Effects of Extended-Release Niacin With Laropiprant in High-Risk Patients
Does the benefit of niacin on the low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels translate into improvement in outcome, and is it safe?
After a prerandomization run-in phase to standardize the background statin-based LDL-C–lowering therapy and to establish participants’ ability to take extended-release niacin without clinically significant adverse effects, 25,673 adults 50-80 years old with vascular disease were randomly selected to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. All subjects received simvastatin 40 mg, and ezetamibe 10 mg was added if the total cholesterol was >135 mg/dl after 4 weeks. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization).
Mean age was 64.9 years and 82.7% were men. Baseline lipids during the run-in phase were an average LDL-C of 63 mg/dl and HDL-C level of 44 mg/dl. During a median follow-up period of 3.9 years, participants assigned to extended-release niacin–laropiprant had an LDL-C level that was an average of 10 mg/dl lower and an HDL-C level an average 6 mg/dl higher than the levels in those assigned to placebo. Adherence to the niacin–laropiprant was 89% at 1 year and 70% at the end of the study. Assignment to niacin–laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval, 0.90-1.03; p = 0.29). Niacin–laropiprant was associated with an increased incidence of disturbances in diabetes control that was considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; p < 0.001) and with an increased incidence of diabetes diagnoses as well as increases in serious adverse events associated with the gastrointestinal system, musculoskeletal system, skin, and unexpectedly, infection and bleeding.
Among participants with atherosclerotic vascular disease, the addition of extended-release niacin–laropiprant to statin-based LDL-C–lowering therapy did not significantly reduce the risk of major vascular events, but did increase the risk of serious adverse events.
There was a significant trend (p = 0.02) toward a benefit of niacin–laropiprant in the subgroup with a higher baseline LDL-C. It is of interest that only 19% of participants (total of 4,900 in the entire study) had an HDL-C of <35 mg/dl, which has been considered by advocates to be the major indication for niacin, and 65% of subjects had a total cholesterol of <135 mg/dl, a value that would make it difficult to assess the effect of any lipid-lowering agent. Like so many studies of lipid-lowering strategies, this study was designed to be inclusive of nearly all patients with vascular disease so as to determine the largest cohort for which the drug might be effective. This strategy so often is underpowered to determine whether the group most likely does benefit. Old niacin is not quite dead, but here comes the PCSK-9 inhibitors and cholesteryl ester transfer protein inhibitors that may ‘put the nail in the coffin.’
< Back to Listings