January 4th, 2013

Why Has Niacin Therapy Failed to THRIVE?


Merck recently announced that Tredaptive, its compound of extended-release niacin and laropiprant, failed to meet the primary-endpoint goal in the HPS2-THRIVE trial, a comparison with statin therapy alone. Dr. John Ryan has now asked Dr. William E. Boden, lead investigator of the AIM-HIGH trial, for his perspective on existing evidence about niacin and other HDL-modifying therapies. A related discussion between Dr. Boden and CardioExchange’s Dr. Harlan M. Krumholz will follow next week.

Ryan: Many practitioners are losing confidence in niacin and other HDL-modifying therapies. Others agree with you that, as you said to theheart.org, “we just have not designed the right trial.” Why haven’t the right trials been conducted, and what aspects of the published trials would you change?

Boden: In designing AIM-HIGH, the NHLBI Ethics Review Panel proscribed a statin washout as being “unethical,” so we were obligated to enroll patients with established coronary disease and low HDL levels who already had a class I indication for a statin. We designed AIM-HIGH with the expectation that our starting baseline LDL level would be about 100–102 mg/dL, but we wound up with 71 mg/dL in 94% of patients who had been on statins for at least 1 year (75% of enrollees) or at least 5 years (40% of enrollees). In short, these patients were too well treated for too long on a statin to discern an incremental clinical benefit of niacin, and we enrolled far too few statin-naive patients.

The placebo tablets (each 500 mg) were spiked with 50 mg of crystalline niacin to impart a mild cutaneous flush and mask the identity of treatment. That meant patients taking 2000 mg daily (four 500-mg placebo tabs) were taking 200 mg of immediate-release niacin. This could explain why the mean on-treatment HDL increased from a baseline of 35 mg/dL to 38 mg/dL in the placebo group. Some have therefore opined that AIM-HIGH was a trial of high-dose vs. low-dose niacin, and was not really placebo controlled.

We also permitted active uptitration of LDL after randomization, by either increasing the dose of simvastatin and/or adding ezetimibe to achieve and maintain an aggressive on-treatment range of LDL (40–80 mg/dL). Mean on-treatment LDL was 62 mg/dL at 3 years—arguably the best LDL control in any randomized controlled trial of lipid-altering therapy.

Lastly, by design, we excluded ACS and acute-MI patients (admittedly, patients with a higher incidence of CV events) because we were concerned that most would undergo early PCI, which would then alter the natural history of the disease and could confound our results. So, for many reasons, in our zeal to be scientifically careful and pristine, we actually outsmarted ourselves by manipulating too many variables. This is what I meant by our not yet having designed “the right trial.”

Neither HPS-2 THRIVE nor the two failed CETP-inhibitor trials specifically targeted patients with low baseline HDL levels, like we did in VA-HIT and AIM-HIGH. These “all-comers” designs presumably seek to test the intervention in the broadest population of patients to make it more generalizable. But given the inverse and curvilinear relationship between HDL and incident CV-event rates, the steepest part of the mortality curve occurs with HDLs below 30 mg/dL, whereas a “normal” baseline HDL level of 50 mg/dL (the population mean) is on the flat part of the event curve. Increasing the HDL level by 20% (from 50 to 60 mg/dL) simply may not have much impact on events, if the risk is already too low at baseline.

Both AIM-HIGH and HPS2-THRIVE had design flaws that, in retrospect, I believe plausibly explain the clinical findings. It’s easy to worship at the altar of evidence-based medicine when you lack a gray scale. Two negative outcomes trials with niacin in studies with clear design limitations should give us some pause. The patients to whom the results apply likewise must be considered. None of the results in any way apply to ACS or acute-MI patients, as these were notable exclusions in both trials.

Ryan: The clinical role of laropiprant, a prostaglandin inhibitor, is largely unproven. Might laropiprant have obscured the clinical effects of niacin?

Boden: In HPS2-THRIVE, concomitant use of laropiprant might very well have caused unforeseen off-target effects negating the clinical benefits of extended-release niacin. With a prostaglandin inhibitor, I would worry about either bleeding or thrombosis. Merck obviously banked on the fact that this duo was a clean-drug combo, and this is a serious study-design flaw in my view. It’s also why the FDA declined to approve Tredaptive in 2008 when it came up for a panel review. Merck should never have conducted a 25,000-patient trial and spent a gazillion dollars (or euros) on an unproven drug combination that had a propensity for off-target effects that might negate niacin’s benefit. I think this was an ill-advised decision to seek regulatory approval for a drug combo before safety and efficacy had first been established in a phase III study.

Ryan: 2012 was a bad year for HDL. After the ILLUMINATE trial of torcetrapib, negative results with dalcetrapib were published in the dal-OUTCOMES trial. These findings have cast doubt on the “HDL-raising hypothesis” of additional benefit on top of statin therapy. At what stage do we just move on from HDL as a therapeutic target rather than continually reserving judgment until we get results from the next study — which is now REVEAL (HPS3-TIMI55)?

