July 16th, 2014

New Evidence Fuels Concerns About The Safety Of Niacin

The string of failures– for HDL therapies in general and for niacin in particular– continues unabated.  The publication of the main results of the HPS2-THRIVE trial, along with new information from the AIM-HIGH trial, provide no evidence of a beneficial effect for niacin but do raise concerns that it may cause serious adverse effects.

In HPS2-THRIVE, published in the New England Journal of Medicine, the combination of extended-release niacin and laropiprant (Tredaptive, Merck) was compared to placebo in more than 25,000 high risk patients already receiving statin therapy. Patients in the treatment group had significant reductions in LDL cholesterol (10 mg/dL), significant increases in HDL  (6 mg/dL), and significant reductions in triglycerides (33 mg/dL). But there was no difference in the rate of major vascular events (13.2% for niacin-laropiprant versus 13.7% for placebo, RR 0.96, CI 0.90 – 1.03, p=0.29).  There was also no significant difference in an exploratory analysis of patients with low HDL and high triglyceride levels who might be expected to benefit the most from niacin therapy.

There were signs of harm associated with niacin-laropiprant. Serious adverse events occurred more often in the combination group (55.6% versus 52.7%, p < 0.001). Diabetes complications were especially concerning. Among patients who had diabetes at the start of the trial, serious complications related to diabetes occurred in 11.1% of patients in the treatment group versus 7.5% of patients in the control group, a 55% increase. Among patients who did not have diabetes at the start of the trial, there was a 32% increase in the diagnosis of diabetes in the treatment group (5.7% versus 4.3%.

Niacin therapy was also associated with significant increases in infections (8% versus 6.6%, p< .001) and bleeding (2.5% versus 1.9%, p < 0.001). These findings came as a surprise to the investigators. There were also significant increases in other, previously known adverse effects of niacin, including gastrointestinal, musculoskeletal, and skin-related adverse events.

The troubling findings of HPS2-THRIVE were not contradicted, and were at least partially confirmed, by a new analysis from the AIM-HIGH trial published in the correspondence section of NEJM. The trial randomized more than 3,400 patients with stable coronary artery disease to extended-release niacin (Niaspan, AbbVie) or placebo in addition to simvastatin and, if needed, ezetimibe. The trial was stopped early for lack of efficacy.

In their new analysis the AIM-HIGH investigators report a significant increase in serious infections (8.1% versus 5.8%, p=0.008) and a nonsignificant increase in serious bleeding events (3.4% versus 2.9%, p=0.36). But there was also a significant increase in all bleeding events in AIM-HIGH (10.1% versus 8.1%%, p=0.04).

The AIM-HIGH authors were reluctant to conclude that the new adverse effects seen in HPS2-THRIVE were also a genuine problem in AIM-HIGH. The findings, they wrote, “should be considered to be provisional and exploratory.” But the HPS2-THRIVE authors were more certain:

In light of the consistency of the results with those from previous trials of niacin alone, we believe that the findings from HPS2-THRIVE are likely to be generalizable to all high-dose niacin formulations. Although niacin might still be relevant for particular patient groups (e.g., patients at high risk for vascular events who have high levels of LDL cholesterol), any potential benefits should be considered in the context of the observed hazards.

Much of the initial discussion about HPS2-THRIVE revolved around the relative importance of the niacin and laropiprant components of the drug. In an accompanying editorial, Donald-Lloyd Jones writes that  “the consistency of the overall findings with earlier trials of niacin alone suggest that niacin is the major problem.”

What now should we make of niacin and the HDL cholesterol causation hypothesis? On the basis of the weight of available evidence showing net clinical harm, niacin must be considered to have an unacceptable toxicity profile for the majority of patients, and it should not be used routinely.

The failure of the niacin trials, as well as other HDL-related trials, “lends further credence to the notion that HDL cholesterol is unlikely to be causal.”


Previous posts about niacin:





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