Niacin Ineffective in Treating Cardiovascular Disease

The recently announced results of a long-term study on niacin (NIASPAN) signal a possible end of an era for this drug, used widely for decades to treat high cholesterol.

The study, called the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial, was the largest long-term study of the risks and benefits of niacin in patients with existing cardiovascular disease already taking statins. The study showed that niacin did not prevent any more deaths or cardiovascular events, such as heart attack or stroke, but did cause a significant increase in dangerous side effects compared with statin therapy alone.[1]

Study overview

Niacin became a standard treatment option for patients at high risk for vascular disease following the 1975 completion of a large trial, the Coronary Drug Project, in which it was shown to prevent the recurrence of heart attacks in men with a history of heart disease.[2] However, this study was performed before statins, now the standard of care, were available.

The HPS2-THRIVE trial results were announced at the March 2013 meeting of the American College of Cardiology conference. The researchers stated that the trial found no additional benefit of niacin therapy for patients with vascular disease and at high risk for stroke, heart disease and arterial occlusion who were already on optimal therapy with statins.

However, the trial did demonstrate that niacin therapy came with many dangers, some life-threatening and potentially increasing the risk of the same adverse outcome, heart attacks, that the drug had been assumed to prevent because the drug caused an increase in diabetes. (Diabetes is a major risk factor for heart attacks.) Niacin caused diabetes complications in an additional 3.7 percent of subjects and new-onset diabetes in an additional 1.8 percent of subjects, compared with those given statin therapy alone.

Niacin also caused infections in an additional 1.4 percent, gastrointestinal (GI) complications in an additional 1 percent and bleeding in the GI tract or head in an additional 0.7 percent of subjects, compared with statin therapy alone.[3] (The bleeding risks may be attributable to laropiprant, which was given along with niacin to minimize flushing and which has been associated in small studies to increase bleeding time when given with clopidogrel,[4] a drug that a minority of subjects in HPS2-THRIVE may have been taking.[5]) Because the trial was restricted to those patients who were able to tolerate and remain compliant with niacin for a month,[6] the trial results did not factor in some of the drug’s more common effects, such as flushing, that often cause people to stop taking it.

“Finding out a drug is not helping people is just as important as finding it has benefits,” said Jane Armitage, a University of Oxford professor and lead author of the HPS2-THRIVE trial, in MedPage Today. “Niacin has been used for many years in the belief that it would help patients and prevent heart attacks and stroke, but we now know that its adverse side effects outweigh the benefits when used with common treatments [such as statins].”[7]

HDL significance questioned

The HPS2-THRIVE results serve as yet another cautionary tale to physicians who have grown accustomed to chasing laboratory values rather than focusing on the greater impact on a patient’s health.

Niacin became a blockbuster drug because of its ability to raise so-called “good” HDL cholesterol, long believed to be an indicator of improved cardiovascular health. However, the HPS2-THRIVE trial showed that using niacin led to higher HDL levels without clinical benefits, thus casting considerable doubt over the usefulness of artificially raising HDL to improve cardiovascular outcomes.

These trial results followed closely on the heels of another randomized trial that tested niacin in subjects with cardiovascular disease and low HDL levels.[8] Although niacin significantly raised HDL levels, it did not reduce the risk of cardiac death or nonfatal heart attacks or strokes. The trial was halted early due to the lack of niacin’s benefit.

A recent Harvard Medical School study cast considerable doubt over the significance of the correlation between higher HDL levels and improved cardiovascular health. The researchers studied individuals with genetically higher HDL levels and compared their heart attack risk to people who were at a similar risk of heart attack but had lower HDL levels. Those with genetically higher HDL levels did not display any reduced risk of heart attack compared with people with lower HDL levels.[9]

Other unproven drugs

In response to the HPS2-THRIVE findings, MedPage Today published an article cataloging other cholesterol-lowering medications that, like niacin, have not been shown to reduce the severity of, or death from, cardiovascular disease.[10] This list includes fenofibrate (TRICOR); fenofibric acid (TRILIPIX); ezetimibe (ZETIA); the combination ezetimibe/simvastatin (VYTORIN); and the omega-3 fatty acid LOVAZA, a prescription fish oil product that treats very high triglyceride levels.

The introduction of statin therapy for patients with cardiovascular disease in the late 1980s[11] represented a paradigm shift in the treatment of heart and blood vessel disease. Most statins (with two exceptions: fluvastatin [LESCOL and LESCOL XL] and pitavastatin [LIVALO]) have been shown to reduce the occurrence of death and/or progression of cardiovascular disease. Rosuvastatin [CRESTOR] does not reduce death or heart attacks in people with elevated cholesterol, only in a group with normal cholesterol but other abnormalities. For this reason, earlier studies of nonstatin cholesterol-lowering drugs, which may have shown a benefit on these outcomes before statins became widely available, may not be valid indicators of their effectiveness today.

