January 9th, 2013

Niacin Therapy in the Crossfire


This discussion between William E. Boden, lead investigator of the AIM-HIGH trial, and CardioExchange’s Harlan M. Krumholz follows John Ryan’s interview with Dr. Boden last week about the results from HPS2-THRIVE.

Boden: Harlan, I have a scenario for you: A 55-year-old man with recent acute MI undergoes PCI of the infarct artery and returns to the CCU post-procedure. His fasting admission labs show a total-cholesterol level of 149 mg/dL, LDL 105 mg/dL, HDL 23 mg/dL, triglycerides 190 mg/dL, and non-HDL 126 mg/dL. Following evidence-based practice guidelines (PROVE-IT), the patient is started on atorvastatin 80 mg daily (which, by the way, may further reduce HDL at that dose). You’ll likely get his LDL at or near 70 mg/dL, and because his non-HDL level is <130 mg/dL, this doesn’t become a necessary secondary treatment target. Does AIM-HIGH or HPS-2 THRIVE even apply here? A lot of evidence from many sources shows that such a very low HDL level is a powerful predictor of CV events. So I’d prescribe niacin and tell the patient I can’t be certain he’ll live longer or have a lower rate of MI/stroke. But I also tell him that many academicians and opinion leaders would decry my practice because they believe that any RCT result applies equally to all patients without exception.

Krumholz: I wish I had an effective drug to prescribe, but prescribing one that has no evidence of benefit and may be harmful is just something that I could not recommend. I see these drugs as having thousands of effects, and the biomarker of interest likely represents just a small number of them. What I need to know is the net effect, and I am not confident I can predict that based on the movement of the single biomarker.

Boden: There is evidence of clinical outcome improvement (i.e., CHD death/MI reduction) from VA-HIT for gemfibrozil; there is similar clinical outcome improvement for niacin from the Coronary Drug Project. Numerous studies show niacin’s benefit on surrogate outcome measures (i.e., quantitative coronary angiography, IVUS, cIMT, etc.). What more evidence do you need?

Krumholz: The CDP was conducted between 1966 and 1975 — eons ago. And the effect was on nonfatal MI, a secondary endpoint; 5-year mortality was the primary endpoint. I know about the study of the survivors long-term, but that’s hardly definitive evidence. Yes, gemfibrozil was positive in VA-HIT, but I’m not sure the relevance to our discussion of niacin. I think we should drop the use of this billion-dollar drug.

Boden: So do you think that flawed study design could have made some contribution to these “failed” outcomes trials? The LDL story is simple and straightforward. The epidemiology of the direct linear relationship between elevated LDL and increased incident CV risk is supported by many RCTs of statin benefit where the drug—which inhibits HMG coenzyme reductase—lowers LDL and CV risk. It’s a clean cause and effect with a drug that acts solely on the LDL receptor.

By contrast, we have no “pure” HDL drug — that is, no available agent that singularly affects HDL alone. Niacin lowers triglycerides, LDL (modestly), and lipoprotein(a); raises HDL and apolipoprotein-A1; and shifts LDL particle size and number from small, dense pattern B (atherogenic) to large, fluffy, buoyant pattern A (non-atherogenic) LDL.

Finally, Lavigne and Karas have a new meta-analysis of all niacin RCTs that includes AIM-HIGH — in all, 11 RCTs involving 9959 patients with established CHD treated with niacin (alone or combined with other agents). The primary composite outcome measure was CVD events. The odds ratio for niacin was 0.66 (95% CI, 0.49–0.89; P=0.007). Notably, the magnitude of on-treatment HDL difference between treatment arms was not significantly associated with the magnitude of the effect of niacin on outcomes (P=0.86), suggesting that the reduction in CVD events with niacin may be occurring through a mechanism not reflected by — or independent of — changes in HDL concentration.

My concluding thought is that HDL is exceedingly complex—far more so than LDL. For me, AIM-HIGH has been a humbling experience, and one from which I have learned some important lessons of how I might structure and design the next RCT. So, yes, I have not given up on niacin, although I acknowledge that I will likely become part of a grudgingly declining minority of physician-scientists.

