03 Mar With Appropriate Dose and Formulation, Niacin Can Be Lipid Lowering and Cardioprotective
MedicalResearch.com Interview with:
Dr. Richard Dunbar
Dr. Richard L. Dunbar MD MS
Assistant Professor of Medicine, Attending Physician, Preventive Cardiovascular Medicine Clinic, Member, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of MedicineMember, Institute for Diabetes, Obesity and Metabolism,
University of Pennsylvania School of Medicine and
Dr. Harsh Goel
Dr. Harsh Goel
WellSpan Academic Hospitalists
Department of Medicine, York Hospital, PA
MedicalResearch.com: What is the background for this analysis?
Response: Niacin is the first cholesterol lowering treatment to prevent heart attacks and lower long term mortality. It thus provided the first proof that lowering cholesterol reduces cardiovascular risk. However, it is generally poorly tolerated due to almost universal flushing, limiting use. The better-tolerated statin drugs overshadowed niacin, rightly dominating hyperlipidemia therapy. Despite their advantages, statins are far from perfect, leaving important gaps. Firstly, at least 10% of patients simply don’t tolerate statins. Secondly, about 40% of patients have insufficient cholesterol lowering, leaving them far from their target LDL-cholesterol levels. Finally, even though statins lower cardiovascular risk, they by no means eliminate it and significant residual risk remains even in patients who respond to them.
The relatively poor tolerance of niacin motivated development of an extended-release alternative which was dosed very differently from the established cardioprotective regimen used in the Coronary Drug Project (CDP) and the Stockholm Ischemic Heart Disease Study (SIHDS), the two landmark trials that proved niacin’s benefits. These trailblazing trials used 3 grams of niacin divided throughout the fed portion of the day as 1 gram thrice daily with meals. In sharp contrast, the alternative regimen was severely handicapped by a profoundly lower dose of only 2 grams per day. Perhaps worse, the alternative regimen dosed all of the niacin at one sitting, at bedtime before the overnight fast, rather than three times a day before meals. We believe these were critical departures from the established cardioprotective niacin regimen, insofar as they severely undermined the alternative regimen’s efficacy. Accordingly, when added to statins, the alternative regimen failed to recapitulate the benefits seen with the established cardioprotective regimen in two recent large clinical trials, the AIM-HIGH trial and the HPS2-THRIVE trial. Besides the inherent flaws of the alternative regimen, there were also major issues with the trial designs which likely contributed to null results.
From a practice standpoint, this is worrisome, because clinicians may draw erroneous conclusions from the trials of the alternative regimen, and thereby deny a significant population of hyperlipidemic patients the benefits of a well-proven cardioprotective therapy, i.e. the population which does not tolerate or does not respond adequately to statins (almost 50% of at risk patients). Hence, we embarked on a critical analysis and review of the alternative regimen with a special focus on the AIM-HIGH and HPS2-THRIVE trials to bring to light the pitfalls of comparing radically different regimens of what is nominally the same drug.
MedicalResearch.com: What are the main findings?
Response: Our review emphasizes how the alternative regimen contrasts with the gold standard, and strives to put the failed trials of the alternative into the broader context that includes the successful trials of the established cardioprotective regimen. Perhaps one of the most novel contributions was a meta-analysis that included all four of the cardiovascular outcomes trials of niacin (CDP, SIHDS, AIM-HIGH, and HPS2-THRIVE), to see if they prevent hard CHD events: non-fatal myocardial infarction and cardiac death. We found that pooling all four trials revealed substantial heterogeneity, indicating major differences in the trials. Tellingly, this was eliminated by considering the alternative regimen separately from the established regimen. The trials of the established regimen had a combined odds ratio of 0.75, indicating a decisive benefit for niacin (p=0.01, 95% CI 0.60 to 0.93). In marked contrast, the trials of the alternative regimen had an odds ratio of 1.0, suggesting no benefit whatsoever (p=0.97, 95% CI 0.89 to 1.13). Thus, viewing the new trials in the context of the overall evidence, our analysis supports the concept that the alternative has quite failed to prove equivalent to the established regimen. We then performed a meta-regression of risk of CV events and cholesterol lowering in all four outcomes trials using niacin. We found a very clear and strong correlation between the extent of cholesterol lowering and reductions in CV events. It seems that a major reason of the failure of AIM-HIGH and HPS2-THRIVE was that they used a regimen of niacin that did not achieve robust LDL-lowering. Indeed, the alternative regimen only achieved a drop in cholesterol on the order of 5%, whereas the established regimen lowered it between 10% and 15%. Simply put, the benefit of niacin is predicted strongly by the extent of cholesterol lowering, whether or not patients are taking a statin.
