Abstract 190: A Niacin Receptor Partial Agonist, MK-0354, Robustly Reduces Plasma Free Fatty Acids and Produces Little Flushing but Fails to Alter LDL-C, HDL-C, and Triglycerides in Humans
Background: Niacin, an agent proven to reduce cardiovascular events, reduces LDL-C and TG, and elevates HDL-C. Niacin also inhibits adipocyte lipolysis, and it is thus widely held that the beneficial lipid effects are due to a decrease in plasma free fatty acid (FFA) concentration and re-esterification into TG, which could then impact LDL and HDL levels. Niacin is underutilized due to cutaneous flushing induced in most patients. Our objective was to develop a novel niacin receptor agonist that favorably alters plasma lipid profiles without flushing side effects. The niacin receptor partial agonist, MK-0354, was chosen for these clinical studies as it lowered FFA but induced minimal flushing in preclinical models.
Methods: The activity of single and multiple doses of MK-0354 (0.3 g to 4 g) to reduce plasma FFA was evaluated in healthy men. A Phase II study in 65 lipid clinic patients assessed the effects of MK-0354 2.5 g over 4 weeks on the lipid profile.
Results: MK-0354 was well tolerated, induced a robust reduction of plasma FFA comparable to extended-release niacin (figure⇓), and induced modest flushing only at high doses. Post-dose plasma FFA reductions were reproducible over 7 days of treatment. In a 4-week Phase II study in hyperlipidemic patients, MK-0354 2.5 g produced little flushing; however, there was no clinically meaningful effect on lipids versus placebo (mean [median for TG] [95% CI] placebo-adjusted % change from baseline: HDL-C, 0.4% [−5.2, 6.0]; LDL-C, − 9.8% [− 16.8, − 2.7]; TG, − 5.8% [− 22.6, 11.9]).
Conclusion: Suppression of plasma FFA with the niacin receptor partial agonist MK-0354 does not appear to be sufficient to reproduce the beneficial lipid effects of niacin.