Krumholz: That’s great that you are not giving up on niacin, and you may be right about HDL, but we have to face the facts about the trials. They have failed to be supportive, and despite concerns about their flaws, they were developed by some of the best minds in our profession (including yours) and had millions of dollars devoted to them. I just feel that we cannot justify millions of people being prescribed a drug that has failed in two recent, large, prominent trials, which actually had signals of harm (we are awaiting more news about that from HPS2-THRIVE). A meta-analysis that leverages secondary outcomes is hardly strong evidence, particularly given that most of those studies were not in the modern era. Please continue to study strategies that will lower risk and help us find ways to help patients. But please do not say that we should ignore your multimillion-dollar NIH trial, especially after its findings have apparently been validated by a larger, multimillion-dollar industry trial.

Where do you come down in this debate? And stay tuned for for further insights on this topic from Peter P. Toth.

16 Responses to “Niacin Therapy in the Crossfire”

  1. Dan Hackam, MD PhD says:

    Judging my the lipid numbers presented, the patient has significant metabolic syndrome (although data points on BP, waist circumference, blood glucose/A1c/insulin, hsCRP and microalbuminuria were not presented). But assuming for the moment that the patient has metabolic syndrome (as 1 in 2 of us do), this patient needs intensive dietary counselling rather than a prescription for NA. I would agree with the need for atorva 80 mg/d and hope that all such patients would receive it.

    In terms of dietary counselling, where there is “smoke” there is “fire”. A patient with metabolic syndrome has by definition carbohydrate intolerance. They are already on the road to diabetes, heart disease, dementia, stroke (both hemorrhagic and ischemic) and epithelial malignancies. The first thing they need to do is cut back on their carbohydrate intake (especially simple and refined). I will tell them “no sugar, no flour”. I would also caution them on fruit intake, which in the modern era, has been cultivated to maximize fructose and minimize fiber content. I would caution them on consumption of other cereal grains such as rice, oats, quinoa, etc, and tell them not to eat potatoes or other starchy tubers. Once we do that, the rest is basically all minute details. You will see dramatic increases in HDL and drops in TRIGs without any need to resort to NA. As well, NA does not prevent diabetes, cancer or dementia, but most of these conditions are clearly related to the Western diet. Eat like an Easterner, not like a Westerner!

  2. The salutary effects of niacin on CV disease have been attributed to its excellent (theoretical) effect on the lipid profile, in spite of other disturbing metabolic abnormalities (glucose, uric acid…).
    On the other hand, the vasodilatory effects of niacin have been considered a nuisance… but we are using a variety of vasodilators (nitrates, Calcium channel antagonists…) precisely to treat or prevent cardiovascular complications. Is there a chance that some of the beneficial effects of niacin are indeed related to its vasodilatory properties?
    The negative results of the HPS-2 THRIVE trial may therefore relate to a variety of issues: 1) lack of effect on niacin after LDL control with statins; 2) unsalutary direct effects of laropiprant; 3) Laropiprant blunting of the beneficial vasodilation associated with niacin; 4) others; 5) a combination of the above.

    As we wait for the full report of HPS 2-THRIVE result a prudent approach may be: to withdraw niacin in patients with clear side effects; to keep niacin (±laropiprant) in patiens of high cardiovascular risk who tolerate it and remain with poor lipid control in spite of high statin dose.

  3. Jose Gros-Aymerich, MD says:

    An ethnic remark: you find some people in Spain having genetically determined very high HDL Cholesterol levels, around 80 mg/dl or more, and as far as I know, this doesn’t reduce their Cardio Vascular Risk, but the overall incidence of atherosclerotic CV problems is lower in Mediterranean countries than in the USA. Increasing HDL the way Niacine does may be just a lab. change, lacking any clinical signification, but Niacine is also very helpful in reducing total Cholesterol levels when added to an Statin therapy. Is in all cases the raising in HDL figures a metabolic change having direct influence on the CV Risk, or it’s a surrogate marker of something else? It was previously shown that even when it’s a marker of higher CV Risk, reducing the Homocysteine levels has no effect on the incidence of CV events, and the same can be said about high Uric acid levels, another marker of higher CV risk, but with no interest in being specifically decreased for the purpose of intervention on the CV Risk scores. I’m not a Cardiologist nor a Lipid Metabolism expert, so I may be wrong from the very beginning of the question. Salut +

