Did Niacin Get a Bum Rap?
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EDITORIAL James V. Felicetta, MD, Editor-in-Chief Did Niacin Get a Bum Rap? had thought that my long- Of course, we are still waiting for experienced a niacin flush. The statin standing romance with nia- outcome trials, which will answer dose wound up being higher in the cin was finally over. Although it the critical question: Are these dra- control group, and the use of the add- was a very early love of mine, re- matic falls in LDL-C levels actually as- on lipid-lowering agent ezetimibe was Iluctantly I had gone along with the sociated with meaningful reductions also greater (22% vs 10%) in the con- mainstream consensus. It seemed in the occurrence rates for cardiovas- trol group. All these factors would tend that niacin had been sent into near- cular events such as myocardial infarc- to blunt the differences between the permanent pharmaceutical exile by tion and stroke? For now, inhibiting 2 groups, and indeed lipid levels did the devastating one-two punches PCSK-9 seems to be a good way to improve significantly in both groups. of the AIM HIGH (Atherothrom- change the lipid profile dramatically. To add insult to injury, the trial bosis Intervention in Metabolic Even if niacin is not nearly as potent was stopped after just 3 years. A num- Syndrome With Low HDL/High Tri- an inhibitor of the PCSK-9 enzymes as ber of other lipid trials that were ulti- glycerides: Impact on Global Health some newer compounds, the fact that mately positive had not yet reached a Outcomes) and the HPS2-THRIVE it has measurable inhibiting activity statistically significant separation be- (Treatment of HDL to Reduce the In- seems enough to earn it a second look. tween the control and the experimen- cidence of Vascular Events) studies. I The concerns over niacin derive tal groups after that relatively brief had even stopped taking my own self- almost entirely from the results of study interval. Although these study prescribed niacin 2,500 mg twice a the AIM HIGH study and the HPS2- flaws are hardly fatal, when taken day, which I had been religiously con- THRIVE trials. Thus, any effort to together, they suggest the need to suming for over 2 decades. But before rehabilitate niacin will require a reck- maintain an open mind. If niacin is long, I found that I had real difficulty oning with each of these major trials. like Brylcreem and “a little dab’ll do divorcing myself completely from the I was one of the original AIM HIGH ya,” then the small dusting received by charms of this lipid-lowering Lorelei. investigators, but our study site at the the control subjects might have been Now, after agonizing over the issue for Phoenix VA eventually was removed cardioprotective enough to blunt any some time, I’m here to tell you that from the trial because of poor enroll- differences in event rates between the niacin almost certainly did get a bum ment. Nonetheless, I had a front-row 2 groups, especially over the truncated rap and should be restored as an im- seat to observe the conduct of the period of the actual trial. portant tool in your therapeutic arma- trial, and it seemed less than optimal. What about the much larger HPS2- mentarium. The relatively infrequent monitor vis- THRIVE study; surely there can’t be A recent report that niacin seems to its for this study probably contributed similar flaws in that study as well? function partially as an inhibitor of the to the finding that the lipid differences Well, a critical review identifies a PCSK-9 enzyme accelerated my recon- between the 2 study groups were con- number of significant shortcomings. sideration. The inhibition of PCSK-9, siderably smaller than they could have Although conducted by British aca- an enzyme that removes low-density been. It was my impression that study demics through the Medical Research lipoprotein cholesterol (LDL-C) re- sites did not have their feet held to the Council, the trial was funded and ceptors from hepatocytes, is the hot fire when niacin compliance became largely designed by Merck, which had new way of dropping LDL-C levels. problematic for subjects randomized hoped it would demonstrate the clin- And I mean really dropping LDL-C to the larger dose of niacin. ical utility of its new combination of levels. Studies conducted with inves- The study design also contributed extended-release niacin and an anti- tigational compounds developed by to blunting the difference between the flushing agent called laropiprant, a Amgen and Pfizer have shown truly 2 study groups. Subjects in the con- prostaglandin-inhibiting compound. dramatic drops in LDL-C levels by as trol group actually received 200 mg of One has only to remember the fiasco much as 80%—often down to ridicu- immediate-release niacin to help blind with the cyclo-oxygenase-2 inhibitor lously low levels (around 25 mg/dL). the study by ensuring that all subjects celecoxib to recognize the potential 6 • FEDERAL PRACTITIONER • APRIL 2015 www.fedprac.com EDITORIAL increase in cardiovascular events of tients who would normally be started to lower either triglyceride levels or any agent that blocks prostaglandins. on niacin. LDL-C levels in a patient already tak- Any failure of the niacin/laropiprant The supposedly airtight case ing as much statin as they can toler- arm to show a reduced cardiovascu- against niacin isn’t really so strong after ate, niacin would be a very reasonable lar event rate on top of baseline statin all. Where does this leave us? Let’s not drug to consider. My romance with ni- therapy might have been because the forget that there is a sizable population acin has been rekindled, and perhaps laropiprant was increasing events of individuals who cannot or will not you’ll want to give it a second look as enough to cancel any reductions take statins. Surely these individuals well. ● the niacin might have produced. would be better off on niacin therapy A fair trial of the potential effec- than on no therapy, particularly if they Author disclosures tiveness of a niacin preparation on have a combination of low HDL-C lev- The author reports no actual or poten- top of statin therapy should test ni- els, elevated triglyceride levels, and el- tial conflicts of interest with regard to acin in a clinical setting in which evated LDL-C levels. this article. it is typically prescribed. I’m not I currently prescribe this combina- going far out on a limb by assert- tion in patients who have persistently Disclaimer ing that the majority of niacin pre- elevated triglyceride levels even after The opinions expressed herein are scriptions are written for patients who their statins have been maxed out, be- those of the author and do not necessar- have low levels of high-density lipo- cause I believe that lowering triglycer- ily reflect those of Federal Practitioner, protein cholesterol (HDL-C), typically ides in such patients may well translate Frontline Medical Communications < 40 mg/dL but often much lower into lower cardiovascular risk. Some Inc., the U.S. Government, or any of its than that. Yet the mean HDL-C in recent evidence suggests that the epi- agencies. This article may discuss un- the HPS2-THRIVE study was a robust demiologic association of low HDL-C labeled or investigational use of certain 44 mg/dL, and the mean LDL-C level levels with cardiovascular events may drugs. Please review the complete pre- was a well-controlled 63 mg/dL. The not be due so much to the low HDL-C scribing information for specific drugs or subjects who were randomized to re- levels per se, but rather to the very fre- drug combinations—including indica- ceive either placebo or niacin/laropip- quent association of elevated triglycer- tions, contraindications, warnings, and rant on top of their preexisting statin ide levels—the true culprit, with low adverse effects—before administering therapy were simply not the typical pa- HDL-C levels. So if you have a need pharmacologic therapy to patients. .