PracticeUpdate Diabetes June 2019

EXPERT OPINION 12

New Data and New Concepts in Managing Triglycerides Interview with Peter Libby MD by Aman Shah MD

Dr. Libby is Mallinckrodt Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

Dr. Shah: It seems like triglycerides are making a comeback. They seem to be a little bit more important than we thought they were. What is the state of the data on this? Dr. Libby: Well, there’s a very interesting story about medical thought and how we tend to be like the little kids on the soccer field following the ball. There was abso- lutely consistent and compelling evidence that high-density lipoprotein, good choles- terol, HDL, was protective. And we spent years and years chasing after HDL as a therapeutic target in the firm belief that it was protective, based on observational data. Meanwhile, we know that HDL and triglycerides tend to vary inversely – the higher your triglycerides, the lower your HDL. And when the epidemiology commu- nity would take triglyceride concentration and look at cardiovascular outcomes, yes, there was a relationship, but they adjusted it for the HDL. And that attenuated the risk, and even if you adjust for non-HDL choles- terol, you flatten the risk. So people have, for generations, discarded triglycerides as a causal risk factor and that has really undergone quite a change recently. Dr. Shah: That’s interesting. But on the other hand, it seems like omega-3 fatty acids, which could have been addressing the triglycerides, have caught on with the general public, but

at the AHA (American Heart Association Scientific Sessions) of the REDUCE-IT trial, which caused us to stand up to attention because there was a 25% reduction to the primary endpoint with 4 g a day of eicosapentaenoic acid. Not the stuff you get at the nutrition store, at the supplement store, but a pharmaceutical grade that is quality controlled, assayed, and purified. Dr. Shah: So, was that the difference? Because previous studies did not quite show clear evi- dence omega-3 fatty acids working for triglycerides. So, was it the increased dose, was it the pharmaceutical grade, category of this agent, or what was the difference in this study that showed such a dramatic benefit versus previous ones? Dr. Libby: Well, I think it’s a matter of dose, by and large, because a lot of the previous studies used much lower doses like 1 g a day. The only study that was positive was the JELIS study performed in Japan, where they already have a high fish intake and they used 1.7 g of eicosapentaenoic acid. So, I think that was the dose in the JELIS trial, which was positive. And you know the VITAL study, which our colleague JoAnn Manson presented at the same meeting at the AHA in 2018, used a much lower dose of omega-3 fatty acids and did not show a cardiovascular benefit, at least in the primary

there wasn’t a scientific consensus on what these agents do. So, has that picture changed? Dr. Libby: Well, you know, we bet a lot on the HDL side of that teeter-totter. And what’s come out in the last few years, based on human genetics and a re-evaluation of the observational epidemiology, based on the consistent failure of interventions that raise HDL to improve cardiovascular outcomes, we’ve really undergone a revi- sion, or at least I have, where the human genetic evidence, which has cast doubt on the protective effect of HDL, has become ever more strong in support of triglycer- ide-rich lipoproteins as a causal risk factor for atherothrombotic events. Now, triglyc- erides what we get on the lab slip is just a biomarker for a class of lipoprotein parti- cles known as triglyceride-rich lipoproteins or remnant lipoproteins. I like to call them TGRL, triglyceride-rich lipoproteins. And there’s really compelling evidence, I won’t go into here, based on some terrific human genetics, that those particles are causal in atherothrombosis giving us a new therapeutic target, which is the TGRLs, rather than trying to raise the HDL. You bring up omega-3 fatty acids, which do decrease the triglyceride-rich lipoproteins. And we got a real boost to the idea that this would have clinical payoff with the presentation by Deepak Bhatt in November of 2018

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