According to the MedPage Today article, while all of the nonstatin drugs reduce so-called “bad” LDL cholesterol and/or triglycerides, none have been shown (nor are approved)[12] to affect the course of cardiovascular disease — the true outcome of interest in high-risk patients — more than statin therapy.[13] (The data on fish oil are more mixed. Earlier studies showed a benefit in subjects with a previous history of heart attack or congestive heart failure, but more recent studies demonstrate no benefit in diabetics or subjects at high risk of — but with no history of — heart attacks.)[14] While the benefits of most of these nonstatin cholesterol-lowering drugs are uncertain or nonexistent, their side effects, including muscle, liver and kidney damage, are well-established.[15]

The lack of demonstrated benefit — beyond statins — for many of these drugs has not dampened physicians’ willingness to prescribe the drugs to millions of patients. Despite questions regarding niacin’s benefit in treating heart disease that existed even before the HPS2-THRIVE trial, 5.3 million prescriptions were written for just one variant, NIASPAN, to the tune of $1.1 billion in 2012. All told, 40 million prescriptions for these unproven, nonstatin cholesterol-lowering medications were written to the tune of $6.8 billion in 2012.[16]

What You Should Do

Do not take niacin to treat heart disease. If you have heart disease or have had a heart attack or stroke in the past, statins are appropriate therapies when used with diet and exercise to lower cholesterol.

All statins have been proved to reduce the risk of having a heart attack or stroke in those with cardiovascular disease, with two exceptions, fluvastatin[17] and pitavastatin,[18] which have never been proved to reduce death or progression of heart disease. Do not use these two statins. Rosuvastatin also should not be used due to its unique dangers of serious kidney toxicity and potentially more muscle damage compared with other statins, as well as its lack of any evidence for preventing heart attacks in people with elevated cholesterol levels.[19] All statins can cause a number of serious side effects, including severe muscle damage and liver damage, so your doctor should follow you closely once you start the drugs.

If you do not have heart disease and are not diabetic, ask your doctor whether statin therapy is necessary for you. The evidence that the benefits of statins outweigh their risks for what is called primary prevention — in people without pre-existing heart disease — is not clearly established. The most important and safest approach for primary prevention is a diet and exercise program to reduce your “bad” LDL cholesterol and triglyceride levels and risk of heart disease. If you smoke, see your doctor immediately for ways to quit, because smoking is a major risk factor for heart attacks. See the recommendations for high cholesterol and smoking cessation therapies.

See the table below for a complete list of currently available cholesterol-lowering therapies, and then discuss this information with your doctor.

Currently Available Cholesterol-Lowering Therapies*[20]

* List compiled from: Mayo Clinic. Cholesterol medications: Consider the options. Accessed on May 15, 2013. http://www.mayoclinic.com/health/cholesterol-medications/HB00042. List does not include various combinations of these drugs.

** This drug is only approved to prevent heart attacks or strokes in people with normal cholesterol levels, not in those with elevated cholesterol levels.[21]

*** Niacin provides no benefit in those already on statin therapy. Gemfibrozil is approved to prevent heart attacks, strokes, or death from cardiovascular disease only in certain Type IIA diabetics. However, we do not recommend this drug for anyone because of severe risks, including malignancy, non-cardiac death, gallbladder disease and severe abdominal complications.

**** There is possible cardiovascular benefit of fish oil in patients who have had a heart attack in the past[22] or in those with congestive heart failure who are not taking statins.[23] However, there may be no additional benefit for those already on statin therapy for these conditions. In patients with coronary heart disease, fish oil may be beneficial in those already on statin therapy.[24]

† Niacin and cholestyramine should only be used by patients with cardiovascular disease or at high risk for heart attack or stroke who cannot tolerate statin therapy. Fish oil can be used in certain, limited circumstances in addition to optimal statin therapy for patients with established coronary heart disease.

References

[1] Peck, P. ACC: HPS2-THRIVE may signal the end for niacin. MedPage Today. March 09, 2013. http://www.medpagetoday.com/MeetingCoverage/ACC/37771. Accessed on May 14, 2013

[2] Niaspan label. “Clinical Studies”. Updated February 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020381s048lbl.pdf

[3] Peck, P. ACC: HPS2-THRIVE may signal the end for niacin. MedPage Today. March 09, 2013. http://www.medpagetoday.com/MeetingCoverage/ACC/37771. Accessed on May 14, 2013.

[4] Note that there is no significant interaction with aspirin, only clopidogrel and only at 4-h post-dose. Dallob A, Luo WL, Luk JM, et al. The effects of laropiprant, a selective prostaglandin D2 receptor 1 antagonist, on the antiplatelet activity of clopidogrel or aspirin. Platelets. 2011;22(7):495-503.

[5] Table 2: Asprin taken by approximately 86%, while “other anti-platelet agents” (likely clopidogrel in the vast majority of cases) only taken by around 18%. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013 May;34(17):1279-91.

[6] See “Methods: run-in period and randomization”. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013 May;34(17):1279-91.

[7] Fauber, J. Big bucks, no benefits with many drugs. MedPage Today. March 09, 2013. http://www.medpagetoday.com/Cardiology/Dyslipidemia/37772?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&xid=NL_DHE_2013-03-11&eun=g417437d0r&userid=417437&email=salmashat@citizen.org&mu_id=5517052. Accessed on May 14, 2013.

