mk-0524 and Cardiovascular-Diseases

Although treatment with statins reduces cardiovascular (CV) events in patients with dyslipidemia, a residual 60 - 70% CV risk remains. This CV risk may be inversely related to high-density lipoprotein-cholesterol (HDL-C). Interest in niacin has re-emerged because of its HDL-C raising effects. The flushing associated with niacin which has previously affected patient compliance can now be significantly blocked with laropiprant (LRPT).. This review aims to assess the efficacy, clinical effectiveness and safety of extended-release niacin (ERN) with LRPT. The authors searched PubMed and MEDLINE for literature published between January 2006 and November 2011, for efficacy, clinical effectiveness and safety reports of ERN with LRPT.. Niacin has been shown to prevent CV events, reduce mortality and has beneficial effects on vascular endothelial function. Evidence suggests that this is due to its broad-spectrum lipid altering properties, including lowering lipoprotein (a) (Lp(a)), and its pleiotropic actions. While side effects associated with niacin have limited its use in the past, the extended-release formulations and co-administration of LRPT have increased its tolerability, particularly by reducing flushing. The authors advise that ERN should be used in patients with a high risk of cardiovascular disease, who have failed to reach conventional targets.

Topics: Animals; Cardiovascular Diseases; Delayed-Action Preparations; Dyslipidemias; Evidence-Based Medicine; Flushing; Humans; Hypolipidemic Agents; Indoles; Lipids; Niacin; Practice Guidelines as Topic; Treatment Outcome

Prevention of cardiovascular disease has been only partially successful with the use of cholesterol-lowering drugs like statins. There is a residual risk remaining, which may be addressed by increasing protective high-density lipoprotein (HDL) cholesterol and apolipoprotein A1. The best drug available for that purpose is niacin. In addition to increasing HDL cholesterol and apolipoprotein A1, niacin decreases triglycerides, low-density lipoprotein (LDL)-cholesterol and lipoprotein(a) and has been named the broad-spectrum lipid drug.. This review summarizes to what extent a new formulation of niacin may meet this request. The effects of niacin on lipoproteins, atherosclerosis and cardiovascular disease are described, from its first publication in 1955, and also its mechanism of action on lipoproteins and on flushing. The flushing inhibitor laropiprant is described as well as the antiflushing effect of this compound when added to extended-release niacin.. The reader will gain knowledge of the development of niacin as an antiatherosclerosis treatment and of the added value that laropiprant may offer this treatment principle; and also the present place of niacin/laropiprant in the armamentarium of cardiovascular preventive drugs.. Niacin/laropiprant is a welcome means to address the residual risk in high-risk patients on statin therapy. However, the drug combination cannot completely eliminate niacin-induced side effects. Prescribing this treatment, therefore, will require careful provision of information and instruction to the patient.

Topics: Atherosclerosis; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Drug Therapy, Combination; Dyslipidemias; Flushing; Humans; Indoles; Lipid Metabolism; Niacin

