Commentary on Niacin’s Effect on Lp(a) in AIM HIGH
In 2013 we have already published two commentaries on niacin (Commentary on Niacin vs Ezetimibe as add on to Statin) and (Examination of the Recently Announced Preliminary Results of the HPS2-THRIVE Study), specifically extended release available as Niaspan, a seemingly potent lipid- and lipoprotein-modulating drug that dates back to the 1960’s. Initially it was used to reduce elevated cholesterol levels but eventually it was found to also raise HDL-C which for a variety of reasons was assumed to be very desirable (thought being that if low HDL-C is a strong CV risk factor, then raising it must be beneficial). Also of interest was niacin’s ability to significantly reduce lipoprotein (a) mass [Lp(a)]. Indeed, a group entitled European Atherosclerosis Society Consensus Panel issued a statement strongly advising niacin be used for CV benefits in patients with elevated Lp(a) [1]. Interestingly that panel noted there was virtually no clinical trial support for this recommendation other than the fact that niacin does indeed reduce Lp(a) mass. Most lipidologists agreed with the belief that even if reducing Lp(a) does not matter, niacin would at least reduce apolipoprotein B (apoB) which is seemingly always desirable. NCEP ATP-III simply advocated achieving LDL-C goals in persons with risk related to Lp(a) issues.
Recent trials [The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM HIGH) and large Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events (HPS THRIVE 2)] have not shown additional event reduction in well-treated patients with stable CHD related to adding niacin to a statin or statin/ezetimibe regimen [2,3]. To say the results of those studies were a shock to the lipidology community is an understatement. AIM HIGH (all of the patients had low HDL-C at baseline) was published first and for those who believed niacin’s benefit was related to raising HDL-C, the results were a punch to the jaw. Despite a substantial (25%) HDL-C increase (remember the old well accepted but never proven caveat that for every 1% rise in HDL-C there is a 3% event reduction) there was no CV outcome improvement. The usual side effects associated with niacin were present including a questionable nonsignificant rise in ischemic stroke. Then along came the still not published HPS THRIVE 2 (baseline HDL-C was not an enrollment criteria) where again the addition of niacin to a statin or statin/ezetimibe regimen provided no additional outcome benefit. Common to both AIM HIGH and HPS THRIVE 2 was the fact that the lifestyle with statin or statin/ezetimibe had normalized LDL-C, non-HDL-C and apoB. Thus niacin was being added to patients who were at those goals (keeping in mind that there is no NCEP ATP-III goal for HDL-C). Should we really have expected niacin, whose primary mechanism of action is to lower apoB (or its lipid surrogates) to do anything to CV events in persons with normal apoB? The answer is yes if raising HDL-C or lowering Lp(a) mass is critical to event reduction (well accepted concepts that have never ever been proven in any type of trial). Well we may have those answers now and at this point one has to reasonably conclude the evidence is strong that in patients on LDL-receptor inducing drugs (statins or statin + ezetimibe) raising HDL-C (note – niacin also raises apoA-I, but not apoA-II or total HDL-P) [4] or reducing Lp(a) mass with niacin provides no benefit in folks who are at apoB (LDL-C, non-HDL-C) goal.
In AIM HIGH baseline apoB and apoA-I levels were low and baseline Lp(a) was elevated at 33.8 nmol/L [using Caucasian adult data from Framingham as a comparator, Lp(a) averaged 20 nmol/L]. Nearly 30% of AIM HIGH patients had severe Lp(a) elevations > 100 nmol/L compared to 20% of Framingham cohort. The addition of niacin to statin or statin + ezetimibe raised HDL-C by 25%, apoA-I by 7% and reduced LDL-C by 12%, TG by 30% and apoB by 13%. [5]
Lp(a) as expected was significantly associated with CV events despite the fact that LDL-C was at goal and thus elevated Lp(a) is associated with residual risk. A one standard deviation of Lp(a) was associated with a 21% increase in CV risk. There was a 21% overall reduction [but with a 20%, 39% and incredible 64% decreases in patients at the 50th, 75th and 90th percentile cut points] in Lp(a) in the niacin group compared to 6% in placebo group. So the higher the Lp(a) level, the more dramatic was niacin’s ability to lower it. Here is the shocker: there was no difference in event rate between those on or not on niacin (remember all were statin or statin + ezetimibe) DESPITE GREATER DECREASES in Lp(a) for those using niacin. Even in those in the highest Lp(a) quartile (> 125 nmol/L) there was no reduction in events when niacin was added.
