No Need for Niacin? Meta-analysis Argues the End Is Nigh

Evidence supporting the use of extended-release niacin monotherapy is out-of-date and potentially not applicable to today’s patients, according to a new meta-analysis. The only remaining reason to use the agent would be in a limited number of secondary prevention circumstances, for example among patients intolerant to statin treatment, authors say.

It’s time for the US Food and Drug Administration to reexamine the role of niacin in practice, they argue.

“Despite the widespread availability of low-cost, high-potency statins in the current market, some patients may still experience intolerable adverse effects or want to avoid potential drug-drug interactions,” write lead study author Elvira D’Andrea, MD, MPH (Brigham and Women’s Hospital, Boston, MA), and colleagues. “Based on our findings, niacin may be a reasonable clinical choice in these cases, but the results from these subgroup analyses were mainly derived from the Coronary Drug Project (1975), the study that also serves as the main reference in the FDA labeling for this specific indication (Cholesterol-Lowering Atherosclerosis Study I [1987] and Familial Atherosclerosis Treatment Study [1990] are also cited in the labeling), and the Stockholm Ischaemic Heart Disease Secondary Prevention Study (1988).

“Thus, results supporting this indication are based on a target population that may not be generalizable to the current population receiving usual care,” they explain.

Additionally, in their paper published online April 12 in JAMA Network Open, the authors write that the aggregate effect of changes in the way cardiovascular medicine has been practiced over the last three decades, “including more widespread use of aspirin, antiplatelet therapy, and beta-blockers for patients with previous myocardial infarction as well as inhibitors of the renin-angiotensin system,” might have also changed the underlying cardiovascular risk for all patients and potentially have “reduced the marginal benefit that niacin might provide for contemporary patients.”

Harlan Krumholz, MD (Yale School of Medicine, New Haven, CT), who was not involved in the research, told TCTMD that the meta-analysis “codifies what is well known.”

“In the modern statin era there is precious little evidence to support the use of niacin,” he said. “And even for those who are statin intolerant, there are enough options with recent efficacy evidence that those who might consider the using niacin should be quite small–and even those people should know the data are old and generally weak (secondary outcomes). All people on niacin should have their regimens reviewed and should understand the weakness of the evidence to support the medication.”

It deserves a careful, clean study that’s long enough and large enough and not disturbed by market-based or scientific priorities that lead us to know if the drug works. Allen Taylor

However, Allen Taylor, MD (MedStar Washington Hospital Center, Washington, DC), who also was not involved with the study, told TCTMD it is too soon to rule out the potential for benefit from niacin in certain populations. “In 2019, we don’t know if niacin works or niacin doesn’t work. We have no earthly clue, but to conclude that it doesn’t work I think is as faulty is claiming it does work,” he said.

“We need to look at where the pharmacopeia is moving,” Taylor continued. “We’re seeing new interest in Lp(a), and that is something that niacin does impact. There are no alternative therapies for Lp(a), and there are new therapies under development that are going to be potentially very effective but also potentially very, very expensive. Maybe we need to be selecting people with high Lp(a) . . . and using niacin in them.”

A Need for Niacin Today?

The meta-analysis included 35,760 patients from 17 clinical trials documenting the effect of niacin on at least one cardiovascular disease outcome conducted through 2017. Just under half (47.8%) of patients were randomized to niacin treatment, and the remainder received placebo, usual care, or other lipid-lowering agents.

There was no preventive association found for niacin with cardiovascular outcomes including CVD mortality, CHD mortality, stroke, ACS, or MACE in secondary prevention patients.

While there did seem to be an association of niacin monotherapy with a reduction of some cardiovascular events among patients not on statins—ACS (RR 0.74; 95% CI 0.58-0.96), stroke (RR 0.74; 95% CI 0.59-0.94), and revascularization (RR 0.51; 95% CI 0.37-0.72)—these results were mainly found in two trials conducted in the 1970s and 1980s.

More recent trials like AIM-HIGH and HSP2-THRIVE, which showed a lack of clinical effectiveness, have led many to believe there is no longer a role for niacin in practice.

Taylor stressed that both of these trials were flawed in that neither gave a “clean signal” on niacin. Because this meta-analysis included these studies, it “doesn't really tell us anything we didn't already know,” he argued. “It tries to make sound homogenous what’s actually quite heterogeneous. . . . If we think there’s a therapeutic opportunity still—and there is, there is still lots of residual risk in statin-treated patients—it deserves a careful, clean study that’s long enough and large enough and not disturbed by market-based or scientific priorities that lead us to know if the drug works.”

In the paper, the authors "recommend that the FDA convene an advisory committee to reconsider this approved indication for niacin products, leading to a new trial, perhaps funded by the National Heart, Lung, and Blood Institute, to confirm that it remains relevant.

“An additional concern is the over-the-counter use of niacin for cardioprotection,” they continue. “In this context, any incremental benefits of niacin as monotherapy become even more indeterminate, especially because the dosage of the over-the-counter formulation is substantially lower than the cardioprotective regimen administered in the clinical trials. This inappropriate use might also be associated with an increase in the risk of adverse events without an improvement in outcomes.”

Future prospective trials of niacin are needed to “determine what role [niacin] may have in the current range of therapies intended to manage CVD,” the authors conclude.

Even if niacin was shown to have equivalent effects on outcomes as a drug like icosapent ethyl (Vascepa; Amarin), Taylor said the latter would still be a “clinical winner” because niacin is not an easy drug to take. “There’s always going to be headwinds to niacin,” he said. “That's why I think it's going to take finding some novel subpopulations . . . that seem at high risk and unfortunately there's very few alternatives that are low-cost options. [Maybe] that would be a better starting point rather than trying to recreate this sort of messy past of the past four decades or try to create clarity where there is none.”

Ultimately, Taylor said niacin is the “bell-bottom jeans” of cardiology fashion. “You can throw [them out] but they are probably going to come back,” he said. “Maybe they don't come back where they are everyday wear like the norm, but they'll be some place in the closet where maybe they fit.”