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Again, Niacin Proves Ineffective in Statin-Treated Patients with Vascular Disease

July 16, 2014

Again, Niacin Proves Ineffective in Statin-Treated Patients with Vascular Disease

  1. Allan S. Brett, MD

In a large randomized trial, niacin was associated with serious adverse effects but no cardiovascular benefit.

  1. Allan S. Brett, MD

In the 2011 AIM-HIGH trial, niacin (added to a statin) failed to improve outcomes in patients with cardiovascular disease (NEJM JW Gen Med Nov 15 2011). We now have results from another randomized niacin trial — the industry-sponsored HPS2-THRIVE study. The study involved nearly 26,000 patients with known vascular disease whose mean LDL and HDL cholesterol levels were 64 mg/dL and 44 mg/dL, respectively, while taking simvastatin (40 mg daily; with ezetimibe in some cases). Patients received either 2 g of extended-release niacin daily or placebo; niacin was combined with laropiprant, a drug that lessens niacin-related flushing.

During median follow-up of 4 years, niacin lowered LDL cholesterol levels by a mean of 10 mg/dL and raised HDL cholesterol levels by a mean of 6 mg/dL, compared with placebo. However, there was no significant difference between groups in incidence of major adverse cardiovascular events (13.2% vs. 13.7%; P=0.29), and even the subgroup with the lowest HDL cholesterol levels and highest triglyceride levels at baseline showed no benefit from niacin. Niacin was associated with a slight excess in overall mortality (6.2% vs. 5.7%; P=0.08). Niacin recipients had significant excess risk for serious adverse events traditionally associated with this drug (e.g., gastrointestinal, musculoskeletal, and diabetes-related), as well as for infection and bleeding.

Comment — General Medicine

  1. Allan S. Brett, MD

Why the investigators expected benefit from niacin therapy in this population is unclear: LDL cholesterol levels in this group of statin users were extremely low, and HDL cholesterol levels — although low — were not rock-bottom low, so substantial additional benefit from niacin would almost have to be mediated through some putative non–lipid-related effect. In any case, if AIM-HIGH didn't put niacin out of business as add-on therapy for statin-treated patients, HPS2-THRIVE should. The results also raise the possibility that medications might push total and LDL cholesterol levels too low, perhaps creating harms that would offset potential benefits (average LDL cholesterol level in this trial's niacin recipients was 54 mg/dL). Final note: Combination niacin-laropiprant was approved by the European Medicines Agency in 2008 and withdrawn several years later; the combination has never been approved in the U.S.

Comment — Cardiology

  1. Harlan M. Krumholz, MD, SM

In a letter published in the same issue as this report, the AIM-HIGH investigators provide data on serious side effects of niacin in their study. Especially in this context, HPS2-THRIVE represents an astonishing reversal for niacin. We are now learning that in the statin era, niacin — for years, a billion-dollar drug — has no demonstrated ability to lower risk and is associated with serious side effects. It's true that niacin's effects have not been evaluated in every patient population, but the evidence supporting this drug is from the 1960s and is not that strong. I don't see any indication for niacin at this point.

(To join a discussion of these findings, read Harlan Krumholz and Nicholas Downing's blog on CardioExchange, an online community hosted by the New England Journal of Medicine and NEJM Journal Watch and dedicated to improving cardiac patient care. Membership is free for medical professionals.)

  • Disclosures for Allan S. Brett, MD at time of publication Nothing to disclose

  • Disclosures for Harlan M. Krumholz, MD, SM at time of publication Consultant / Advisory board United Healthcare; VHA, Inc.; Premier, Inc. Equity ImageCor Grant / Research support FDA; NIH-NHLBI; Commonwealth Fund; The Catherine and Patrick Weldon Donaghue Medical Research Foundation; Robert Wood Johnson Foundation; Medtronic Editorial boards BMJ.com/us; American Journal of Managed Care; American Journal of Medicine; Archives of Medical Science; Central European Journal of Medicine; Critical Pathways in Cardiology; Current Cardiovascular Risk Reports; JACC: Cardiovascular Imaging; Journal of Cardiovascular Medicine; Circulation: Cardiovascular Quality and Outcomes Leadership positions in professional societies American Board of Internal Medicine (Chair, Assessment 2020 Task Force)

Citation(s):

Reader Comments (9)

Petros Kanellopoulos Physician, Internal Medicine, Hospital, private practice

Nevertheless, I see no good article about niacin use in patients who need to, but cannot take statins; these patients have no alternative medicine to reach the advisable levels of lipids.

