Reducing Cardiovascular Risk with Niacin

by Timothy J. Polacek, BS

Niacin has been used as a dyslipidemic intervention since 1955.¹ The mechanisms of action when used at pharmacologic doses (>50 times the RDA for this vitamin) are complex and multifactorial, but ultimately lower low-density lipoprotein (LDL)-C, triglycerides (TGs), and apolipoprotein B (ApoB); raise HDL-C; lower lipoprotein(a) (Lp[a]); shift LDL to larger particle size and lower particle number (pattern B to pattern A); reduce thrombosis and vascular inflammation, including the markers C-reactive protein and myeloperoxidase; and reverse progression of atherosclerosis (including regression) in carotid, coronary, and femoral arteries. ^2–9 Following ischemic tissue injury, niacin limits reperfusion injury and reduces maladaptive vascular remodeling.^10,11 Most importantly, niacin has consistently demonstrated reductions in cardiovascular disease clinical events, including coronary and cerebrovascular, and was the first dyslipidemic agent to demonstrate a reduction in total mortality.¹²

In 1988, the National Cholesterol Education Program (NCEP) guidelines recommended the lowering of elevated LDL-C as a primary target of cholesterol management. “Landmark” trials generally demonstrated that a 25% to 35% decrease in LDL-C resulted in a 25% to 35% decrease in risk of cardiovascular events.¹³ Currently, the use of a statin (HMG-CoA reductase inhibitor) is emphasized as a first-line intervention due to the LDL-lowering capabilities and large body of outcomes-based studies that have accumulated for this class of drugs over the past three decades. This has not always been the case, however, as niacin was originally listed as one of two “first-line” therapies to lower LDL-C when NCEP guidelines were first issued in 1988, and affirmed again in 1993.¹⁴ Since the guideline change in 2001, niacin has been left as an alternative or second-line agent along with other lipid therapies, when a statin alone is insufficient to reach LDL-C goals.¹⁵

As the “successful” use of statins results in a relative risk reduction of 20% to 35%, there is much debate about what approach should be used to effectively deal with the “residual risk” and, unfortunately for niacin, its use in combination with a statin has been questioned as a result of the unexpected results of the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial were announced in May 2011 and published in the New England Journal of Medicine on Dec 15, 2011. ^16–18 This review examines the study design, its potential limitations, and attempts to analyze any significance the AIM-HIGH study has, as compared with previous niacin studies of cardiovascular outcomes.

The AIM-HIGH Trial

This NIH/industry-sponsored trial in 3414 patients with stable coronary disease was stopped early after 32 months when those receiving intensive statin therapy and extended release (ER) niacin showed no further reductions in a composite of cardiovascular endpoints over those receiving intensive statin therapy alone. The early termination was criticized by many, as it assumes that the event curves necessarily remain linear. In fact, trials of gemfibrozil and statins have failed to separate event curves until after two years.^19,20 The high-risk patients (Table 1) were considered well treated not only for lipids, but for other cardiovascular risk factors as well, with aspirin and other antiplatelet therapies, beta blockers, and renin-angiotensin inhibitors. Nevertheless, the overall event rate in this study of secondary prevention was 5% per year, and both the control and treatment arms remain conventional therapy under NCEP guidelines.

Table 1

N Engl J Med. December 15, 2011;365;24.

The AIM-HIGH trial was unique among niacin trials, as it was specifically designed by its investigators “as a rigorous test of the HDL hypothesis”; that is, whether the HDL-raising ability of niacin, and that ability alone, accounts for the benefits seen in previous trials.²¹ Participants met eligibility criteria when they were treated with a statin successfully to LDL-C goal and had low HDL-C levels. The baseline LDL-C was 71 mg/dL , HDL-C 32 mg/dL, and TGs 164 mg/dL; however any patient could receive additional LDL-lowering therapy as needed to remain at goal. This included increasing the simvastatin dose or adding ezetimibe, a blocker of cholesterol absorption. As would be expected, since niacin lowers LDL, the control arm received significantly more maximum statin dose (simvastatin 80mg) and ezetimibe use (21.5% vs. the pretrial estimate of 5%) than the treatment arm. This makes the trial not a comparison of niacin vs. placebo, but niacin vs. other LDL-lowering therapies.

