ESC: Investigative Niacin Combo Turns Down the Heat on Flushing

VIENNA, Sept. 4 -- Six months of an investigational niacin compound, compared with placebo, led to an expected significant drop in LDL, triglycerides, and total cholesterol -- plus a bonus, researchers said here.
And although those findings (P<0.001 for all) were anticipated with niacin, the bonus with the novel combination was that it did all that at the same time that it reduced chemical flushing compared with extended release niacin.
The drug, which is being developed under the trade name Cordaptive, combined niacin with laropiprant, a potent, highly selective prostaglandin antagonist, and the first public release of phase III data created a buzz in the poster hall at the European Society of Cardiology meeting.
In the trial of 1,600 patients who were randomized to placebo, extended-release niacin, or niacin-laropiprant, the drug administered alone or with a statin was associated with an 18.9% decrease in LDL, an 18.8% increase in HDL, a 21.7% decrease in triglycerides, and a 9.2% decrease in total cholesterol compared with placebo, said Darbie L. Maccubbin, Ph.D., of the Merck Research Laboratories in Rahway, N.J., and colleagues.
Compared with extended release niacin, the combination drug reduced moderate flushing by 26%, severe flushing by 61% and extreme flushing by 50%, results that Steven Nissen, M.D., of the Cleveland Clinic called modest.
Dr. Nissen, who said he was a fan of niacin and who regularly prescribed it for his patients, said he had expected the drug to completely block the prostaglandin receptor that triggers flushing. But he said that the reduction in flushing could be enough to make niacin a more palatable option for some patients and physicians.
Although flushing, which was measured by patient diaries, was associated with a 10.2% dropout rate in the niacin combination arm, this was significantly lower than the 22.2% flushing dropout rate with extended-release niacin (P<0.001). As with extended release niacin alone, flushing with the niacin-laropiprant diminished over the first four to six weeks of treatment.
Dr. Nissen, who was not involved in the study, said he had two other immediate concerns with the study. Eight of the 10 authors, including the first author, were Merck employees. "You have to be careful when no independent people are lead authors and this is surprising since it is traditional for scientific findings to be made by people outside the company."
His second concern was about the safety of manipulating prostaglandin receptors. "Keep in mind that prostaglandins are affected by NSAIDs and by Cox-inhibitors, so there is the potential for widespread biological effects that signal the need for caution," he said.
The lipid benefits "were what one would expect with niacin", Dr. Nissen said.
The safety data reported by Dr. Maccubbin and colleagues included a woman who had a spontaneous abortion while on the study drug (Merck said the woman became pregnant after enrollment), which Dr. Nissen said could be a concern, but he doubted it would derail the drug. He noted, for example, that pregnancy is a contraindication for any drug not specifically tested in pregnant women, which includes all statins.
Other reported toxicities were a case of angina triggered by extreme flushing, one gallstone, and one case of drug intolerance.
The trial randomized 800 patients to 24 weeks of the niacin-laropiprant combination and 543 to extended-release niacin, both at 1 gram titrated to 2 grams over two to six weeks, or to 270 placebo controls.
The mean age of patients was 57 in the placebo arm and 58 in the two active treatment arms.
Average baseline LDL ranged from 112.5 mg/dL to 114.2 mg/dL, HDL was 50.2 mg/dL to 51.9 mg/dL, triglycerides ranged from 130 to 123.5 mg/dL; and total cholesterol ranged from 192.3 mg/dL to 192.9 mg/dL.
There were no significant liver or muscle toxicities across the treatment groups.
The trial was funded by Merck, which has submitted a new drug application to the FDA. Dr. Nissen declared no financial conflicts. Primary source: European Society of CardiologySource reference: Maccubbin DL et al "Lipid-altering Efficacy and Tolerability of Extended-release Niacin/Laropiprant in Patients with Dyslipidemia" Poster 715