H ROBERT SILVESTEIN Physician, Preventive Medi ine Center

What if a study treated patients with rosuvastatin 40 mg and the goal/perfect/disease reversing non-HDL cholesterol of 90 was reached (HDL 44 and LDL 63, as in HPS2-THRIVE). And then it was decided to add 80 mg of atorvastatin to the 40 mg rosuvastatin to look for improved atherosclerotic endpoints. Since disease stabilizing/reversing values had already been obtained before adding the second lipid-lowering medication, no doubt only further toxicity would be apparent, as was the case in HPS2-THRIVE. It is disappointing to see such a large study created by such important lipid specialists. Frankly, I consider HPS2-THRIVE unethical and the authors should be appropriately criticized for this pointless undertaking. I felt the same about AIM-HIGH. HRS, MD, FACC. No conflicts.

Francois Veillon Fellow-In-Training, Other

In all that almost systematical bashing of Niacin there is disturbing constant unwillingness displayed to acknowledge the exceptional efficacy of Niacin as the only drug able to drastically (up to 40%) reduce lp(a) which is knowingly an atherosclerotic risk factor to be taken seriously..
The European Atherosclerosis Society since 2010 has recommended screening for lp(a)

David Freiman Physician, Radiology, Univ of Penn

The problem with many of these studies is that they only tested the profitable timed-release formulations. The very generic non-patentable crystalline formulation hasn't been tested in years.
I agree with the above comments that the latest studies test only nonsensical combination therapy of using two drugs known to be toxic separately rather than the less toxic crystalline niacin vs other drugs or placebo.there is no money in it for the manufacturer.

Fernando BALLERIO Physician, Cardiology, Hospital Británico de Buenos Aires

I am a little bit dissapointed; is the second knock-out punch agaist niacin. I`ll say my patients stop taking it.

Russell Blaylock, M.D. Physician, Surgery, Specialized, Theoretical Neuroscience Research, LLC

What thus study actually tells us is completely missed by most commentators and the study authors. While I have never advocated niacin as a preventative for CVD nor cerebrovascular disease, this study adds very little to what we already knew, except that adding two dangerous drugs together is even more hazardous. While such statements as “serious side effects” and “increased mortality” is used to describe niacin the same can be said of statins, which also have shown minor benefits in preventing these vascular disorders. The actual increase in mortality is 0.5%, which is non-significant. Statins are known to damage the liver and severely deplete CoQ10 essential for cellular metabolism. Niacin in high doses is also known to damage the liver and the additive and possibly synergistic toxic effect must not be ignored. I noticed that the media telling of this story completely ignored that these patients were also receiving statins—the story was directed only at the niacin. As for the infectious risk and risk of diabetes, these are both major complications of statins. Statins are known to be major immune-suppressing drugs. They also have serious neurological consequences, including the risk of ALS and dementia.

SHELDON BALL Physician, Geriatrics, Anvita Health

Some time ago, I read in JW discouragement for extending the implications of a study outside of the study group. This study only examines outcomes with the combination statin + sustained-release niacin* + laropiprant.
* Immediate release nicotinic acid does not have the same adverse risk profile as sustained release niacin.

Eddie Vos Other, Sutton QC, Canada

There is NO WAY to know if it was that prostaglandin inhibitor that caused the lack of benefit and thus show the role of an extended release niacin, oft seen as not having the benefit of quick release crystalline niacin, as found in the non-pharma supported LRC study.

The second problem was that the placebo was simvastatin, a drug proven by 4S + HPS not to reduce deaths in women.

REBECCA BROTHERS Other Healthcare Professional, Pharmacology/Pharmacy, Cincinnati VAMC

It would be nice to see a study that will help with clinical decision making in practice; we do not need to know what niacin does if added on to a statin. We do need to know what to do with patients that cannot take any statin or refuse to retry a statin after a significant side effect to a statin.
Right now my only use for niacin would be as an add on (or monotherapy if no CAD or risk equivalent ) if TGs are >500mg/dL to decrease the risk of pancreatitis in a patient that cannot take/tolerate fish oil; since I generally avoid any fibrate use with statins.
I believe HATs HDL Atherosclerosis Treatment Study (2001) is the only study with simvastatin + niacin that showed some positive outcomes in patients with baseline low HDL.

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