While LDL-C is the primary treatment target in NCEP guidelines, non-HDL-C is a secondary target for NCEP treatment goals when TGs remain elevated. A close look at the AIM-HIGH baseline characteristics shows that non-HDL-C was only 106 mg/dL. Non-HDL cholesterol is readily available from a standard lipid panel, and is simply the total cholesterol minus the HDL, and thus is a better measure of all ApoB particles, including intermediate density lipoproteins (IDLs), VLDLs, chylomicrons, remnant proteins, and Lp(a). With the non-HDL-C goal for high-risk patients at 100 mg/dL (30 points higher that LDL-C targets), and baseline TGs well below 200 mg/dL, existing guidelines suggest that the majority of these patients don’t need any further lipid treatment. Further lipid analysis from this study group such as ApoB or particle number is not available, and as they have proved to be better predictors of risk than LDL-C, would likely have identified a subgroup who might benefit from niacin.²² The predictive value of LDL-C is most discordant when lipoprotein particle number is high, which is associated with elevated TGs and low HDL-C.²³ Even the notion that the benefit derived from statin use is due to lowering of LDL-C is controversial, as some have suggested that the primary benefit comes from the reduction of inflammation.²⁴

While it may then seem reasonable to conclude that targeting HDL with niacin does not matter in these patients when LDL is this low, further confounders remain. Patient enrollment at the sites included those previously taking niacin for low HDL, and 20% of participants became eligible for enrollment with a minimum four-week washout period from niacin. This could have very likely blunted the HDL response as compared with a trial of subjects new to niacin. This is also highly significant in that niacin has demonstrated a legacy effect on mortality reduction nine years after the discontinuation of the Coronary Drug Project (CDP).²⁵ Additionally, the actual difference in HDL increase between groups was only 5 mg/dl (Table 2). According to one niacin researcher, this less-than-expected HDL separation between the two groups resulted in the underpowering of this study to detect differences in outcomes at 32 months.²⁶

Table 2

Placebo + Statin

ER Niacin + Statin

N Engl J Med. December 15, 2011;365;24.

This lower-than-expected differentiation of HDL could have been due to both a lack of increase in the treatment arm as described above and to a significant 4mg/dl (12%) increase in the control arm. A highly significant 24% of subjects discontinued taking niacin during the study. This is significantly higher than previous studies of ER niacin, and particularly higher than an ER preparation known for its overall tolerability and low drop-out rates. ^27–29 As AIM-HIGH trial results used an intent to treat (ITT) analysis, this very high percentage of the study group not on therapy adversely influenced the HDL response. Lastly, it is not known if the attempts to blind the flushing response between groups may have resulted in an HDL response in controls, as the placebo tablets contained 50 mg of immediate release (IR) niacin per tablet, and most received 200mg daily.

Studies

with Cardiovascular Outcomes

Previous randomized controlled studies of niacin have consistently demonstrated a benefit on cardiovascular disease outcomes. The CDP previously mentioned was the first study of niacin to demonstrate a clinical impact and was conducted in the late 1960s and early 1970s.³⁰ This randomized, double-blinded, multicentered, placebo-controlled trial involving 8341 male myocardial infarction survivors involved four total treatment arms, two of which ended early due to an increase in harm, including an increase in heart attacks for desthyroxine, and clotting problems and increased heart attacks for conjugated estrogens. Clofibrate was used in a third group and completed the study, however showed no benefit in cardiovascular outcomes. The niacin arm targeted 3000 mg daily of IR niacin, but in fact 2000 mg daily was the average dose due to the significant amount of flushing seen with this preparation. The trial averaged 6.2 years for participants, and resulted in reductions in nonfatal MI (−27%), cerebral-vascular attacks (−24%), hospitalizations (−12%), and the need for cardiovascular surgery (−46%), but not for total mortality – the primary outcome. As noted earlier, a follow-up analysis nine years after completion of the study demonstrated a clinically significant 11% reduction in total mortality. In another published analysis of the trial, patients were stratified by baseline fasting insulin levels, and the event reduction became more pronounced for higher insulin level groups.³¹

In the Stockholm Ischemic Heart Disease Secondary Prevention Study, 555 patients post MI were randomized to IR niacin in combination with clofibrate or placebo and followed for five years.³² At the end of the trial, the combination treatment had a 26% risk reduction in total mortality, and a 36% reduction in cardiovascular mortality vs. the control group. While the study design makes it impossible to determine the individual contributions of either niacin or clofibrate, clofibrate was used in over 1100 nearly identical patients in the CDP with no benefit demonstrated as a single agent over 6 years. This trial is of further interest, as the treatment benefit was most correlated with patients who achieved less than 30% reduction in TGs and not with total cholesterol lowering.

The Familial Atherosclerosis Treatment Study (FATS) assessed 120 men with CAD, a family history of vascular disease, and ApoB levels greater than or equal to 125 mg/dL over a 2.5-year period.³³ Patients were randomized to one of three groups; lovastatin 20mg twice daily plus colestipol 30g/day, IR niacin 1 g four times daily plus colestipol 30 g/day. Or placebo plus colestipol 30/gm daily. Coronary artery disease progression was smallest in the niacin plus colestipol group, and the rates of combined cardiac events (death, MI, symptom-driven revascularization) were lowest for both lovastatin and niacin-treated groups compared with placebo.