  4. Stephen Austin, MD says:

    I completely agree with Dr. Krumholtz–It’s hard to ignore science, particularly in the context of “primun non nocere.” It would be of interest to know this hypothetical patient’s BMI–He would likely benefit more from a post MI cardiac rehabilitation program, including the aforementioned intensive dietary counseling, and weight reduction as necessary.

  5. Vikki Stefans, MD, MS says:

    I’m frustrated by the fact that nearly all current studies have assessed niacin and combinations with niacin *only in patients already on statins* where it not be expected to have a lot of additional effect.

    What are we supposed to use for evidence for the statin-intolerant? What are we supposed to use, period? (See the recent report that Tredaptive will not be introduced and may be withdarwn in Europe as well.) Something seems to be wrong with this, unless we all want to stay in denial that there are a significant number of people who cannot take statins.

  6. Robert Caulkins, DO says:

    for me there is no debate. Niacin on top of statin in patients with controlled LDL is useless and possibly harmful – until proven otherwise. In statin intolerant patients – and ones without metabolic syndrome (you have to move out of Kitsap County to find a single one) – Niacin can be used on the basis of CDP. Post MI patients with uncontrolled LDL on statins – probably as well, on the basis of HATS. This is kind of it…
    Most maddening to me is that these “book smart” people do not even see an elephant in the room (instead concentrating on tiny particles of HDL) – when discussing the patient. Dude has metabolic syndrome. He needs to get off sugar and starch and get off his ass. Unless he does it – no drug will help him (on top of statin). We came across statins, that indeed help patients post ACS – by accident. We still have no idea how they work. We first found they lower LDL (we had no other tools available to see what they are doing at that time – except for centrifuge for lipids). We built lipid theory on the basis of that random and probably irrelevant observation (fibrates, niacin, zetia, tropibs – all lower LDL but do not result in benfits). Well…statins still work – but the rest of the lipid theory – when put to test does not- fibrates, niaicn, Zetia, tropibs, fish oil – do not deliver consistent across the board results (like statins) despite “improving” lipid panel.
    Thus – outside statins – lifestyle modifications is the only responsible general prescription for high risk patients. In some very particular circumstances other lipid modifying drugs may be occasionally beneficial – but mostly not.

  7. Jean-Pierre Usdin, MD says:

    I think now we have definitly to stop with Niacin
    it is so badly tolerated, so ineffective even in high dosage, there is not anymore room for this product
    without speaking of the real effect of “upgrading” HDL C still deabated
    sincerely yours

  8. Neville Wilson, M.B., Ch.B., D.Fam. Med., M.Sc., D.Obs (COG) SA., B.A. says:

    It is not surprising that HDL would soon be labelled as “ugly” (Chagai), given the repeated failure to manufacture a safe pharmacological product that would effectively raise HDL-C levels.
    We cannot allow ourselves to lose sight of the evidence that low levels of HDL-C are predictive for major CVE, even in statin patients who have achieved target levels of LDL (70 ug/dl).
    The 39% lower risk of a major CVE associated with high levels of HDL-C(>55ug/dl)was significant in TNT and evident in LRC (mortality followup), CPPT & MRFIT, and the meta-analysis (TUFTS Med Centre) by Lavinge & Karas, JACC 2012, show a significant 34% reduction of the composite end points of CVE and 25% reduction in CHD.
    HDL-C is a complex lipoprotein with many fractions, amongst which are the small dense HDL3 which possess multiple anti-atherogenic properties, via E-Selectin and PON 1. Hyperfibrinoginaemia, a significant underlying factor in FH is associated with reduced levels of HDL2. The reverse transport pathway mediated by CETP is only one of several protective mechanisms provided by HDL.
    I agree entirely with Dan that the recommendation to lower dietary carbohydrate as a strategy to reduce the risk of METABOLIC SYNDROME and improve HDL levels naturally is a good one,and based on sound science and experimental evidence, and flies in the face of AHA recommendations to replace saturated fats with carbohydrates. The latter is a significant risk factor for Insulin resistance, raised TG, lowered HDL and Metabolic Syndrome.
    HPS2-THRIVE is unfortunately of questionable design, ignoring the independent effects of Niacin and laropiprant, and their possible cross reactions. A mix of products with opposing properties does not make for a good design, aggravated by the absence of a placebo group to measure the outcome differences.
    Keep the dietary processed carbohydrates to a minimum, include healthy dietary saturated fats, and note the natural improvement in TG reductions, HDL improvement, with a likely reduction in risk for morbidity and mortality. Do we need the drugs ?

