November 12th, 2014
Newly Identified Mutations Act Like a Lifetime of Treatment with Ezetimibe
Larry Husten, PHD
A very large genetic study published in the New England Journal of Medicine offers compelling evidence in support of a central role for LDL cholesterol in coronary heart disease.
In a series of studies analyzing blood samples from nearly 100,000 people, Sekar Kathiresan and colleagues identified 15 rare mutations that block the activity of a single gene — called Niemann-Pick C1-Like 1 (NPC1L1). The mean LDL level was 12 mg/dL lower in mutation carriers than noncarriers. There were just 11 carriers of the mutations among 29,954 people with CHD versus 71 carriers among 83,140 people without known CHD (carrier frequency: 0.04% vs. 0.09%). This worked out to a 53% reduction in CHD risk for mutation carriers.
NPC1L1 is the same gene that is blocked by the cholesterol-lowering drug ezetimibe, and the researchers believe that the newly identified mutations may produce an effect that would be similar to a lifetime of ezetimibe treatment. Ezetimibe is the controversial drug being tested in the soon-to-be-revealed IMPROVE-IT trial. But the new genetic study is unable to answer whether the relatively short-term impact of drug treatment is able to deliver benefits that are comparable to the lifelong effects of the genetic mutations observed in the study.
James Stein, the Director of Preventive Cardiology at the University of Wisconsin Hospital and Clinics, offered the following comment about the paper:
I think this is expected and gets to the often forgotten or at least confused point, that lower LDL-C is better. If you can lower LDL-C safely for a long enough amount of time, you will have less CHD events. This mutation is associated with lower LDL-C and even a modest reduction in LDL-C like seen here– when considered over a lifetime– will reduce risk of coronary heart disease. Though the pleiotropic effects of statins are an interesting and a sexy topic, I always have thought that their main effect is lowering atherogenic lipoproteins (mainly LDL). Indeed, many of the so-called “pleiotropic” effects may be a direct effect of lowering LDL.
What does this say for ezetimbe? If it is safe, its long term use likely will reduce CHD risk. It is unclear if any of our current studies will be adequate to test that. I am looking forward to seeing the results of IMPROVE-IT, but its results won’t really have any effect on the findings of this study or the fundamental truth that lower LDL means less CHD risk.
Echoing Stein’s perspective, Kathiresan offered the following comment:
One of the key concepts here is that it may not be “how you lower LDL” or “how low you take LDL” but rather “how long the LDL is lowered.” We should think about LDL like we do smoking. Smoking is typically quantified as “pack-years”, a product of the number of years smoked times the number of packs per day. The concept to stress may be “LDL-years”.
15 Responses to “Newly Identified Mutations Act Like a Lifetime of Treatment with Ezetimibe”
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This is an excellent study by an exception research group, but it should be clear that this study has no relevance to clinical practice. It is helpful in directing next step research – but in its own right is not germane to decisions being made today.
While this superb study does not have immediate relevance to clinical practice, it can provide a good pathophysiologic explanation for the possible success of ezetimibe in the IMPROVE-IT trial, if indeed it led to a positive clinical outcome. Based on this NEJM paper, I am now much more optimistic that ezetimibe and similar drugs in the pipeline will lower CVD events; hopefully, we will not see any noncardiovascular adverse efforts that outweigh the favorable reduction in CVD events. We should know the answer by 12:30 PM on Monday! IMPROVE-IT may have important implications for the update of the 2013 Cholesterol Treatment Guidelines.
Roger S. Blumenthal
Mendelian randomization studies have already shown that the lifetime reduction of cholesterol levels by a variety of genes produce about double protection as compared to equivalent cholesterol reduction achieved in statin trials (J Am Coll Cardiol. 2012;. doi:10.1016/j.jacc.2012.09.017). The extraordinary reduction of risk described associated with NPC1L1 variants is surprisingly even higher. While this finding lends support to the potential benefits of inhibitors of NPC1L1 activity with drugs such as ezetimibe, the actual risk-benefit ratio can only be demonstrated by appropriate clinical trials. If the IMPROVE-IT trial offers protective CV effects in agreement with genetic studies the lipid theory of atheroscleosis will be back with us with renewed strength.
Carlos: I couldn’t agree more. And what I think is important about this study is that even if IMPROVE-IT is negative, it still may be promising to investigate drugs that block NPC1L1.
I think this study provides reassuring data that lifetime of lower LDL whether from NPC1L1 (also true with PCSK9 gene variants) is associated with lower cardiovascular risk of a magnitude likely higher than drug induced LDL lowering in middle age ; this augers well for Ezetimibe would be my educated guess.