The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial of patients at high risk of vascular disease found that adding extended-release niacin-laropiprant to intensive statin-based LDL-lowering therapy had no benefit on cardiovascular outcomes. However, the trial also identified previously unrecognized serious adverse effects (including new-onset diabetes, bleeding, and infection). Our objective was to explore the safety profile of niacin-laropiprant and examine whether any patients were at lower (or higher) risk of its adverse effects.. HPS2-THRIVE was a randomized, double-blind trial of niacin-laropiprant (2000/40 mg/d) versus placebo among 25,673 patients at high risk of vascular disease. Information on all serious adverse events was collected during a median of 3.9 years of study treatment. Effects of niacin-laropiprant on new-onset diabetes, disturbances of diabetes control, bleeding, infection, and gastrointestinal upset were estimated by (1) time after randomization, (2) severity, (3) baseline characteristics, (4) baseline risk of the adverse event of interest, and (5) risk of major vascular event.. The hazard ratio (HR) for new-onset diabetes with niacin/laropiprant was 1.32 (95% CI, 1.16-1.51; P < .001), which corresponded to an absolute excess of 4 people (95% CI, 2-6) developing diabetes per 1000 person-years in the study population as a whole. Among the 8299 participants with diabetes at baseline, the HR for serious disturbances in diabetes control was 1.56 (95% CI, 1.35-1.80), corresponding to an absolute excess of 12 (95% CI, 8-16) per 1000 person-years. The HR was 1.38 (95% CI, 1.17-1.63; P < .001) for serious bleeding, corresponding to an absolute excess of 2 (95% CI, 1-3) per 1000 person-years and 1.22 (95% CI, 1.11-1.34; P < .001) for serious infection, corresponding to an absolute excess of 4 (95% CI, 2-6) per 1000 person-years. The excess risks of these serious adverse events were larger in the first year after starting niacin-laropiprant therapy than in later years (except for the excess of infection, which did not appear to attenuate with time), and the risks of nonfatal and fatal events were similarly increased. The absolute excesses of each of these adverse effects were similar regardless of the baseline risk of the outcome.. Practitioners or patients considering the use of niacin (in addition to, or instead of, a statin) despite the lack of evidence of cardiovascular benefits (at least when added to effective statin therapy) should take account of the significant risks of these serious adverse effects when making such decisions. ClinicalTrials.gov identifier: NCT00461630.

Topics: Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus; Double-Blind Method; Drug Therapy, Combination; Dyslipidemias; Female; Hemorrhage; Humans; Hypolipidemic Agents; Incidence; Indoles; Infections; Male; Niacin

Extended-release niacin with laropiprant did not significantly reduce the risk of major vascular events and increased the risk of serious adverse events in Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), but its net effects on health and healthcare costs are unknown.. 25 673 participants aged 50 to 80 years with previous cardiovascular disease were randomized to 2 g of extended-release niacin with 40 mg of laropiprant daily versus matching placebo, in addition to effective statin-based low-density lipoprotein cholesterol-lowering treatment. The net effects of niacin-laropiprant on quality-adjusted life years and hospital care costs (2012 UK £; converted into US $ using purchasing power parity index) during 4 years in HPS2-THRIVE were evaluated using estimates of the impact of serious adverse events on health-related quality of life and hospital care costs. During the study, participants assigned niacin-laropiprant experienced marginally but not statistically significantly lower survival (0.012 fewer years [standard error (SE) 0.007]), fewer quality-adjusted life years (0.023 [SE 0.007] fewer using UK EQ-5D scores; 0.020 [SE 0.006] fewer using US EQ-5D scores) and accrued greater hospital costs (UK £101 [SE £37]; US $145 [SE $53]). Stroke, heart failure, musculoskeletal events, gastrointestinal events, and infections were associated with significant decreases in health-related quality of life in both the year of the event and in subsequent years. All serious vascular and nonvascular events were associated with substantial increases in hospital care costs.. In HPS2-THRIVE, the addition of extended-release niacin-laropiprant to statin-based therapy reduced quality of life-adjusted survival and increased hospital costs.. URL: http://clinicaltrials.gov. Unique identifier: NCT00461630.

Topics: Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; China; Cost-Benefit Analysis; Delayed-Action Preparations; Drug Combinations; Drug Costs; Drug Therapy, Combination; Dyslipidemias; Female; Hospital Costs; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Incidence; Indoles; Lipids; Male; Middle Aged; Niacin; Quality of Life; Quality-Adjusted Life Years; Risk Factors; Scandinavian and Nordic Countries; Time Factors; Treatment Outcome; United Kingdom

