Merck's investigational extended release Cordaptive (niacin/laropiprant) showed less flushing and significantly fewer discontinuations due to flushing than patients treated with Abbott Laboratories' Niaspan.
The study was conducted in patients with dyslipidemia. Niacin is a proven lipid-modifying agent; however, a major barrier to its use is the side effect of flushing. These phase III study results were presented at the Scientific Session of the American College of Cardiology in Chicago.
Cordaptive is an investigational lipid-modifying agent in development by Merck & Co., Inc. that combines Merck-developed extended release (ER) niacin with the agent laropiprant, a novel flushing pathway inhibitor. Niacin-induced flushing is caused primarily by a prostaglandin, PGD2, a chemical that acts through the DP1 flushing pathway to cause vasodilation in the skin and flushing symptoms. Laropiprant selectively blocks the binding of PGD2 to its receptor, DP1 thereby reducing flushing associated with niacin. One tablet of Cordaptive contains 1 g of Merck-developed ER niacin and 20 mg of laropiprant.
"Niacin lowers 'bad' cholesterol (LDL-C) and triglycerides, is a highly effective therapy for raising 'good' cholesterol (HDL-C) and is proven to reduce the risk of cardiovascular events in patients with heart disease. Yet, the severity, frequency and duration of the flushing side effect of niacin limits patients from staying on therapy and reaching the recommended dose of 2 g," said Michael J. Koren, M.D., F.A.C.C., CEO and Medical Director, Jacksonville Centre for Clinical Research, and co-author of the study. "This study shows that the improved tolerability profile of Cordaptive may prevent more patients from discontinuing therapy due to flushing."
The double-blind, randomised, parallel, 16-week study of 1,455 patients with dyslipidemia evaluated flushing symptoms with Cordaptive (n = 726) dosed at 1 g for four weeks and then advanced to 2 g (two 1 g tablets) for 12 additional weeks versus Niaspan (n = 729) dosed at 500 mg for four weeks and titrated in 500 mg increments every four weeks (1 g after four weeks, 1.5 g after eight weeks, and 2 g after 12 weeks for the last four weeks of the study).
The primary endpoint was to compare the effect on flushing between the two treatment groups as measured by the number of days per week with moderate, severe or extreme flushing according to the validated Global Flushing Severity Score (GFSS >4) over the 16 week duration of the study. All patients were permitted to use aspirin or non-steroidal anti-inflammatory drugs (NSAIDS) and were advised that if taken 30 minutes prior to study medication these agents may help to mitigate niacin-induced flushing symptoms.
Significantly fewer niacin-induced flushing events were reported in the study with Cordaptive versus Niaspan. Across the 16-week treatment period, patients on Cordaptive reported significantly less flushing as measured by the number of days per week with moderate, severe or extreme flushing compared to the Niaspan group (p<0.001). More than twice as many patients on Cordaptive experienced no episodes of moderate, severe or extreme flushing compared to Niaspan, 46.7 per cent (337/722) and 22 per cent (160/727), respectively. This difference was seen despite a study design in which patients on Cordaptive were on a higher dose of niacin therapy than patients on Niaspan throughout most of the study.
At the end of the 16-week treatment period, patients in the Cordaptive group experienced fewer days per week with moderate, severe or extreme flushing than patients in the Niaspan group, 0.2 versus 0.7 days/week (i.e. approximately 1 day/month versus 1 day/week) respectively. Additionally, the per centage of patients with a maximum GFSS of moderate, severe and extreme flushing at week 16 was 7.7 pe rcent (39/505) for the Cordaptive group versus 21.3 per cent (108/506) for the Niaspan group.
Significantly fewer patients on Cordaptive discontinued therapy due to flushing compared to patients on Niaspan, 7 per cent versus 12 per cent, respectively (p=0.002). The discontinuation rates due to non-flushing clinical and laboratory events were 11.2 per cent and 8 per cent, respectively. When adjusted for time of exposure to 2 g of niacin (week eight for Cordaptive and week 16 for Niaspan), the estimated discontinuations due to non-flushing events were similar, 9.2 per cent and 8.8 per cent, respectively.
Twice as many patients in the Niaspan group used aspirin or NSAIDS to attempt to mitigate flushing than in the Cordaptive group (22 per cent versus 11 per cent respectively).
"The improved flushing profile of Cordaptive supports a recommended dosing regimen in which patients start at the 1 g dose and advance to a 2 g maintenance dose after four weeks, thereby increasing the therapeutic potential of niacin," said John F. Paolini, M.D., Ph.D., Clinical Research, Cardiovascular Disease, Merck Research Laboratories.