Author's Note: Any discussion on the clinical place of niacin after publication of the AIM HIGH trial¹ and, at time of writing this article, the presentation of the HPS2 THRIVE trial² has to be considered in the context of niacin's long history of its use for over half a century.

In pharmacologic doses, niacin (nicotinic acid) remains a unique agent whose broad-spectrum effects on lipids and cardiovascular disease are impressive. As monotherapy, it lowers atherogenic apo B lipoproteins [e.g. LDL, VLDL and Lp(a)] and raises HDL. In basic science studies have been shown to augment reverse cholesterol transport, ameliorate vascular inflammation, lower vascular endothelial oxidative stress and endothelial dysfunction.³ Its non-lipid effects include, decreasing myeloperoxidase and raising adiponectin, Well known adverse effects include flushing, gastrointestinal symptoms, increasing glycemia and uric acid. In clinical trials, it significantly reduced risk for cardiovascular events. In arteriographic studies, it slows or reverses atherosclerosis in coronary, femoral and carotid arteries when used with bile sequestrants or statins.⁴ Recent research on its mechanism of action on oxidative stress, triglyceride lowering via diacylglyceroltransferas 2 (DGAT2) and ABCA1 indicates in part how it mediates its lipid and non-lipid effects on cardiovascular events in and reversal of arterial stenosis.³ Indeed, a meta-analysis of published randomized clinical trials on efficacy of niacin for reducing cardiovascular disease (CVD) events, and including the AIM HIGH trial but not the unpublished HPS2 THRIVE trial, concluded that niacin significantly reduced CVD events by approximately one-third.⁵ Thus it appears to decrease arterial stenosis and CVD events in certain groups of patients and therapeutic settings.

Clinical trials with statins which primarily lower LDL-C, indicate an approximately one quarter to one-third reduction in events in primary and secondary CVD prevention trials. Thus the majority of patients continue to have residual risk. Mitigating this residual risk is clearly one of the biggest challenges in preventive cardiology.

Two major clinical trials have been recently completed to determine whether incremental benefit could be obtained using niacin in high risk patients with CVD in whom the LDL-C was intensively lowered by statin-based therapy optionally using ezetimibe. In the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial, 3414 patients with a history of CVD and low HDL-C were randomized to simvastatin plus extended release niacin (ERN, (1500-2000 mg/day) or simvastatin alone ( dose adjusted for a goal LDL-C of 40-80mg/dl) and ezetimibe as needed. The average patient was an obese white male aged 64 years with metabolic syndrome and mild to moderate combined dyslipidemia (with baseline median HDL-C, 35 mg/dl and triglycerides (TG), 162 mg/dl and LDL-C, 74 mg/dl who had been on statin therapy for more than one year and in 40% of patients over five years. The primary endpoint was a composite of time to first event for coronary death, MI, stroke, hospitalized CS or symptom driven revascularization. Overall the results showed no difference in primary endpoints with niacin at three years including stroke.

The limitations of this study have been acknowledged. For unclear reasons (including the fact that the placebo group was given a small dose (100-150mg per day) of immediate-release niacin to prevent unblinding), the difference in on-treatment median HDL-C between the two groups was only 4 mg/dl. Only 6% of patients were statin naïve and prolonged previous therapy with statins may already have conferred risk protection which could have impacted power calculations. Because niacin has LDL-C lowering effect, results could have been confounded by the increased use of ezetimibe and higher simvastatin dose in the placebo arm to maintain the LDL-C goal compared to the niacin group. The study omitted a large number of patients in whom the combined effects of niacin with statin therapy on CV events are still unclear. These include patients with more severe combined acquired or genetic dyslipidemia, men < 45 years old, women, persons with recent ACS, LDL not at goal, elevated Lp(a), statin naive patients, other ethnicities. Importantly, this being a secondary prevention trial, many patients were also on other recommended therapies (in addition to statins) for those with CHD, making it difficult to show a further incremental benefit from niacin.

In November 2012, subgroup analysis⁵ was presented from the AIM-HIGH trial which showed that in 552 patients with the upper tertile TG (>=198mg/dl) and lowest tertile HDL-C (<33mg/dl), there was an almost significant (p=0.07) reduction in events (HR 0.74). The trend to benefit was more evident in 439 patients with triglycerides >=200mg/dl and HDL < 32mg/dl with a significant (p=0.03) decrease in primary events from 25% in the placebo group to 16.7% in the niacin group representing an incremental benefit of another one-third beyond that conferred by statins alone. It is acknowledged that this is a subgroup analysis and not conclusive. Nevertheless, it is hypothesis generating and points to the heterogeneity of the recruited patients. This group of patients with clinically significant combined dyslipidemia (acquired or familial Fredrickson Type IIb phenotype ) may represent in part, different genotype(s) than the majority of AIM-HIGH patients who had mild/moderate low HDL-C with borderline TG elevation often associated with obesity (metabolic syndrome and with Type IIa phenotype, mainly polygenic hypercholesterolemia). Future trials should focus on these patients with the Type IIb phenotype that are not uncommon in practice. It is of interest that a similar observation was made in the ACCORD trial in statin treated high risk diabetics treated with fenofibrate or placebo. A subgroup of the patients with highest TG tertile and lowest tertile HDL-C showed an almost significant (p=0.057 reduction in CVD events.