This study investigated the effect of long-term niacin/laropiprant therapy on CV risk and IR in obese women with PCOS.. In this double-blind randomized placebo-controlled trial, 13 and 12 PCOS women completed a 12 week course of niacin/laropiprant or placebo, respectively. Fasted subjects had an endothelial function test (EndoPat2000) and then consumed a mixed meal with blood sampled postprandially for 6 h before and after intervention.. By 12 weeks, niacin/laropiprant lowered low-density lipoprotein cholesterol (LDL-c) (13%) and increased HDL-c (17%). Despite a reduction in fasting triglycerides (21%), the drug had no effect on their postprandial rise (2.69 ± 1.44 vs. 2.49 ± 1.14 mmol/l, p = 0.72). However, following the mixed meal, plasma glucose area under the response curve increased from 13.1 ± 2.9 to 14.0 ± 2.8 mmol/l, p = 0.05, as a consequence of both increased insulin resistance [HOMA-IR: 2.2 (1.2, 4.2) vs. 3.8(1.3, 5.5), p = 0.02] and a reduced acute insulin response to glucose [424 (211, 975) vs. 257(122, 418) pmol/mmol, p = 0.04]. Niacin/laropiprant did not improve RHI (1.97 ± 0.40 vs. 2.05 ± 0.58, p = 0.33) or hsCRP.. In PCOS, niacin/laropiprant had a significant negative impact on postprandial glucose and no improvement in postprandial hypertriglyceridaemia, with at least the former mediated through increased IR and reduced β-cell function. This data may help explain why the improvement in fasting lipids has not translated into improved CV risk markers in PCOS.

Topics: Adult; Blood Glucose; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Indoles; Lipid Metabolism; Niacin; Polycystic Ovary Syndrome; Postprandial Period; Risk Reduction Behavior; Treatment Outcome; Triglycerides; Young Adult

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.. 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.. 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.. 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.. 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.

Topics: Adult; Aged; Apolipoproteins B; Biomarkers; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Indoles; Linear Models; Middle Aged; Niacin; Risk Factors; Simvastatin; Time Factors; Treatment Outcome

The effects of different hypolipidemic treatment strategies on emerging atherosclerosis risk factors remain unknown.. This is a prespecified analysis of a prospective, randomized, open-label, blinded end point (PROBE) study (ClinicalTrials.gov identifier: NCT01010516). Patients (n = 100) with mixed dyslipidaemia on a standard statin dose who had not achieved lipid targets were randomized to switch to the highest dose of rosuvastatin (40 mg/day) or to add-on-statin extended release nicotinic acid (ER-NA)/laropiprant (LRPT) or to add-on-statin micronized fenofibrate for a total of 3 months.. Following 3 months of treatment, low-density lipoprotein (LDL) particle size increased equally in all groups. Similarly, all treatments were associated with comparable small dense LDL cholesterol reduction. Apolipoprotein B levels decreased by 15%, 7% and 4% in the rosuvastatin, add-on ER-NA/LRPT and add-on fenofibrate group, respectively (P < 0.01 for all compared with baseline, P < 0.01 for all comparisons between groups). Only add-on ER-NA/LRPT was associated with lipoprotein (a) reduction (26%, P < 0.01 compared with baseline). Rosuvastatin monotherapy and add-on ER-NA/LRPT groups were associated with 56% and 24% reduction in high-sensitivity C-reactive protein levels (hsCRP), respectively (P < 0.01 compared with baseline), while add-on fenofibrate was not associated with changes in hsCRP concentration. Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity decreased similarly in both rosuvastatin and add-on fenofibrate groups, while add-on ER-NA/LRPT was associated with a more pronounced Lp-PLA2 activity reduction. ER-NA/LRPT was associated with more side effects compared with rosuvastatin and add-on fenofibrate.. Add-on ER-NA/LRPT followed by switch to the highest dose rosuvastatin were associated with more pronounced beneficial modifications in emerging cardiovascular risk factors compared with add-on fenofibrate in patients with mixed dyslipidaemia.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adult; Aged; Apolipoproteins B; Atherosclerosis; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, LDL; Drug Therapy, Combination; Dyslipidemias; Female; Fenofibrate; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Indoles; Male; Middle Aged; Niacin; Pilot Projects; Prospective Studies; Pyrimidines; Risk Factors; Rosuvastatin Calcium; Sulfonamides; Time Factors

