Adding extended-release niacin plus laropiprant to effective statin-based LDL-lowering therapy failed to prevent major vascular events in patients with atherosclerotic vascular disease, but it did raise the rate of serious adverse events, according to a report published online July 16 in the New England Journal of Medicine.
"We believe that [our] findings are likely to be generalizable to all high-dose niacin formulations," and any potential benefits of the therapy must be weighed against those important hazards, reported Martin J. Landray, Ph.D., of the University of Oxford (England), and his associates in the HPS2-THRIVE (Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events) clinical trial.
The study involved 25,673 high-risk men and women at 245 sites in the United Kingdom, Scandinavia, and China whose LDL cholesterol was already controlled by statins and who were randomly assigned to receive either oral niacin plus laropiprant (a prostaglandin-receptor antagonist that improves adherence to niacin by reducing flushing) or a matching placebo (N. Engl. J. Med. 2014;371:203-12).
The goal was to determine whether raising the HDL level with niacin would prevent major coronary events, stroke of any type, or revascularization procedures. Participants were followed for a median of 4 years.
Even though the study drug reduced LDL cholesterol by an average of 10 mg/dL, raised HDL by an average of 6 mg/dL, and reduced triglyceride levels by an average of 33 mg/dL, it failed to significantly decrease the incidence of major vascular events, compared with placebo (13.2% vs. 13.7%, respectively), either overall or in any of more than 30 subgroups of patients.
In fact, using the niacin-laropiprant combination raised the risk of death from any cause by 9%, compared with placebo, a difference that was not significant (P = .08), the investigators reported.
Niacin plus laropiprant was associated with numerous adverse events already linked to niacin therapy, such as serious gastrointestinal, musculoskeletal, and skin-related disorders. Of particular concern was the 55% increase in severe disturbances of metabolic control among patients who had concomitant diabetes (most of whom required hospitalization), and a 32% increase in new-onset diabetes. That contradicts previous assurances that niacin is safe for people who have diabetes, Dr. Landray and his associates noted.
Two serious adverse events that haven’t previously been associated with niacin or laropiprant also were identified: a wide range of infections affecting many body sites, and a similarly wide range of bleeding events, including intracranial hemorrhage and severe gastrointestinal bleeding.
HPS2-THRIVE was supported by Merck, maker of the study drugs; the U.K. Medical Research Council; the British Heart Foundation; and Cancer Research UK. Dr. Landray and several associates reported receiving grant support from Merck; no other relevant conflicts of interest were reported.