mk-0524 and Myocardial-Infarction

Raising high-density lipoprotein cholesterol (HDL-C) is an important strategy for reducing residual cardiovascular risk. In the present study, we sought to assess the effect of extended-release niacin/laropiprant on endothelial function in patients after a myocardial infarction with target low-density lipoprotein cholesterol (LDL-C). In this double-blind, placebo-controlled trial, 63 men (35-60 years of age) after a myocardial infarction were randomized to either niacin/laropiprant (1000/20 mg daily for 4 weeks and 2000/40 mg daily thereafter) or placebo. Flow-mediated dilation (FMD) and nitroglycerin-induced (GTN) dilation of the brachial artery, total cholesterol (TC), LDL-C, HDL-C, triglycerides (TG), lipoprotein(a) [Lp(a)], and apolipoprotein (Apo) A1/B were measured at baseline and after 12 weeks of intervention. FMD significantly increased (from 3.9 ± 5.1 to 9.8 ± 4.4%, p < 0.001) in the niacin/laropiprant group, but not in the placebo group (4.6 ± 4.4 to 6.1 ± 4.4%, p = 0.16) (p = 0.02 for comparison of interventions). GTN dilation also increased in the niacin/laropiprant group (from 12.5 ± 6.1 to 16.7 ± 4.8%, p = 0.02), but not in the placebo group (13.4 ± 5.0 to 15.1 ± 5.2%, p = 0.18), (p = 0.60 for comparison of interventions). Niacin/laropiprant reduced TC and LDL-C (p = 0.05 for both) and increased HDL-C (p < 0.001) without influencing TG, with no changes in the placebo group. Lp(a) (p = 0.026) and ApoB (p = 0.014) were significantly lower in the niacin/laropiprant group, with no difference in the placebo group. ApoA1 did not change in either of the groups (p = 0.13; p = 0.26). FMD and GTN dilation improvements did not correlate with changes in the lipid profile. Niacin/laropiprant improves endothelium-dependent and endothelium-independent dilation of the brachial artery. This improvement does not correlate with changes in lipid parameters.

Topics: Adult; Biomarkers; Brachial Artery; Cholesterol, HDL; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Indoles; Male; Middle Aged; Myocardial Infarction; Niacin; Slovenia; Time Factors; Treatment Outcome

Niacin has potentially favourable effects on lipids, but its effect on cardiovascular outcomes is uncertain. HPS2-THRIVE is a large randomized trial assessing the effects of extended release (ER) niacin in patients at high risk of vascular events.. Prior to randomization, 42 424 patients with occlusive arterial disease were given simvastatin 40 mg plus, if required, ezetimibe 10 mg daily to standardize their low-density lipoprotein (LDL)-lowering therapy. The ability to remain compliant with ER niacin 2 g plus laropiprant 40 mg daily (ERN/LRPT) for ~1 month was then assessed in 38 369 patients and about one-third were excluded (mainly due to niacin side effects). A total of 25 673 patients were randomized between ERN/LRPT daily vs. placebo and were followed for a median of 3.9 years. By the end of the study, 25% of participants allocated ERN/LRPT vs. 17% allocated placebo had stopped their study treatment. The most common medical reasons for stopping ERN/LRPT were related to skin, gastrointestinal, diabetes, and musculoskeletal side effects. When added to statin-based LDL-lowering therapy, allocation to ERN/LRPT increased the risk of definite myopathy [75 (0.16%/year) vs. 17 (0.04%/year): risk ratio 4.4; 95% CI 2.6-7.5; P < 0.0001]; 7 vs. 5 were rhabdomyolysis. Any myopathy (definite or incipient) was more common among participants in China [138 (0.66%/year) vs. 27 (0.13%/year)] than among those in Europe [17 (0.07%/year) vs. 11 (0.04%/year)]. Consecutive alanine transaminase >3× upper limit of normal, in the absence of muscle damage, was seen in 48 (0.10%/year) ERN/LRPT vs. 30 (0.06%/year) placebo allocated participants.. The risk of myopathy was increased by adding ERN/LRPT to simvastatin 40 mg daily (with or without ezetimibe), particularly in Chinese patients whose myopathy rates on simvastatin were higher. Despite the side effects of ERN/LRPT, among individuals who were able to tolerate it for ~1 month, three-quarters continued to take it for ~4 years.

Topics: Arterial Occlusive Diseases; Chemical and Drug Induced Liver Injury; Death, Sudden, Cardiac; Delayed-Action Preparations; Drug Therapy, Combination; Female; Humans; Hypolipidemic Agents; Indoles; Male; Middle Aged; Muscular Diseases; Myocardial Infarction; Myocardial Reperfusion; Niacin; Simvastatin; Stroke