[8] AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15;365(24):2255-67.

[9] Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012 Aug 11;380(9841):572-80.

[10] Fauber, J. Big bucks, no benefits with many drugs. MedPage Today. March 09, 2013. http://www.medpagetoday.com/Cardiology/Dyslipidemia/37772?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&xid=NL_DHE_2013-03-11&eun=g417437d0r&userid=417437&email=salmashat@citizen.org&mu_id=5517052. Accessed on May 14, 2013.

[11] Nature. Timeline: History of the statins. Lovastatin approved 1987, first-in-class. http://www.nature.com/nrd/journal/v2/n7/fig_tab/nrd1112_I1.html. Accessed on May 21, 2013.

[12] Tricor label. Updated February 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021656s023lbl.pdf; Vytorin label. Updated October 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021687s046s047lbl.pdf; Trilipix label. Updated September 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022224s007s008lbl.pdf; Zetia label. Updated January 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021445s033lbl.pdf; Lovaza label. Updated August 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021654s034lbl.pdf.

[13] Fauber, J. Big bucks, no benefits with many drugs. MedPage Today. March 09, 2013. http://www.medpagetoday.com/Cardiology/Dyslipidemia/37772?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&xid=NL_DHE_2013-03-11&eun=g417437d0r&userid=417437&email=salmashat@citizen.org&mu_id=5517052. Accessed on May 14, 2013.

[14] One of the largest studies testing the purported heart benefits of fish oil was published in May 2013 in The New England Journal of Medicine (Risk and Prevention Study Collaborative Group; N Engl J Med. 2013 May 9;368(19):1800-8). The Italian trial compared n−3 polyunsaturated fatty acids (unique to fish oil) with olive oil in over 12,000 subjects at high risk for, or with established cardiovascular disease, but who had never had a heart attack. Daily consumption of fish oil did not reduce deaths or hospital admissions from cardiovascular causes in comparison to olive oil in these subjects with no prior history of heart attack. A trial published in 2012 in NEJM found a similar lack of benefit of fish oil in reducing cardiovascular death in diabetic patients and those at risk for diabetes (ORIGIN Trial Investigators; N Engl J Med. 2012 Jul 26;367(4):309-18). Previous trials had shown that fish oil significantly reduced cardiovascular death in subjects who had survived a previous heart attack (GISSI-Prevenzione trial; Lancet. 1999 Aug 7;354(9177):447-55) and in patients with congestive heart failure (Gissi-HF Investigators et al. Lancet. 2008 Oct 4;372(9645):1223-30), but statin use in these two trials was about half (around 20%) of that in the 2012/2013 NEJM trials (40-50%). A third earlier trial (Yokoyama et al. Lancet. 2007 Mar 31;369(9567):1090-8) had shown a significant benefit of fish oil in Japanese patients with a history of CHD beyond the effect seen with statins (intervention groups were fish oil/statin versus statin alone).

[15] Tricor label. Updated February 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021656s023lbl.pdf; Vytorin label. Updated October 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021687s046s047lbl.pdf; Trilipix label. Updated September 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022224s007s008lbl.pdf; Zetia label. Updated January 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021445s033lbl.pdf; Lovaza label. Updated August 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021654s034lbl.pdf.

[16] Fauber, J. Big bucks, no benefits with many drugs. MedPage Today. March 09, 2013. http://www.medpagetoday.com/Cardiology/Dyslipidemia/37772?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&xid=NL_DHE_2013-03-11&eun=g417437d0r&userid=417437&email=salmashat@citizen.org&mu_id=5517052. Accessed on May 14, 2013.

[17] WorstPills.org. Fluvastatin monogaph. Fluvastatin, while since having been indicated for the prevention of revascularization procedures in CHD patients, still has no indication for the prevention of MIs or strokes. http://worstpills.org/member/drugprofile.cfm?m_id=191. Accessed on May 14, 2013.

[18] Pitavastatin (LIVALO) label. “Limitations of Use” on page 1. Updated October 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022363s010lbl.pdf. Accessed on May 14, 2013.

[19] WorstPills.org. Rosuvastatin monograph. http://worstpills.org/member/drugprofile.cfm?m_id=193. Accessed on May 14, 2013.

[20] Column 2 based on the “Indications and Usage” section of the most current labels available from the Drugs@FDA site as of May 15, 2013. Column 3 based on information on each drug on the WorstPills.org site as of May 15, 2013, with one exception: Niacin was previously recommended therapy but was subsequently changed on the site to a “Limited Use” drug (for patients who cannot for whatever reason tolerate statin therapy).

[21] Crestor label. December 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021366s026lbl.pdf. Accessed on May 24, 2013.

[22] Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 1999 Aug 7;354(9177):447-55.

[23] Gissi-HF Investigators, Tavazzi L, Maggioni AP, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Oct 4;372(9645):1223-30.

[24] Yokoyama et al. Lancet. 2007 Mar 31;369(9567):1090-8.