and non-HDL cholesterol in patients with dyslipidemia.

BACKGROUND: Statins modify correlations between apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C) and apoB and non-high-density lipoprotein cholesterol (non-HDL-C); however, it is not known whether niacin-based therapies have similar effects. OBJECTIVE: To evaluate the effects of extended-release niacin (ERN)/laropiprant (LRPT), simvastatin (SIMVA), and ERN/LRPT + SIMVA (pooled ERN/LRPT + SIMVA) on apoB:LDL-C and apoB:non-HDL-C correlations in dyslipidemic patients. METHODS: This post-hoc analysis of a 12-week study evaluated the apoB:LDL-C and apoB:non-HDL-C correlations in dyslipidemic patients randomized equally to double-blind ERN/LRPT 1 g/20 mg, SIMVA 10, 20, or 40 mg, or ERN/LRPT 1 g/20 mg + SIMVA (10, 20, or 40 mg) once daily for 4 weeks. At week 5, doses were doubled in all groups except SIMVA 40 mg (unchanged) and ERN/LRPT 1 g/20 mg + SIMVA 40 mg (switched to ERN/LRPT 2 g/40 mg + SIMVA 40 mg). Simple linear regression analyses were used to calculate LDL-C and non-HDL-C levels corresponding to known apoB baseline values (ie, in untreated patients) and following treatment. RESULTS: The apoB:LDL-C and apoB:non-HDL-C correlations were higher and the predicted LDL-C and non-HDL-C levels for a known apoB value were considerably lower following treatment with ERN/LRPT, SIMVA and ERN/LRPT + SIMVA compared with untreated patients at baseline. CONCLUSION: Greater dissociation of apoB, LDL-C, and non-HDL-C targets occur following treatment with ERN/LRPT, SIMVA, and ERN/LRPT + SIMVA in patients with dyslipidemia. The achievement of more aggressive LDL-C and non-HDL-C goals in patients receiving lipid-modifying therapy may further reduce coronary risk by normalizing apoB-containing atherogenic lipoproteins.

Lipids, safety parameters, and drug concentrations after an additional 2 years of treatment with anacetrapib in the DEFINE study.

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n = 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was ∼640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C.

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 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.

Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression.

Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D2, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.

Effectiveness and safety of laropiprant on niacin-induced flushing.

Extended-release niacin (ERN) improves multiple lipid parameters but is underused owing to niacin-induced flushing (NIF). Laropiprant (LRPT) reduces NIF; however, its effects on chronic flushing (>6 months) have not been studied. We examined whether after 20 weeks of treatment with ERN/LRPT, patients who continued ERN/LRPT would experience less NIF than patients who stopped LRPT and continued ERN alone. A total of 1,152 dyslipidemic patients were randomized 2:2:1 to group 1, ERN/LRPT 1 g/20 mg/day from 0 to 4 weeks and then ERN/LRPT 2 g/40 mg/day from 5 to 32 weeks; group 2, ERN/LRPT 1 g/20 mg/day from 0 to 4 weeks, ERN/LRPT 2 g/40 mg/day from 5 to 20 weeks, and then ERN 2 g/day without LRPT from 21 to 32 weeks; or group 3, placebo for the entire study. The end points included the number of days each week with a moderate or greater Global Flushing Severity Score (GFSS) ≥4 (primary end point) and the percentage of patients with a maximum GFSS of ≥4 (secondary end point) during the postwithdrawal period (weeks 21 to 32). ERN/LRPT produced significantly less NIF than ERN alone during the postwithdrawal period, as measured by the number of days each week with a GFSS of ≥4 (p <0.001) and the percentage of patients with a maximum GFSS of ≥4 (p <0.001; ERN/LRPT 19.6%; ERN 48.9%; placebo 9.2%). Compared with ERN alone, ERN/LRPT produced fewer drug-related adverse experiences during the postwithdrawal period. After 20 weeks of stable maintenance therapy, dyslipidemic patients treated continuously with ERN/LRPT experienced less NIF than did patients who had had LRPT withdrawn and had continued with ERN alone. In conclusion, the results of our study support the long-term efficacy of ERN/LRPT in reducing NIF symptoms.

Effects of coadministered extended-release niacin/laropiprant and simvastatin on lipoprotein subclasses in patients with dyslipidemia.