  9. I’m afraid I have to disagree with some of the other comments. There is a long literature on the effectiveness of niacin, not just one recent study. My reading of that literature is that niacin is effective in raising HDL, whether or not the patient is also on a statin. I think we need to pay attention here to the overall literature, which, I think, says that niacin should continue to be used, because it is perhaps the most effective drug in raising HDL. The problem comes when you add laropiprant to the mix. It reduces or eliminates the niacin effect and will now, of course, no longer be used. Patients can be started on niacin alone in very small doses and gradually raised to effective doses, reducing or eliminating the flushing problem. As to increasing HDL, the other thing that, of course, is very helpful is regular, vigorous exercise.

  10. Neville Wilson, M.B., Ch.B., D.Fam. Med., M.Sc., D.Obs (COG) SA., B.A. says:

    I agree with Barry. Before the advent of Tredaptive I used Niacin (without a statin ) with good effect over many years, and see no reason to discontinue doing so. With the discontinuation of niacin plus laropiprant I will revert back to using niacin on its own, where indicated.

  11. Sergio Kaiser, M.D., PhD, F.A.C.C. says:

    My question is: does niacin on top of modern therapy for LDL reduction reduce residual risk? The answer: We don’t know! If we take into account the results from published meta-analyses like the one by Lavigne et al…Well,fibrates were also studied by meta-analyses already incorporating ACCORD (see the one by Lee M et al published in Atherosclerosis in 2011) and they also seem to reduce secondary endpoints with less undesirable effects. Unfortunately no metaregression was attempted for fibrates.

  12. Barry: could you detail the long list of outcomes studies that show that niacin provides benefit for patients on statins. And Neville – could you provide some support for your use of niacin, aside from its affect on the lipid profile. On what basis do you believe that for your patients who tolerate a statin, that the addition of niacin is worthwhile and that you can dismiss AIM-HIGH and HPS2-THRIVE – the 2 recent multimillion dollar, multi-center trials that were constructed by niacin advocates and designed to test whether niacin improves outcomes. I agree that there may be some situations where niacin could be beneficial – I am just hoping someone can find it – and in the meantime wonder why we should expose patients to a drug with 2 negative trials.

    • Sergio Kaiser, M.D., PhD, F.A.C.C. says:

      Perfect, dr. Krumholz, everyone hopes to find a winner for HDL-raising competition, but so far, there is too much fog in the air. Just by curiosity, does anyone feel more confortable in prescribing fenofibrate for those high-risk patients already on a statin, with HDL below 34 and TGL above 200?

  13. Judith Andersen, AB, MD says:

    I arrived late to the party with regard to registering end-of-the-year wishes, so can only add to the discord above. We are, I think, missing the point, when we expect specific drug, a.k.a. vitamin, fibrate or HMG-CoA reductase, interventions to prevent or undo the consequences of decades of behavioral malfeasance. Our interventions in these studies are layered upon multiple-drug regimens, including antihypertensives, hypoglycemics and lipid-lowering agents, and a veneer of poor advice. Niacin, as cardioprevention, was initially evaluated in a more innocent era, when most patients were not overweight, not taking 11 – 20 drugs — and may emerge as all the more powerful, because of that. Why are we asking one agent, obnoxious because it causes visible flushing, to redact the effects of decades of bad behavior? And why are we so willing to advocate multi-drug therapy when the really tough issue is to change behavior? Most of us — I haven’t see a single image of an obese Cardioexchange member — get the program. Can we not influence our patients’ behavior by strenuously advocating non-drug therapies like exercise and dietary discretion?