The HDL Atherosclerosis Study (HATS) evaluated the combination of simvastatin plus niacin with and without antioxidants compared to simvastatin plus placebo in 160 patients with CAD and low HDL-C over three years.³⁴ The trial design called for a HDL-C target of therapy, and when the use of a sustained release niacin preparation failed to achieve this target, patients were then switched to IR niacin, resulting in additional HDL-C improvements. This trial produced the most dramatic risk reduction yet seen among lipid interventions, with an impressive 90% relative risk reduction of cardiovascular endpoints for the simvastatin plus niacin arm vs. simvastatin plus placebo. This trial is also notable for demonstrating a “blunted” risk reduction in the antioxidant arm, meaning that the use of vitamins E, C, and beta-carotene in combination with niacin and simvastatin reduced the benefit seen in the combination without antioxidants.

The Armed Forces Regression Study (AFREGS) followed 143 military retirees with angiographically proven CAD and low HDL-C, randomizing participants to intensive combination therapy (gemfibrozil 1.2 g/d, IR niacin up to 3 g/d, cholestyramine 16 g/d) or placebo for 2.5 years.³⁵ Coronary stenosis increased by 1.4% in the placebo group while decreasing 0.8% in the combination group (absolute difference −2.2%). In addition, intensive drug therapy resulted in a statistically significant decrease in cardiovascular events (9% vs. 19%) compared with placebo.

The Arterial Biology for the Investigation of Treatment Effects of Reducing Cholesterol (ARBITER 2 and ARBITER 3) studies assessed 1g/d of ER niacin in addition to baseline statin therapy in patients with known CHD and low HDL-C. HDL-C increased 16 mg/dL in the niacin group and was unchanged in the placebo plus statin group.^36,37 The primary endpoint was change in carotid intima-media thickness, and at 12 months, CIMT was unchanged in the niacin group while progressing significantly in the placebo group. ARBITER 3 patients continued on niacin therapy, and at 24 months demonstrated CIMT regression, suggesting that the effects of niacin may continue to accrue over longer treatment periods.

In 2009, the results of the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol – HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER-6 HALTS) were reported.³⁸ This trial compared two different combination strategies: statin plus ER niacin vs. statin plus ezetimibe on CIMT progression in patients with coronary heart disease, or CHD equivalent. Patients enrolled were stable and had been on statin therapy and average duration of 6 years. As would be expected, the niacin arm resulted in significantly greater HDL and TG improvements (+18.4%, −28.6%) while the addition of ezetimibe achieved primarily significant reductions in LDL-C (−21%). This trial was stopped early after 14 months, when an interim analysis showed superior efficacy in the niacin arm based on change in CIMT between the two groups, and a reduction in cardiovascular events (1% vs. 5%) among patients completing the entire 14 months. Final analysis of all participants confirmed the initial findings.³⁹ It is interesting to note that niacin-treated patients experienced regression, while the additional LDL-lowering of ezetimibe resulted in continued progression of carotid atherosclerosis.

In conclusion, there are numerous limitations of the AIM-HIGH study that make it difficult to interpret the results. The large body of clinical outcomes trials described above consistently demonstrates the benefit of niacin on risk reduction, including total mortality. Patients with known cardiovascular disease and high risk will continue to be managed aggressively with combination therapy in attempts to reduce risk. Researchers and clinicians must continue to search for risk factors and hidden clues that can guide therapy and reduce or eliminate the remaining residual risk, such as micronutrient status, markers of inflammation, advanced lipid analysis, and less-invasive imaging techniques. The single-minded pursuit of lowering LDL-C has failed to appreciably address residual risk as demonstrated by the event rate in this trial. A more global approach to individual risk assessment should provide treatment targets that hopefully translate to improved patient care. While this review has focused primarily on studies of secondary prevention, niacin, as a promoter of normal biochemical reactions and its overall safety profile, will remain a cornerstone of cardiovascular risk reduction when diet and lifestyle modifications fail to correct biomarkers of risk, both as a single agent for primary prevention, and when used in combination with other agents in secondary prevention.

Notes

1. Altschul R, et al. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem. 1955;54:558-559

2. Parsons WB, et al. Changes in blood lipids following prolonged administration of nicotinic acid to persons with hypercholesterolemia. Proc Mayo Clin. 1956;31

3. Knopp RH, et al. Equivalent efficacy of a timed-release form of niacin given once a night vs. plain niacin in the management of dyslipidemia. Metabolism 1998;47:1097-1104

4. Superko HR, et al. Differential effects of nicotinic acid in subjects with different LDL subclass distributions. Atherosclerosis 1992;95:69-76.