Another interesting point from our review supports the concept that niacin benefits patients to the extent it lowers cholesterol. In the HPS2-THRIVE study, a subset of subjects had sub-optimal LDL on entry to the trial (LDL>58 mg/dL). This subset fared better than those with LDL<58 mg/dL, having an odds ratio of cardiovascular events of 0.89 (p=0.01, 95% CI 0.81 to 0.97). This also seems to be related to the fact that the subjects with suboptimal LDL had a much bigger drop in LDL when placed on niacin. This suggests the alternative regimen might be redeemed by studying it in patients who actually have an LDL problem.
MedicalResearch.com: What should clinicians and patients take away from your report?
Response: We assert that niacin remains a very viable and evidence-based therapy for patients who, 1) do not tolerate a statin, and 2) who tolerate a statin but are not able to achieve target LDL-cholesterol levels. However, the new extended-release alternative regimen appears to be a “dud.” As used currently, it is not equivalent to the established cardioprotective regimen and we feel it should not be used as a long-term replacement of the latter. Rather, niacin should be dosed three times daily before meals, at a minimum of 3 grams daily and preferably titrated upwards based on LDL-cholesterol levels.
That said, we have found the alternative regimen is an excellent bridge to get people to tolerate niacin before switching them to the established cardioprotective regimen. We start them slowly on the extended-release formulation at bedtime, and after they get to 2 grams, we switch them to 1 gram thrice daily with meals. By this point, we have done this in three randomized clinical experiments, and have found this titration scheme well tolerated. In two of those experiments, we went on to dose immediate-release niacin at the maximum FDA-approved dose of 2 grams thrice daily (i.e. 6 grams daily), and again found this well-tolerated.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Future studies assessing the benefits of niacin therapy, whether alone or in combination with other therapies, should employ the established cardioprotective regimen at minimum. It is likely that if used in an adequate dose (≥ 3 grams daily) and administered three times daily, even extended-release formulation would prove to be of cardiovascular benefit. This is especially important because numerous novel niacin-based compounds are currently being developed to augment our current armament of lipid lowering agents. Clinical trials to prove benefits of such agents should ideally use a lipid-targeting strategy, rather than simply using a dose that may be well tolerated but ineffective in lowering cholesterol.
MedicalResearch.com: Is there anything else you would like to add?
Response: Part II of our review was just published, and discusses some exciting new developments in this area. We briefly review some basic fundamentals of the mechanism of action of niacin and its receptor, GPR109A. We also review the encouraging early results of several novel niacin-based therapies under active development. Of special interest, we discuss the pitfalls that some developers may have fallen prey to during some of these initial studies, leading to apparently unimpressive results and how those can be avoided in future research in this field.
Citation:
Curr Atheroscler Rep. 2016 Feb;18(2):11. doi: 10.1007/s11883-016-0563-8.
Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part I: Alternative Niacin Regimens.
Dunbar RL1,2,3,4,5, Goel H6.
Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions
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Dr. Richard Dunbar and Dr. Harsh Goel (2016). Niacin Can Be Lipid Lowering and Cardioprotective with Appropriate Dose and Formulation
Last Updated on March 3, 2016 by Marie Benz MD FAAD