So where do we stand with niacin? There is no level one evidence anywhere supporting the use of niacin to reduce clinical events: The Coronary Drug Project (CDP) is often quoted as proof of niacin’s efficacy but few realize that niacin monotherapy (high dose of immediate release preparation) had no impact on the primary endpoint of the study (mortality): thus the benefit of reducing non-fatal myocardial infarction (a secondary endpoint) makes this benefit hypothesis generating [6].Of course there is the famous 15 year follow up of CDP which encompassed 6 years of the trial where niacin was used and then a subsequent 9 year period off niacin. Mortality was significantly reduced in that post hoc analysis (data derived not from examination or in person review but questionnaires sent to participants): this is the weakest data imaginable [7]. So this supposedly late benefit of niacin is in fact analysis of post hoc follow data up from a trial where niacin failed to reduce the primary endpoint. If niacin was a new drug, it would have no prayer of gaining FDA approval based on the CDP. Several subsequent trials using angiographic or CIMT endpoints showed niacin monotherapy or combination with bile acid sequestrants or statins showed imaging benefit. One small (~500 patients) open-label outcome trial (Stockholm Ischemic Heart Disease Secondary Prevention Trial), combining clofibrate and IR niacin did reduce clinical events with statistical significance [8].
In my opinion niacin became a major lipid drug because of its ability to raise HDL-C and to lower Lp(a) and not for what is likely its real mechanism of action, namely lowering LDL-C and apoB and LDL-P. After extended-release niacin (Niaspan) hit the market, it was also heavily promoted because of its ability to increase both HDL and LDL size. KOS made a fortune by promulgating those messages as it seemingly made so much sense. Of course over time, we have learned that influencing LDL or HDL particle size or raising HDL-C and apoA-I has no effect on outcomes. Looking at lipid/lipoprotein risk factors in 2013 the outcome evidence only supports lowering apoB (LDL-P) or perhaps raising total HDL-P. At this time unfortunately, there is no support for reducing Lp(a) with niacin: admittedly the Lp(a) data from the much larger HPS THRIVE 2 study of 25,000 patients is pending.
So is niacin a dead drug? Here are my thoughts as a clinical lipidologist: We must get apoB (LDL-P) to goal in all at-risk patients. Lifestyle therapies and statins are the mainstay of therapy. However residual risk is high if apoB (LDL) remains elevated despite at-goal LDL-C, non-HDL-C), any level of HDL-C or if Lp(a) mass is elevated. So I would have no hesitancy in adding niacin to high and very high risk patients who have not achieved apoB (LDL-P) goals with whatever therapies they are using or using niacin as a monotherapy in those intolerant of other apoB lowering meds. Data from HPS THRIVE 2 (discussed in a recent commentary [ADD LINK]) suggested statin plus ezetimibe was better at event reduction than statin plus niacin [9]. In view of that and the very significant side effects reported in HPS THRIVE 2 [bleeding (GI, intracranial, other) in the niacin group: 326 (2.5%) to 238 (1.9%) and infection 1031(8%) to 853 (6.6%)] [3] makes niacin a tertiary or quaternary add-on drug (some may prefer the bile acid sequestrant colesevelam as an apoB lowering medication).
What about our patients with elevated Lp(a) mass or Lp(a)-P? The only therapy that has so far shown an inkling of success is LDL apheresis. For now we should all try to lower apoB (LDL-P as aggressively as possible and that often requires multiple combination therapies. What about future drugs: just published is the data the PCSK9 monoclonal antibody AMG 145 reduces Lp(a) by 32% in patients on statins [10]. There is also promising data that the remaining CETP inhibitors also reduce Lp(a) but the reality is that until such reductions by these drugs are linked to outcome benefit they are of hypothetical interest. Hopefully in the future there will also be development of an apoprotein (a) antisense oligonucleotide inhibitor.
References:
[2] The AIM-HIGH Investigators Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. N Engl J Med 2011;365:2255-67.
[3] Presentation by Jane Armitage on behalf of the HPS2 THRIVE group to the National Lipid Association Annual Scientific sessions, Las Vegas NV June 2013.
[6] Coronary Drug project group. Clofibrate and Niacin in Coronary Heart Disease. JAMA 1975;231:360-381.
[7] Fifteen Year Mortality in Coronary Drug Project Patients: Long Term Benefit with Niacin. JACC 1986;8:1245-55.
[8] Reduction of Mortality in the Stockholm Ischaemic Heart Disease Secondary prevention Study by Combined Treatment with Clofibrate and Nicotinic Acid. Acta Med Scand 1988;223:405-418.[9] Masana, A. Cabré, N. Plana. HPS2-THRIVE results: Bad for niacin/laropiprant, good for ezetimibe? Atherosclerosis 2013;229:449-450.
=================================================================================================
Read the complete article here.
No comments:
Post a Comment
I appreciate appropriate comments but reserve the right to publish those with credible, verifiable, significant information to contribute to the topic at hand. I will not post comments with commercial content nor those containing personal attacks. Thank You.