November 12th, 2014
Newly Identified Mutations Act Like a Lifetime of Treatment with Ezetimibe
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”.