    Niacin is not cyanide. Its adverse effects are cosmetic, not lethal. And for many of our patients, too late to be useful. We know what the clinical issues are for our hypertensive, hyperglycemic, overweight patients, but we take the easy way out. We recommend, but do not enforce — and welcome the efforts of the pharmaceutical industry to provide products to decrease morbidity in an increasingly obese and morbid population. Let’s get tough. Drugs — and the clinical trials that promote their efficacy — are expensive. Dietary discretion and exercise are cheap — and hard to promote.

    Are we wimps? And are our patients slugs? Think about the 60″, 300 lb accountant who has angina and needs VTE prophylaxis for knee replacement, because she can’t exercise with her “bad” knee (she has never exercised before); the still-smoking executive for whom a green vegetable is unrecognizable and needs coronary artery intervention. Niacin and other B-vitamins, statins, and diuretics and antihypertensives are likely helpful in folks who are already diseased from dietary and behavioral malfeasance, but can’t we turn the tide? Making dietary and exercise interventions obligatory parts of a care plan, reserving drug interventions for those few whose heredity makes such intervention necessary?

    Folks elsewhere in the world, where walking to a destination is encouraged by geography, don’t need the interventions we prescribe. Why can we not be the force for change in this regard, rather than the prescribers of the most recently vetted “corrective” agent, after the fact and helpful but not life-changing. Walking is still an option in many locales, and an intelligent impassioned recommendation from a physician as to how walking can be safe and health-promoting (mall, down-town, suburbia, etc) can be a powerful force for compliance.

    Our patients ask a great deal of us: “Doctor, can’t you help me with this?” We don’t ask enough of our patients. I have no animus toward pharma — it is fueled by our failure — and does provide us options for those for whom no functional intervention is possible. But our tolerance for the life-styles we take for granted in our patients, but not for ourselves — is the culprit. We should routinely demand things for our patients (that we now don’t even consider because we are accustomed to and compliant with the multidrug regimens they present to us): exercise, dietary discretion, deliberate weight loss, etc.

    I’ll step down off my soap-box, but I grieve for those who take 20 of the most vetted drugs and have no real well-being to show for it. I put my money where my mouth is: in Detroit, where an iceberg lettuce leaf on a Big Mac is regarded as a daily vegetable requirement, as are french fries, it is an uphill battle, but we are dedicated to fighting it — and, on occasion, winning.

    • Dan Hackam, MD PhD says:

      Kudos to you, Dr Andersen. Kudos. I am getting to the point where I am telling patients that I am not going to add another (tenth) medication to regress their plaque – they will have to do it themselves.

      I do I hope we do not just mouth the nearly useless advice to “eat less, exercise more”, “take smaller portions”, etc, as what is more helpful is to change macronutrient distribution in the diet, particularly away from processed foods, fast foods, refined and simple carbohydrates such as sugar, fructose and so-called “enriched” flour (which is anything but). I have created a 14 page handout on nutrition for my patients to follow, with foods that they can buy at the local grocer.

      I have seen dramatic improvements in cardiovascular and metabolic health with this approach – far better than when I was in the usual, “tsk tsk” mode of “eat less, move more” (which is unhelpful and only aggravates the mood of our dysmetabolic patients).

      One problem I see is that people can easily get locked into taking multiple medications which may then harm them when you effectively modify their diet — meaning side effects of hypoglycemia (for those on hypoglycemic agents), hyponatremia or hypotension (for those on diuretics), etc. Effective dietary modification really requires reducing the burden of pharmacological modification so that there is no double-additive effects. We do not want blood sugars and blood pressures dropping through the floor.

  14. Stephen Hansen, md says:

    Yes,exercise more,eat less, dump niacin.