Boden: It has been a bad 12 to 18 months for HDL-raising therapies. We have no “pure” (isolated) HDL-raising therapeutic intervention. All available agents affect multiple lipid parameters, so isolating a treatment effect to one lipoprotein may be difficult, if not impossible. Some have argued that because CETP inhibitors may create large HDL particles, the result could be dysfunctional HDL, which might explain the negative/neutral effects seen in ILLUMINATE and dal-OUTCOMES. Also, both were “all-comers” designs. Expecting to raise the HDL from 50 mg/dL to 60 or even 70 mg/dL may not translate into clinical CV-event reduction in the super-normal range.

Regarding the “HDL hypothesis,” VA-HIT proved that one could lower CHD death/MI and death/MI/stroke by 22% and 29%, respectively, with gemfibrozil versus placebo in the absence of any LDL change from baseline (111 mg/dL) to 5 years of follow-up (113 mg/dL). HDL increased from 32 to 34 mg/dL, and triglycerides dropped from 164 to 120 mg/dL. So a 6% increase in HDL and a 31% decrease in triglycerides were associated with significant clinical benefit without any change in LDL — but also in the absence of statin therapy. So I think the HDL hypothesis has been upheld, but in the contemporary era of optimal medical therapy, where patients may take 6 to 8 concomitant medications, it’s becoming harder to demonstrate incremental benefit when you are layering the 7th or 8th drug on top of so many other effective agents.

What are your thoughts about HPS2-THRIVE? And don’t forget to stay tuned for the discussion between Boden and Krumholz next week.

7 Responses to “Why Has Niacin Therapy Failed to THRIVE?”

  1. I think that Dr. Boden’s remarks are right on target. Niacin has had a bad year or so, but these recent studies of the effects of niacin on HDL and on cardiovascular events are a few among over 900 studies conducted to date. The vast majority of those studies do suggest niacin benefits in raising HDL and in reducing CVD events and major CHD events, though not in stroke. These benefits are summarized in the recent Lavigne-Karas (2012) meta-analysis and in earlier reviews, as well as in the individual studies. Moreover, even during the niacin “dry-spell,” some studies have shown substantial benefits of niacin-simvastatin combination therapy (Toth et al., 2012) that are not seen with simvastatin alone.

    I think it would be a major error to throw out the niacin baby with the bath water based on a small number of recent studies. I agree with Dr. Boden that laropiprant may, indeed, be a culprit here, reducing the beneficial effects of niacin. If patients are given a gradually increasing dose of niacin until they reach 2000 mg or more, most will stay with the drug and not drop it due to flushing effects if the benefits of the drug are carefully explained to them. Thus, it may be that we need to move away from laropiprant, study its effects separately, and/or develop other drugs that will reduce flushing without having negative effects on the benefits of niacin. I also think that the designs of recent studies need to be taken into consideration, as Dr. Boden suggests, and that additional studies, with appropriately modified designs, need to be conducted, with and without laropiprant being added to the niacin.

  2. Chagai Dubrawsky, M.D. says:

    Niacin-Nicotinic Acid,did not get the “fair share”,of fame,as other vitamins of the B group got.To start with,while other vitamins were
    repeatedly mentioned,mainly in studies about cognition-neuropsychiatry,
    niacin always remained the”Forgotten child”
    Lack of purity in the specific molecule is another significant factor in
    failure of the niacin to reach its place in the history of medicine.
    Counting Niacin-Nicotinic acid with Nicotin-amid,at the same breath is like counting apples and oranges in the same count.Same goes for the matter of immediate release and slow release.
    Then there is the issue of Lapopiprant vs. niacin:Original vs synthetic.
    Self vs. None-Self molecule.This is a complete different molecule.
    mixing original vs isomer is another:No-No:prohibited.
    Last and not least:The dosage.Are you trying to kill a fly with an elephant?What about side effects.
    All those issues can now be solved with the introduction of Molecular Medicine,where:The size that matters(The size of the molecule.)
    It is about time that the Innate Immune mechanism of action,be revealed
    C.A. Janeway .Immunebiology 5,textbook,Pp.608,Garland Pub. 2001.
    Article:Future Direction in immunebiology resarch.