The Heart Protection Study-2: Treatment of HDL to Reduce the Incidence of Vascular Events trial28 (HPS2-THRIVE) has not yet been fully published at time of writing this article but has been presented recently.² In this trial, 25,673 patients with atherosclerotic cardiovascular disease irrespective of lipid levels were initially treated with simvastatin+/- ezetimibe to achieve total cholesterol to 135 mg/dl and randomized to extended-release niacin added to a flush reducing agent laropiprant (ERN-LRPT,) or placebo. The baseline mean LDL-C was 63mg/dl; HDL-C, 44mg/dl and TG, 125mg/d ( with 36% of patients non-fasting for 8 hr) Based on this lipid profile, most of the patients had elevated LDL-C as the major lipid abnormality (Fredrickson Type IIa phenotype ). The average follow up was 3.9 years and the results did not show a statistically significant difference between the groups in the primary endpoint of major vascular event (ERN/LRPT 14.5% vs. Placebo 15%). Results in the subgroup with very low HDL-C (eg <32-33mg/dl and clinically significant TG elevations (eg >200mg/dl, as in AIM HIGH) were not presented. Of note, the risk ratio for coronary and any vascularization was significantly lower in the niacin group (p <0.05, RR 0.89, 0.90, respectively) and consistent with arteriographic studies alluded to earlier. Europeans tended to have a greater benefit in terms of reduction in Major Vascular Events (MVE) compared to Chinese (p=0.06 for difference in effect). ERN-LRPT patients showed an 8.7% absolute increase in serious adverse events (SAEs). There was a statistically significant increase in myopathy (especially in Chinese). Skin, GI, diabetes and musculoskeletal related side effects all of which are known to occur with niacin were noted. Unlike past trials, there was significant increase in bleeding and infections in the HPS2-THRIVE trial. In spite of these SAEs, the all cause mortality was not significantly different. It is also unclear whether the addition of laropiprant in the niacin group had any role in SAEs seen as there was not a randomized arm of patients on laropiprant only. Detailed publication(s) addressing these issues may shed more light.

Discussion and Conclusions

Although these trials in aggregate represent a large body of data they have to be taken on the context of the totality of our knowledge on niacin. Significant limitations have been acknowledged by the investigators and other authorities. It would be premature to abandon the use of niacin based therapy on these two trials. The field is still in evolution in determining the patients in whom benefits exceed the risk of niacin therapy. The major limitations of these trials are that the patients studied were clinically and genetically (and racially) heterogeneous. Patients who may have benefitted were diluted by those that did not.

Based on the AIM HIGH recently presented data, a case may be made to conduct another trial in patients with very low HDL-C (<32-33mg/dl and high TG, especially >200mg/dl) or those with metabolic syndrome, for instance with these lipid cut-offs. Such patients pose significant residual risk and niacin could be considered as an option in current practice.

In HPS2 THRIVE, the data presented for the average lipid profile, confirm the recommendations of the NCEP ATP III guidelines, the National Lipid Association that in CHD patients with elevated LDL-C (aggressively treated with statin-based therapy to target), and average ("normal") HDL-C(>40mg/dl and normal TG(<150)(Type IIa phenotype), niacin therapy is not indicated. Its adverse effects would not justify its use in these patients except possibly as an adjunct to lowering LDL-C after other remedies have failed to get the very high risk patient to goal and in statin-intolerant patients. Finally, more research is needed on populations of patients that were not studied in sufficient detail or numbers in these two recent trials.

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References

1. Aim-High Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. New Engl J Med 2011; 365:2255-67.
2. Armitage J. HPS2-THRIVE: Randomized placebo-controlled trial of ER niacin and laropiprant in 25,673 patients with pre-existing cardiovascular disease. American College of Cardiology Annual Scientific Sessions. San Francisco, 2013. www.hps2-thrive.org/hps2-thrive_ACC_slides.ppt.
3. Vaijinath S. Kamanna, Shobha H. Ganji and Moti L. Kashyap. Recent advances in niacin and lipid metabolism. Curr Opin Lipidol 2013; 24:239–245.
4. Michos ED, Sibly CT, Baer JT, et al. Niacin and statin combination therapy for atherosclerosis regression and prevention of cardiovascular disease events: reconciling the AIM-HIGH trial with previous surrogate endpoint trials. J Am Coll Cardiol 2012; 59:2058–2064.
5. Lavigne PM, Karas RH. The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression. J Am Coll Cardiol 2013; 61:440–446.5.
6. Guyton JR, Slee AE, Anderson T, et al. Relation of lipoprotein levels to cardiovascular events in the Atherothrombosis Intervention in MetabolicSyndrome with Low HDL/High triglyceride and Impact on Global HealthOutcomes (AIM-HIGH) Trial. Circulation 2012; 126 (Suppl 21): abstract 14501.

Keywords: Adiponectin, Apolipoprotein B-100, Apolipoproteins B, Atherosclerosis, Cholesterol, Inflammation, Lipids, Lipoproteins, Niacin, Nicotinic Acids, Oxidative Stress, Peroxidase

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