Niacin's effect on cardiovascular risk: Have we finally learned our lesson?
HPS2–THRIVE
The Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), with more than 40,000 patients, was the largest cardiovascular outcomes trial of lipid-modifying therapy to date.13 Its purpose was to determine whether extended-release niacin plus the prostanoid receptor antagonist laropiprant would reduce the rate of cardiovascular events in patients with clinically established vascular disease.
Patients age 50 to 80 with a history of myocardial infarction, ischemic stroke, transient ischemic attack, peripheral arterial disease, or diabetes with other forms of coronary heart disease received a standardized LDL-C-lowering regimen with simvastatin 40 mg daily, with or without ezetimibe 10 mg daily, to achieve a total cholesterol target of 135 mg/dL or below. All were treated with extended-release niacin 2 g daily plus laropiprant 40 mg daily for 1 month to assess compliance. They were then randomized to treatment with extended-release niacin 2 g plus laropiprant 40 mg or placebo daily. At baseline, the mean lipid values were LDL-C 63 mg/dL, HDL-C 44 mg/dL, and triglyceride 125 mg/dL.
Before the end of the trial, the investigators reported a high rate of myopathy-related adverse events in the niacin group, particularly in Chinese patients.13 This contributed to a high dropout rate in the niacin group, in which one quarter of patients stopped taking the study drug.
During the study, niacin lowered the LDL-C level by a mean of 10 mg/dL, lowered triglycerides by 33 mg/dL, and raised HDL-C by 6 mg/dL. On the basis of previous observational studies and randomized clinical trials, the authors calculated that such lipid changes should translate to a 10% to 15% reduction in vascular events. However, no reduction was observed in the primary end point of major vascular events, which included nonfatal myocardial infarction, coronary death, any nonfatal or fatal stroke, and any arterial revascularization, including amputation. The rates were 15% in the placebo group vs 14.5% in the niacin group (P = .96).
A statistically significant 10% reduction in the rate of arterial revascularization was observed in the niacin group, perhaps consistent with earlier observations of an antiatherosclerotic effect.
Subgroup analyses, while always to be interpreted with caution, also provide some interesting findings for consideration. A significant interaction was observed between treatment and baseline LDL-C, with those in the highest LDL-C tertile (> 77 mg/dL) demonstrating a potential reduction in the primary end point with niacin treatment. In addition, a trend toward potential benefit with niacin in patients in Europe, but not in China, was also observed; however, this just failed to meet statistical significance.
HPS2-THRIVE provided important information about the safety of extended-release niacin in combination with laropiprant. The niacin group experienced higher rates not only of myopathy but also of diabetic complications, new diagnosis of diabetes, serious infections, and bleeding. Whether these observations were related to niacin or to laropiprant is unknown. In fact, recent reports suggest laropiprant has adverse effects that may have substantially reduced the potential benefits of niacin.
The overall conclusion of HPS2-THRIVE was that there was no widespread clinical benefit from the combination of niacin and laropiprant in statin-treated patients with vascular disease, and that there was a potential increase in adverse events. Accordingly, the combination treatment will not be integrated into clinical practice.
WHERE DO WE GO FROM HERE?
Despite their limitations, these two large trials suggest that niacin does not reduce cardiovascular risk in patients already receiving a statin.
Might some subgroups be more likely to benefit from niacin? The finding of potential benefit in patients with higher baseline LDL-C suggests this may be true. At baseline, the HPS2-THRIVE patients had very good LDL-C control and had HDL-C levels within the normal range, not necessarily reflecting the patients we see in daily practice, who require more effective reductions in vascular risk. Furthermore, failure of both fibrates and niacin to reduce risk may have reflected the attempt to study these agents in broad patient populations as opposed to focusing on specific cohorts, such as patients with mixed dyslipidemia, for which there is suggestion of benefit.14 It seems unlikely that such a study will be performed in a clinical setting in which niacin may be of greater utility. The experience of adverse events would appear to make that a certainty.
For now, niacin will remain useful in lipid clinics for managing refractory dyslipidemia. Specifically, its ability to lower triglyceride and lipoprotein (a) and to raise HDL-C will continue to be of interest in the clinical management of patients and in the formulation of treatment guidelines. Another reason to use it is to lower LDL-C in patients who cannot tolerate statins. However, there is currently no evidence from randomized controlled trials to support its broader use.
While registry information could provide some sense of real-world effects of niacin’s use, this is a suboptimal way to evaluate the potential efficacy of a therapy—randomized controlled trials are the gold standard. The major flaws of both of the large trials of niacin point out the need for thoughtful study design to avoid incorrectly dismissing potentially useful therapies. But for now, the renaissance of niacin as a means of lowering cardiovascular risk is only wishful thinking.