Recent studies have shown that pharmacological increases in HDL cholesterol concentrations do not necessarily translate into clinical benefits for patients, raising concerns about its predictive value for cardiovascular events. Here we hypothesize that the size-modulated lipid distribution within HDL particles is compromised in metabolic disorders that have abnormal HDL particle sizes, such as type 2 diabetes mellitus (DM2). By using NMR spectroscopy combined with a biochemical volumetric model we determined the size and spatial lipid distribution of HDL subclasses in a cohort of 26 controls and 29 DM2 patients before and after two drug treatments, one with niacin plus laropiprant and another with fenofibrate as an add-on to simvastatin. We further characterized the HDL surface properties using atomic force microscopy and fluorescent probes to show an abnormal lipid distribution within smaller HDL particles, a subclass particularly enriched in the DM2 patients. The reduction in the size, force cholesterol esters and triglycerides to emerge from the HDL core to the surface, making the outer surface of HDL more hydrophobic. Interestingly, pharmacological interventions had no effect on this undesired configuration, which may explain the lack of clinical benefits in DM2 subjects.

Topics: Adult; Aged; Cardiovascular Diseases; Cholesterol, HDL; Diabetes Mellitus, Type 2; Female; Fenofibrate; Fluorescent Dyes; Humans; Indoles; Lipid Metabolism; Lipids; Magnetic Resonance Spectroscopy; Male; Microscopy, Atomic Force; Middle Aged; Niacin; Simvastatin; Surface Properties; Triglycerides

Topics: Bayes Theorem; Cardiovascular Diseases; Delayed-Action Preparations; Dyslipidemias; Flushing; Humans; Indoles; Lipid Regulating Agents; Niacin; Prostaglandin D2; Risk Assessment

Topics: Adaptor Protein Complex 3; Adaptor Protein Complex beta Subunits; Anticholesteremic Agents; Azetidines; Cardiovascular Diseases; Ezetimibe; Humans; Hypolipidemic Agents; Indoles; Niacin; Simvastatin

According to prior analyses, extended-release niacin/laropiprant (ERN/LRPT) consistently reduces low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C) levels across a wide range of dyslipidemic patient subgroups.. This analysis examined ERN/LRPT's consistency across four phase III, randomized, double-blind trials in improving other lipid/lipoprotein parameters associated with cardiovascular risk, across several key dyslipidemic patient subgroups.. In three of the studies, the randomized population included patients with primary hypercholesterolemia or mixed hyperlipidemia; in the remaining study, the population included patients with type 2 diabetes mellitus. The lipid-altering consistency of ERN/LRPT's efficacy was evaluated versus the pre-defined comparator (placebo or active control) among key subgroups of sex, race (White, non-White), region (US, ex-US), baseline age (<65 years, ≥65 years), use of statin therapy (yes, no), coronary heart disease (yes, no), risk status (low, multiple, high), and type of hyperlipidemia (primary hypercholesterolemia, mixed dyslipidemia), as well as across baseline LDL-C, HDL-C, and TG levels. The consistency of the treatment effects on lipoprotein(a).[Lp(a)], apolipoprotein B (ApoB), non-HDL-C, ApoA1, and ApoB/ApoA1 ratio was evaluated by examining treatment difference estimates of the percentage change from baseline with 95% confidence intervals.. Treatment with ERN/LRPT produced significantly greater improvements in Lp(a), ApoB, non-HDL-C, ApoA1, and ApoB/ApoA1 ratio compared with placebo/active comparator in each study. These effects were generally consistent across key subgroups within each study.. ERN/LRPT produced lipid-altering efficacy on the parameters evaluated in four controlled studies; these effects were generally consistent across all examined subgroups. ERN/LRPT represents an effective and reliable therapeutic option for the treatment of dyslipidemia in a wide range of patient types.. Registered as Clinicaltrials.gov NCT00269204, NCT00269217, NCT00479388, and NCT00485758.

Topics: Aged; Apolipoprotein A-I; Apolipoproteins B; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Double-Blind Method; Dyslipidemias; Female; Humans; Hypolipidemic Agents; Indoles; Lipids; Lipoprotein(a); Male; Niacin; Randomized Controlled Trials as Topic