Although I share Dr. Blumenthal’s admiration for Dr. Krumholz, I disagree that “this study has no relevance to clinical practice”. Dr. Krumholz seems determined to prevent us from seeing any potential evidence for clinical benefit from ezetimibe (although it is an NPC1L1 inhibitor). Yes, genetic mutations are quite different from drug interventions, but as Dr. Blumenthal implies, the favorable CHD outcomes in this study do indeed have clinical implications for the drug, since it shares its main MoA with the mutations in the study. In making therapeutic decisions clinicians should always consider the mechanism by which a medication works, instead of limiting themselves exclusively to results of clinical trials, as Dr Krumholz appears to imply.
Unfortunately, the IMPROVE-IT trial is not likely to provide much clinically relevant information regarding CVD effects of ezetimibe, because, ironically, trial subjects were generally selected NOT to need the study drug! (Estimated mean on-treatment LDL-C is about 66 mg/dL.) Instead, as noted by Dr. Blumenthal, IMPROVE-IT does promise to provide key safety data for ezetimibe beyond that which can be inferred from this genetic study.
I am hopeful as well that IMPROVE-IT will be positive. And this study supports the investigation of these types of drugs. My point is that while this study provides a rationale to investigate these drugs and should give us cause for optimism, it is silent on whether any particular drug can produce a benefit for patients. It would be a mistake to take this evidence as an endorsement of any drug – it is a study to influence our choices about drug development – help us determine what drugs to test. Whether ezetimibe is worthy of the $4b in annual sales is not known – we will learn more soon. I certainly would like another drug that has trial evidence that it can reduce risk. It is the trial evidence that is necessary to know if a drug is effective.
Yes, we are spending nearly $2 Billion per year on ezetimibe, a drug for which we STILL don’t have definitive proof of CVD efficacy. Yes, the optimal use of genetic data such as the NPC1L1 mutation study is for drug development of new drugs.
That being said, don’t clinicians need to treat with best evidence regarding available treatments, rather than waiting for final proof or new drug development? Few if any lipidologists withheld statins from our patients during the many years we waited for the first clinical trial proof of their CVD benefit. If it was ok at that time to use statins to lower LDL-C to goal (as adjuncts to sequestrants and niacin), is it not ok today to use ezetimibe as second-line cholesterol meds (in patients for whom statins are insufficient or not tolerated)? If IMPROVE-IT is compatible with ezetimibe benefit, I believe we can continue to use it, even if (due to poor design) the trial falls short of proving the case. The perfect should not be the enemy of the good.
The purity of the genetic studies can not be compared to a clinical trial, such as IMPROVE IT which biases, flaws and potential analysis, are multiple.
I believe that if the IMPROVE IT gives positive results, it will add and give great information.
But if the result is NOT positive, in any way call into question the lipid theory of atherosclerosis.
I am stunned to think anyone would attach meaning to differences in carrier rates of 0.04% and 0.09%.
Is this a reflection of the unreal world we have constructed for ourselves or just kinkiness on the part of some residents.
From a hard outcome standpoint, I found the SHARP trial informative and don’t think it gets enough attention. While the control group was placebo, not statin monotherapy, simvastatin 20 mg plus ezetimibe 10 mg yielded an average LDL-C reduction of 0.85 mmol/L and corresponding 17% relative reduction in major atherosclerotic CVD events. This is on par with the effects expected from a statin-only regimen of equivalent LDL-C lowering efficacy – CTT data show that statin therapy reduces the relative risk of major atheroclerotic CVD events by ~20% per 1 mmol/L LDL-C reduction. Will IMPROVE-IT match up? We’ll find out in a couple hours!
Obviously both the authors and their reviewers have forgotten the results from the ENHANCE trial where the same method was used as in IMPROVE-IT in patients with familiar hypercholesterolemia (1). Although cholesterol was 26% higher in the simvastatin-only group, the outcome was better.
I disagree with the idea that Mendelian randomization have shown that LDL causes CVD. Other, more beneficial genes may be present on the same gene. Association is not the same as causatioon
1. Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43.
Sorry, I meant of course:” Other less beneficial genes”
Even if we buy, hook, line and sinker, the results and the Sponsor’s and investigators’ conclusions it remains that 2 ‘large’ trials comparing low and high doses of S had failed to demonstrate that the large doses had better clinical benefits than the low dose in spite of the much larger reduction in LDL-C with the high dose.
These 2 trials are A to Z (nearly 5000 with ACS) and SEARCH (about 12,000 survivors of an MI). The LDL-C in A to Z was reduced by 27 and 41%, respectively, while in SEARCH the mean baseline LDL-C at the end of a simvastatin 20 mg run-in period was reduced by a further 35 mmol/l in the 80 mg dose group.
Guy
Sorry, my remark concerned the results of IMPROVE-IT and was not related to the those of on the gene acting like ezetimibe.
G