mk-0524 and Coronary-Disease

Niacin is a B-complex vitamin used as a lipid-altering drug since the 1950s. Niacin improves multiple lipid parameters. Atherosclerotic coronary heart disease outcome studies support niacin's efficacy in reducing coronary heart disease events, either as monotherapy or when used in combination with other lipid-altering drugs. The most commonly reported reason for the lack of its more widespread clinical use is niacin-induced flushing.. Laropiprant is a highly selective prostaglandin D2 receptor 1 antagonist that mitigates niacin-induced flushing.. This review examines the history and provides a perspective regarding the extended-release niacin/laropiprant development program, which was designed to better allow patients to achieve a more therapeutic niacin dose of 2 g/day, without the need for titration. Ongoing coronary heart disease outcome studies will provide better insight as to the benefits of niacin in general, and the safety and efficacy of extended-release niacin/laropiprant specifically.

Topics: Coronary Disease; Delayed-Action Preparations; Drug Combinations; Flushing; Humans; Hypolipidemic Agents; Indoles; Lipids; Niacin; Treatment Outcome

Genetic studies have shown lipoprotein(a) (Lp[a]) to be an important causal risk factor for coronary disease. Apolipoprotein(a) isoform size is the chief determinant of Lp(a) levels, but its impact on the benefits of therapies that lower Lp(a) remains unclear.. HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is a randomized trial of niacin-laropiprant versus placebo on a background of simvastatin therapy. Plasma Lp(a) levels at baseline and 1 year post-randomization were measured in 3978 participants from the United Kingdom and China. Apolipoprotein(a) isoform size, estimated by the number of kringle IV domains, was measured by agarose gel electrophoresis and the predominantly expressed isoform identified.. Allocation to niacin-laropiprant reduced mean Lp(a) by 12 (SE, 1) nmol/L overall and 34 (6) nmol/L in the top quintile by baseline Lp(a) level (Lp[a] ≥128 nmol/L). The mean proportional reduction in Lp(a) with niacin-laropiprant was 31% but varied strongly with predominant apolipoprotein(a) isoform size (. Proportional reductions in Lp(a) were dependent on apolipoprotein(a) isoform size. Taking this into account, the likely benefits of niacin-laropiprant on coronary risk through Lp(a) lowering are small. Novel therapies that reduce high Lp(a) levels by at least 80 nmol/L (≈40%) may be needed to produce worthwhile benefits in people at the highest risk because of Lp(a).. URL: https://clinicaltrials.gov. Unique identifier: NCT00461630.

Topics: Aged; Coronary Disease; Female; Humans; Hypolipidemic Agents; Indoles; Lipoprotein(a); Male; Middle Aged; Niacin; Protein Isoforms; Risk Factors; Simvastatin

To establish determinants of lipid goal attainment in primary care patients, with particular focus on participation in a disease management programme (DMP) on diabetes mellitus (DM) and/or coronary heart disease (CHD), with real-world practical relevance.. The present analysis was based on an observational study in 2359 patients with dyslipidaemia or hypercholesterolaemia that were treated with nicotinic acid 1000 mg/laropiprant 20 mg (Tredaptive) one or two tablets daily. Subgroups were formed by DMP participation (DMP vs. no DMP). A stepwise logistic regression model with backward selection of variables was applied to investigate factors influencing the probability of reaching lipid goals. Follow-up was 23 ± 7 weeks.. Low density lipoprotein cholesterol (LDL-C) <100 mg/dl was achieved by 30.8% in DMP versus 26.8% (no DMP), high density lipoprotein (HDL-C) >40/50 mg/dl in 61.3% versus 66.1%, and triglycerides (TG) <150 mg/dl in 28.9% versus 31.7%. On multivariate analysis, age, sex, concomitant high-risk cardiovascular disease, or participation in a DMP appeared to have inconsistent effects on reaching LDL-C, HDL-C and TG goals. Likelihood to reach the LDL-C goal tended to be higher in males, in patients outside DMP, and in patients with DM or CHD, and those treated with 1 tablet (versus 2 tablets) extended release nicotinic acid 1000 mg/laropiprant 20 mg. The likelihood of reaching the HDL-C goal was higher in males and in patients without DM or DM+CHD (no effect of DMP). The likelihood of reaching the TG goals was higher in females, in patients outside DMP, and in patients with DM and/or CHD. Limitations include potential bias due to study design, physician and patient selection, and missing values at follow-up.. DMP participation was not associated with overall improved lipid goal attainment. Physicians cannot predict the magnitude of effects of newly initiated lipid modifying therapy based on baseline characteristics of their patients.

Topics: Age Factors; Aged; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Diabetes Mellitus; Disease Management; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Male; Middle Aged; Niacin; Sex Factors

In patients with primary hypercholesterolemia or mixed dyslipidemia, extended-release niacin/laropiprant (ERN/LRPT) improves key lipid parameters associated with increased atherosclerotic coronary heart disease (CHD) risk.. This analysis examined data from four Phase III, randomised, double-blind trials to determine the consistency of ERN/LRPT's lipid-altering efficacy among subgroups of patients.. Data from four Phase III, randomised, double-blind trials of ERN/LRPT were analysed to determine the consistency of ERN/LRPT's lipid-altering efficacy among subgroups of gender, race (white, non-white), region (US, ex-US), baseline age (<65, ≥65 years), use of statin therapy, CHD risk status (low, multiple, high) and type of hyperlipidemia (primary hypercholesterolemia, mixed dyslipidemia), as well as across baseline low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. End-points included the per cent change from baseline in LDL-C, HDL-C and TG levels. Consistency of the treatment effects on LDL-C, HDL-C and TG across subgroups was evaluated by examining treatment difference estimates with 95% confidence intervals..   Treatment with ERN/LRPT significantly improved LDL-C, HDL-C and TG levels compared with placebo/active comparator in each study cohort. These effects were generally consistent across all examined subgroups.. Extended-release niacin/laropiprant represents an effective therapeutic option for the treatment of dyslipidemia across a range of patient types.

Topics: Adult; Aged; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Dyslipidemias; Humans; Hypolipidemic Agents; Indoles; Male; Middle Aged; Niacin; Risk Factors; Treatment Outcome; Triglycerides