  3. Judith Andersen, AB, MD says:

    I agree with Dr Boden and Dr Smith that the baby should not be discarded with the bathwater. Actually, what seems amazing to me is that our strategies with regard to cardioprevention depend so heavily on new drugs, rather than on the admittedly difficult strategy of engaging our patients in the pursuit of “healthy lifetyles.” It’s considerably easier to give patients a new medication than it is gaining their participation in eating reasonably — with or without additional niacin, exercising and generally pursuing a good health maintenance strategy. It’s not exciting, not readily reimbursed and not supported by the pharmaceutical industry or clinical researchers who depend on pharmaceutical trials to gain prominence. But I think we are hypocrites,if we do not adhere to basics. The data from the few hunter-gatherer populations left in the world suggest that vegetables, occasional protein-rich meals, and exercise (e.g. walking the 18 miles to the next campsite) are the best protection against atherosclerosis. Why do we not pay attention to this — and push our patients and ourselves to change behavior? Civilization, in so far as it pushes lavish meals, motorized transportation, and drug and catheter therapy of our most common and lethal event,is our worst enemy.

    Yeah,yeah,yeah — I’m an idiotic idealist, but think about it. Why are we inviting patients into trials like this. Niacin is easy and cheap, laropiprant not so much. Flushing from niacin decreases with exposure, and timing is critical — most folks know when the peak occurs and can avoid it. Our prescription pads appear to be the replacement for our brains and our ideals. Go figure.

  4. David Powell , MD, FACC says:

    HDL loses predictive power in aggressive statin trials, such as JUPITER. Mendelian randomization studies have not upheld the HDL hypothesis (in contradistinction from the LDL hypothesis). Numerous studies show that HDL’s pleiotropic properties and functionalities are physiologically significant, rather than the particle concentration. Combined with the large trials mentioned above, adding niacin to low LDL statin-treated patients seems unwarranted. Yes, better trials focusing on other subgroups without confounding drugs can be performed. But at a large expense and not double blinded.
    Notwithstanding the above, I have only withdrawn patients from niacin who are on high dose statins with an LDL less than 60, as the LDL may increase on niacin withdrawal. I have been less concerned with withdrawing niacin in statin-treated patients with side-effects and a higher LDL when I can increase or change statin potency. For those with very low HDLs , I told them to await HPS2 THRIVE. But I still await publication. and what was the significant side effect reported in the media?.

  5. Gregory Pokrywka MD, FACP FNLA NCMP, MD says:

    I agree with some of what Dr. Powell states, but remember that HDL-C is NOT HDL ! The BEST measure (see HPS, MESA data) of HDL functionality we have readily available at the current time IS NMR HDL-particle count (HDL-P), which DOES correlate with lack of disease/ events BETTER than HDL’s cholesterol content (HDL-C), presumably capturing some of the “pleiotropic and significant functional properties ” of HDL.

    Niacin does NOT raise HDL-P , in contrast with fibrates which DO, perhaps explaining the success of trials like VAHIT, vs the failure of AIMHIGH etc. From a particle based (vs. a lipid-based ) perspective, the AIMHIGH results are not surprising. (Otvos, Journal of Clinical Lipidology Vol. 5, Issue 5, Pages 368-370)

    I will continue to use niacin as an apoB modulating drug add on to a statin (or in statin intolerant patients), depending on whether the THRIVE “nonfatal side effects” are serious and if they are due to niacin or the laropiprant. I will NOT use niacin to “raise HDL-C” as we have NO on treatment evidence to support that concept (as opposed to LOTS of evidence supporting the reduction in clinical events/ disease form lowering apoB particles.)

    Gregory S Pokrywka MD FACP FNLA NCMP
    Prevention of Cardiovascular Disease and Women’s Menopausal Health
    Assistant Professor of Medicine
    Johns Hopkins University School of Medicine
    Diplomate American Board Clinical Lipidology and Fellow, National Lipid Assn.
    Certified Menopause Practitioner: North American Menopause Society
    Director: Baltimore Lipid Center. Board Member, South East Lipid Assn.

  6. Dan Hackam, MD PhD says:

    I agree with Dr Andersen completely. The event rate was not low in AIM-HIGH. If I remember correctly, the placebo event rate was something like 5.8% or 5.6% PER YEAR. And these were hard events. Why not give effective and efficient lifestyle modification a try instead of adding a fourth, fifth or sixth drug? You could do the Mediterranean Diet, a vegetarian diet, or a carbohydrate-restricted diet. All appear to have benefits, depending on the underlying pathophys of the patient. We don’t seem to push lifestyle modification nearly enough – it’s not sexy, it takes time, it takes patient buy-in, we could be seeing more patients by writing scripts and getting onto the next patient – but in the long run, lifestyle modification when effectively delivered render pharmacological therapy as a pale shadow.

  7. William DeMedio, MD says:

    When statins were not available, niacin was shown to regress atherosclerosis. I think we have come a very long was in treatment of atherosclerosis with statins in that they are experimentally superior to niacin. However, when studying combinations of niacin and statins the signal to noise ratio is likely too high to pick up any benefit. My personal anecdotal belief is that niacin does more good than harm. I also think it slows graying of the hair but do not have any scholarly articles to back it up. Some questions can’t be answered in a broad statistical sense. It is cases like this where we must individualize treatment.