5. Rosenson RS. Antiatherothrombotic effects of nicotinic acid. Atherosclerosis 2003;171:87-96.

6. Wu BJ, et al. Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids. Arterioscler Thromb Vasc Biol 2010; 30:968-975

7. Thoenes M, et al. The effects of extended-release niacin on carotid intimal media thickness, endothelial function, and inflammatory markers in patients with the metabolic syndrome. J Am Coll Cardiol 2007;61:1942-8.

8. Blankenthorn DH, et al. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 1987;257:3233-3240.

9. Blankenthorn DH, et al. Effects of colestipol-niacin therapy on human femoral atherosclerosis. Circulation 1991;83:438-7

10. Lamping KA, et al. Nicotinic acid, free fatty acids, and myocardial function during coronary occlusion in the dog. J Pharmacol Exp Ther 1984;231:532-8.

11. Oganov RG, et al. Exercise and nicotinic acid delayed action drug Enduracin: Application in outpatient rehabilitation of patients with ischemic heart disease. Terapevticeskij arhiv Y 2004;76:54-59.

12. Bruckert E, et al. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular event and atherosclerosis. Atherosclerosis 2010;210:353-361.

13. Greenfield RS. The rise and fall of LDL-C measurement. Lipid Spin 2011;9 issue 4:6-7.

14. Report on the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults: The Expert Panel. Arch Intern Med 1988;148:36-69.

15. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3. 14-3, 421.

16. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet 2010;376:1670-81.

17. NIH stops clinical trial on combination cholesterol treatment. National Institutes of Health, 2011. http://www.nih.gov/news/health/may2011.

18. Boden WE, et al. Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. N Engl J Med 2011;365:2255-67.

19. Rubins HB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410-418.

20. Scandinavian Simvastatin Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389.

21. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol rationale and study design. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH).Am Heart J 2011;161:471-7 e2.

22. Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk: Consensus conference report from the American diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51:1512-1524.

23. Otvos JD, et al. Clinical Implications of discordance between low-density lipoprotein cholesterol and particle number.

24. Ridker PM, et al. Inflammation, C-reactive protein, and atherothrombosis. J Periodontol. 2008;79(8 suppl):1544-51.

25. Canner PL, et al. fifteen-year mortality in coronary drug project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-1255.

26. AIM-HIGH fallout: Experts disagree over niacin’s niche. http://www.theheart.org/article/1312479

27. Maccubbin D, et al. Flushing profile of extended release niacin/laropiprant vs gradually titrated niacin extended release in patients with dyslipidemia with and without ischemic cardiovascular disease. Am j Cardiol. 2009;104:74-81.

28. Keenan JM, et al. Niacin Revisited. A randomized, controlled trial of wax-matrix sustained release niacin in hypercholesterolemia. Arch Intern Med. 1991;151:1424-1432.

29. Aronov DM, et al. Clinical trial of wax-matrix sustained release niacin in a Russian population with hypercholesterolemia. Arch Fam Med. 1996;5:567-575.

30. The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360-381.

31. Canner PL, et al. Niacin decreases myocardial infarction and total mortality in patients with impaired fasting glucose or glucose intolerance: results from the Coronary Drug Project. Circulation 2002;106(suppl):31-38.

32. Carlson LA, et al. Reduction of Mortality in the Stockholm Ischemic Heart Disease Secondary Prevention Study. Acta Med Scand.1988;223:405-418.

33. Brown G, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289-1298.

34. Brown G, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592.

35. Whitney EJ, et al. A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events. Ann Int Med. 2005;142:95-104.

36. Taylor AJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110:3512-7.

37. Taylor AJ, et al. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin. 2006;22:2243-50.

38. Taylor AJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361:2113-22.

39. Villines TC, et al. The ARBITER 6-HALTS trial: final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol. 2010;55:2721-6.

Timothy J. Polacek, BS, is a medical liaison for Endurance Products Co. (EPC) and a member of the National Lipid Association. He received his bachelor of science degree at Oregon State University, majoring in science education with an endorsement in biology. Tim has spent 19 years in the pharmaceutical industry, all with Roche Labs, promoting both acute-care injectable and chronic-care oral medications. With his focus on developing proficiency in infectious and cardiovascular disease states, Tim’s abilities and interest in teaching led to numerous clinical presentations to peers, and the first field based trainer position created at Roche. Tim has worked since 2009 at EPC, a manufacturer of dietary supplements in Tigard, Oregon. EPC is committed to educational programs focusing on the role of orthomolecular approaches to health and longevity, and sponsors naturopathic residency programs through the Naturopathic Research and Education Consortium, (NERC).