Niacin: the poster child for post-marketing drug surveillance
Since the mid-1950s, niacin (vitamin B3) has been used to reduce the risk of heart attacks and other cardiovascular (CVD) events in at-risk individuals. Its main value proposition has been its ability to increase HDL-C — the “good” cholesterol – while also modestly decreasing “bad” cholesterol, or LDL-C. However, a clinical trial results published in the New England Journal of Medicine (NEJM) on July 17 finds that niacin is not an effective way to reduce CVD events. In fact, it may even increase mortality.
The study, HPS2-THRIVE, was a randomized, placebo-controlled trial that involved more than 26,000 subjects – not including the large number of participants forced to drop out due to niacin-related side effects. It was sufficiently well designed to provide a definitive answer to the question: “Does treatment with niacin decrease risk of CVD events in at-risk individuals?” The answer is no.
The phase III results from HSP2-THRIVE as published in NEJM showed that although niacin combined with laripiprant (previously marketed as Tredaptive by Merck) resulted in LDL-C levels that were 10 mg/dL lower than placebo-treated patients, as well as HDL-C levels that were on average 6 mg/dL higher, those changes did not result in a decreased risk of vascular events. Furthermore, the niacin-based drug combo increased loss of blood sugar control among diabetics by 55%. In fact, there was a 32% increased diagnosis of diabetes among niacin-treated patients. There were also a slew of treatment-related adverse events, including excess bleeding, infections, diarrhea, gout and liver and skin problems.
Strong sales, but even stronger evidence against niacin
While the media treated the HSP2-THRIVE results as big news, members of the clinical community had seen similar data as early as 2011, including findings from another large trial -- AIM HIGH -- which suggested that niacin was not an ideal or effective medication for decreasing the risk of CVD events.
When Merck first developed Tredapative (niacin/laropiprant), it was indicated for the treatment of dyslipidemia, particularly in patients with combined dyslipidemia and hypercholesterolemia. But even though it was approved in Europe, the FDA would not approve Tredaptive in the U.S. without additional evidence. Despite this challenge, Niaspan, AbbVie’s extended-release formulation of niacin, had sales of $5.11 billion in 2012. That figure was bolstered by intense sales and marketing efforts -- between 2002 and 2009, sales of Niaspan tripled, eventually reaching almost 700,000. However, as more clinical data about niacin’s shortcomings became available, prescriptions started to falter.
AIM-HIGH, which evaluated combined use of niacin and a statin in roughly 3,400 patients, was halted early in spring 2011 because the trial’s oversight board noted that all of the benefits seen in the study seemed to be attributable to the statin rather than the niacin. The board also noted that the stroke rate was twice as high in the niacin-treated group compared to the control group. Though the researchers’ data was initially deemed inconclusive, it was becoming clear that niacin was not a superior alternative to statins, which had been available since the early 1990s and had become the standard of care for prevention and treatment of hypercholesterolemia. In short, researchers were beginning to understand that using niacin as an add-on treatment did not improve outcomes. By 2013, sales of Niaspan had dipped below the $1 billion mark.
According to Dr. Barry Mennen, a Washington, DC-based physician, “Niacin has always been a bit of a fringe player in the lipid-lowering CV market. When used at pharmacological levels far exceeding its pellagra-prevention needs, it lowers LDL cholesterol, but the attraction has traditionally been its ability to raise HDL levels. There have been occasional studies over the years that have shown event-lowering, but this latest NEJM study was huge and showed too many side effects for any modest benefit seen in the 1 in 200 patients treated.”
A case for post-marketing surveillance
In the end, proving a drug’s efficacy comes down to solid clinical evidence that is often culled during the post-marketing stage or as part of long-term trials. It seems that niacin’s time has come and gone -- mainly because of the widespread availability of clinical trial data from rigorous studies highlighting its lack of therapeutic value for prevention of CVD events. Regardless of how widely used a therapy is, ongoing clinical testing helps ensure the integrity of clinical decision-making. As Dr. Mennen put it, “This latest study should finally end niacin's 50+ year run.”
- Forbes Why Merck's Niacin Failure Will Scare Drug Researchers
- Medcines and Healthcare Products Regulatory Agency Tredaptive (combined niacin-laropiprant): no longer for prescribing as preliminary HPS2-THRIVE trial failed to show benefit outweighs risks
- New England Journal of Medicine Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients
- Bloomberg Abbott Doubled Niaspan U.S. Sales Before Trials Cut Use