Niacin update

JACC DEC 2012
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The Current State of Niacin in Cardiovascular Disease Prevention

A Systematic Review and Meta-Regression

Conclusions  The consensus perspective derived from available clinical data supports that niacin reduces CVD events and, further, that this may occur through a mechanism not reflected by changes in high-density lipoprotein cholesterol concentration.

There was a total of 4,365 subjects allocated to receive niacin intervention and 5,596 subjects allocated to the respective control arms of included trials. The mean duration of follow-up was 2.7 years (SD 1.7 years).  Of the 11 trials included in the primary meta-analysis, 8 were conducted in a double-blind fashion 

Despite clear efficacy demonstrated by multiple clinical endpoint–driven studies, increasing appreciation of the considerable CVD risk that persists despite intensive statin therapy ((4),(5),32) has heightened interest in alternative therapeutic interventions. 

The consensus perspective derived from previously available data had suggested that niacin could be an effective agent in CVD risk prevention ((23),24).

 Although clinical outcome data supporting its benefits largely predate the advent of statins, several recent trials showed niacin to be an effective adjunct to statin therapy with respect to surrogate measures of atherosclerosis progression ((16),(17),(18),(19),(20),21). 

Contrasting evidence provided by results of the AIM-HIGH trial (22) recently called into question the appropriate role of niacin in clinical practice. The present study, taking in aggregate the cumulative body of relevant empirical clinical data, continues to support that niacin is an effective agent to reduce CVD risk.

In the present meta-analysis including a total of 9,959 subjects derived predominantly from secondary prevention trials, allocation to niacin treatment yielded relative odds reductions of 34% (p = 0.007) and 25% (p = 0.02) for the respective endpoints of any CVD event and major CHD event. 

Furthermore, a significant treatment effect remained in analysis limited to those trials evaluating the effect of niacin in combination with statin therapy for the largest composite clinical endpoint of any CVD event. 

Placing these findings in context, the Cholesterol Treatment Trialists' Collaboration recently reported 22% and 27% reductions in comparable clinical endpoints in statin-treated participants compared with a control population in a meta-analysis of 21 trials including 129,526 subjects (5).

While serving to place the recent results of AIM-HIGH in context with the total body of clinical trial evidence, the current analysis challenges prevalent notions surrounding the mechanism underlying the treatment effect of niacin.  

Widely recognized as the most potent currently available modulator of HDL-C, the potential benefit of niacin in mitigating CVD risk is often attributed to its impact on this target. The rationale for this hypothesis is derived from extensive epidemiological data establishing baseline low HDL-C as an independent marker of CVD risk ((33),(34),(35),(36),37).

 It is important to consider, however, that the pharmacological effects of niacin extend well beyond augmentation of HDL-C concentration.

 In the current study, meta-regression failed to demonstrate an association between on-treatment differences in HDL-C concentration and niacin-mediated improvement of outcomes.

 There are several ways in which this finding can be interpreted.

 One possibility is that the clinical efficacy of niacin may still result from its lipid effects, but that these are not captured in the standard lipid measurements reported in clinical trials. For example, niacin reduces lipoprotein (a) and exerts presumably favorable effects on both HDL-C and LDL-C particle size distribution, not reflected by typical lipoprotein analysis nor assessed in the current study (38). 

 It is also possible that niacin's clinical benefit may result not from its lipid effects, but rather may be contingent on any of its several reported pleiotropic properties. As such, consideration should also be paid to expanding data delineating the various nonlipoprotein-mediated effects of niacin as a means to explain its efficacy. Niacin has been documented to exhibit anti-inflammatory properties as evidenced by a reduction in lipoprotein-associated phospholipase A₂ and C-reactive protein (38), suppress pro-atherogenic chemokines (39), and augment serum concentration of the atherprotective hormone adiponectin ((40),41), each of which could confer cardiovascular protection.

Importantly, decades of clinical data have confirmed the overall safety of niacin therapy, particularly that of the prescription version used in the AIM-HIGH study. A recent review of the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System found prescription niacin to be associated with a lower rate of serious adverse events (defined as resulting in hospitalization or death), hepatotoxicity, and rhabdomyolysis compared with that of several other commonly used lipid-altering drugs including simvastatin, pravastatin, atorvastatin, gemfibrozil, and fenofibrate (48). Furthermore, the safety profile of niacin-statin combination therapy has been found comparable to that of either drug alone ((48),(49),50).