Larger trial study needed to decide fate of niacin

Niaspan is a cholesterol drug manufactured by Abbott Laboratories. Doctors have customarily prescribed Niacin to raise levels of HDL ("good" cholesterol) in patients taking a statin pill that is successfully lowering their LDL ("bad" cholesterol). Yet this practice is now being questioned after a National Institutes of Health study released in late May, called AIM-HIGH, showed that Niaspan failed to prevent heart attacks and slightly raised the risk of a stroke when combined with the cholesterol drug Zocor (simvastatin).

According to the Los Angeles Times, doctors say that statins, including simvastatin, Lipitor and Crestor, are great at lowering bad cholesterol—so good that it's not necessary to add another medication to a patient's regimen. The new study, says the Times, is giving doctors more reason not to add Niaspan, which raises good cholesterol.

"Although this finding may be concerning for future drug development in the HDL field, it again exemplifies the vast complexity surrounding HDL biology," says Amar A. Sethi, MD, PhD, Vice President of Research and Development at Pacific Biomarkers, Inc. (PBI), a Seattle-based provider of biomarker laboratory services to the pharmaceutical, biotechnology and diagnostics industries.

"Due to the large body of positive evidence from previous clinical trials on niacin (the active ingredient in Niaspan), the AIM-HIGH data deserves much more scrutiny and subgroup analysis to support the initial conclusions," Dr. Sethi continues. "The HATS clinical trial, albeit much smaller, used a combination therapy of simvastatin and niacin demonstrating reduction in hard endpoints. Similarly, the ARBITER 6-HALTS study and the Oxford Niaspan study both suggested that the addition of niacin to statins halted the progression of carotid intima media thickness. Thus, we need to be very certain that the conclusions we are drawing at the current time are firm and well founded."

Dr. Sethi says it is remarkable how the results from the AIM-HIGH study contradict earlier findings regarding niacin and cardiovascular disease. In his view, we need to wait for the much larger niacin trial study, called HPS-2 THRIVE, which should give definite answers in regard to this drug's fate. The FDA, he notes, is not recommending any label change. If the AIM-HIGH results hold true in the ongoing much larger HPS-2 THRIVE study, one could, says Dr. Sethi, begin speculating whether HDL matters in cases where LDL-C is treated low enough.

"The addition of Ezetimibe to almost one-third of those treated in the AIM-HIGH study may have added some confounding. We know from the ENHANCE study that ezetimibe, although reducing LDL-C, did not reduce carotid intima media thickness when compared to statin," Dr. Sethi continues. "Also, the ARBITER-6 study comparing niacin with ezetimibe showed greater reduction in carotid intima media thickness for niacin. Therefore, a subgroup analysis of patients not on ezetimibe could be essential for providing some clarification to the overall results."

In Dr. Sethi's view, the AIM-HIGH study was truly trying to "aim high," as it was seeking additional cardiovascular benefits in a group of patients that already were very well treated with respect to their LDL-C levels. All patients had been on statin for a longer period of time, but had elevated triglycerides and low HDL-C levels. This, he says, is a very tough patient population to achieve any additional cardiovascular benefit from. "We know for a fact that there is a residual cardiovascular risk in patients on statin therapy, but currently we just don't know how to treat them, if not with HDL increasing drugs such as niacin. Although no benefits were observed in this study it doesn't mean that niacin would not be beneficial in other dyslipidemic phenotypes. For this reason, it would be of extreme interest to explore the effect of the niacin treatment in specific subgroups of the study population."

Following the failure of the cholesterol drug Torcetrapib, evidence has accumulated that HDL-C alone is not a satisfactory biomarker to predict cardiovascular disease, says Dr. Sethi. The results from the AIM-HIGH study, he says, could spark further research into the usability of HDL function biomarkers, such as cholesterol efflux. "We clearly need better and more improved methods beyond the HDL-C measurement to assess the multiple functional properties of HDL—especially when considering that future HDL therapeutics could modify HDL function differently. PBI is currently evaluating several HDL function assays, including the cholesterol efflux method for potential future inclusion into clinical trials. This may help expand our knowledge of the exact role of HDL in clinical trials such as AIM-HIGH."

SOURCE Pacific Biomarkers