BACKGROUND: The use of extended-release niacin and the prostaglandin D2 receptor antagonist laropiprant (ERN/LRPT) reduces niacin-induced flushing in patients while preserving its lipid-modifying effects. OBJECTIVE: This predefined exploratory analysis examined the individual and combined effects of ERN/LRPT and simvastatin (SIM) on lipoprotein subclasses. METHODS: This double-blind study randomized 1398 dyslipidemic patients equally to ERN/LRPT 1 g/20 mg, SIM (10, 20, or 40 mg), or ERN/LRPT 1 g/20 mg + SIM (10, 20, or 40 mg) once daily for 4 weeks. At week 5, doses were doubled, except SIM 40 mg (unchanged) and ERN/LRPT 1 g/20 mg + SIM 40 mg (switched to ERN/LRPT 2 g/40 mg + SIM 40 mg). Cholesterol associated with lipoprotein subclasses was quantified by vertical auto profile II (VAP II). RESULTS: ERN/LRPT + SIM and SIM alone lowered LDL-C 1 and 3, whereas the effects were variable for ERN/LRPT; all three treatments increased LDL-C 4. ERN/LRPT + SIM and ERN/LRPT raised HDL-C 2 and 3, with greater relative percent changes in HDL 2 than HDL 3. ERN/LRPT + SIM for 12 weeks produced substantial reductions in IDL-C, which was additive compared with each monotherapy. CONCLUSION: Coadministered ERN/LRPT + SIM produced marked reductions in atherogenic lipoproteins, with the greatest effect on IDL-C, and increases in protective HDL subclasses.

Efficacy and safety after cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib (MK-0859) in patients with primary hypercholesterolemia or mixed hyperlipidemia.

This report describes the lipid and safety data collected during an off-drug period that followed 8 weeks of treatment with the cholesteryl ester transfer protein inhibitor, anacetrapib (ANA). A total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia were randomized to placebo, atorvastatin (ATV) 20 mg, and varying doses of ANA, provided as monotherapy or coadministered with ATV 20 mg daily. Patients were treated for 8 weeks, followed by an 8-week follow-up period, during which ANA was switched to placebo. At week 16 (8 weeks after ANA was stopped), persistent reductions in low-density lipoprotein cholesterol (LDL-C) were evident for the monotherapy groups receiving ANA 150 and 300 mg (-9.3% and -15.3%, respectively), and residual increases in high-density lipoprotein cholesterol (HDL-C) were observed for the monotherapy groups receiving ANA 40 mg (18.6%), 150 mg (40.5%), and 300 mg (43.4%). The effects on apolipoprotein B and apolipoprotein A-I were consistent with the changes observed for LDL-C and HDL-C, respectively. Corresponding residual changes in LDL-C and HDL-C were also noted in the ATV coadministration groups at the similar doses of ANA compared with ATV 20 mg alone. Residual plasma drug levels accompanied by reductions in cholesteryl ester transfer protein activity were observed at week 16 and may account for the alterations in plasma lipids 8 weeks after cessation of ANA.

Safety of extended-release niacin/laropiprant in patients with dyslipidemia.

OBJECTIVE: To evaluate the safety profile of extended-release niacin/laropiprant (ERN/LRPT), pooling data from studies in the clinical development program. METHODS: Data were pooled from three active- or placebo-controlled phase 3 studies and three 1-year extensions of phase 2 studies that ranged from 12 to 52 weeks (N = 4747): ERN/LRPT = 2548; ERN or Niaspan® (ERN-NSP = 1268); or simvastatin or placebo (SIMVA-PBO = 931). RESULTS: The safety and tolerability profile for ERN/LRPT was similar to that of ERN-NSP, except for fewer flushing-related adverse experiences and discontinuations with ERN/LRPT than ERN-NSP. The incidence of consecutive ≥3× the upper limit of normal increases in alanine aminotransferase and/or aspartate aminotransferase was numerically (but not statistically) greater with ERN/LRPT (1.0%) than ERN-NSP (0.5%) and similar to SIMVA-PBO (0.9%). Elevations were reversible with therapy discontinuation and not associated with clinical hepatotoxicity. There was no evidence that ERN/LRPT administered alone or concurrently with a statin had adverse effects on muscle. ERN/LRPT and ERN-NSP produced small median increases in fasting blood glucose levels (∼4 mg/dL) after 24 weeks of treatment, consistent with known effects of niacin. CONCLUSION: The favorable safety and tolerability profile of ERN/LRPT for up to 1 year supports the use of LRPT to achieve improved therapeutic dosing of niacin, an agent with comprehensive lipid-modifying efficacy and shown to reduce cardiovascular risk.

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.).