PracticeUpdate Diabetes June 2019

EXPERT OPINION 13

" …we’ve really undergone a revision, or at least I have, where the human genetic evidence, which has cast

Dr. Shah: Yes. Dr. Libby: But we’re, again, at an exciting threshold. It looks like triglyceride-rich lipo- proteins are causal for atherothrombosis, and HDL raising has proven disappointing, but it’s been maybe replaced or supplanted by triglycerides. And we are getting clini- cally actionable because we have omega-3 fatty acids and perhaps other agents, which will allow us to attack triglycerides and improve patient outcomes. Dr. Shah: So, what’s the adverse event profile of these agents? Is it a concern then that if dosages are, say, 4 g, that you should not be using them inmore patients than just the ones who have extremely high triglyceride levels? Dr. Libby: Well, I think we have to go by the entry criteria of the REDUCE-IT trial, which did focus on individuals who have increased cardiovascular risks and who had increased triglyceride concentra- tions. But the safety profile looked pretty good. There was not an enormous bleed- ing risk price you had to pay and the only signal, which I think we need to keep our eye on, was really to me paradoxical, an increase in incident atrial fibrillation. Now, whether that’s a play of chance or it’s real, we’ll find out. But it’s interesting that in REDUCE-IT, there was not an increase in ischemic stroke. And you know, I would think if we were pushing people into atrial fibrillation, we might see a signal in terms of ischemic stroke, which the investigators, led by Deepak Bhatt and Gabriel Steg, did not see. So, very exciting times. It looks like it’s tolerable and efficacious. And it’s another tool in our bag of tricks to try to improve our patients outcomes. as a causal risk factor for atherothrombotic events. " doubt on the protective effect of HDL, has become ever more strong in support of triglyceride-rich lipoproteins

and they actually have a label today from the FDA for extreme hypertriglyceridemia above 500 mg/dL puts you at risk for pancreatitis. So, we can write on label for these omega-3 fatty acid preparations for the triglycerides above 500. But it’s really exciting because there’s also an anti-inflammatory effect, so maybe this intervention is working through mixed mechanisms. A decrease in triglyc- eride-rich lipoproteins and a decrease in inflammation. Now, those twomay be related. It’s little appreciated that LDL, low-density lipoprotein, bad cholesterol, is actually only weakly pro-inflammatory, as gauged by, say, a measurement of C-reactive protein, our biomarker of inflammation. Whereas triglyc- eride-rich lipoproteins consistently show a much greater slope in that relationship as shown by the work of Børge Nordestgaard and I think Anette Varbo and others. Dr. Shah: And I believe you’ve done work on that too. Dr. Libby: Yeah. Well, you know, I’m just a spectator in the triglyceride field, although we’re doing another trial right now with Dr. Ridker and Dr. Aruna Pradhan, which is called PROMINENT. Which is taking another shot on the role of lowering triglycerides and other effects with a selective PPAR-alpha modulating agent known as pemafibrate. The trial is PROMINENT and I’d love to come back and talk about it some other time.

endpoint. So, what we have today is evi- dence that a high dose, 4 g a day, 2 g b.i.d, of a purified grade of eicosapentaenoic acid, icosapent ethyl is the pharmaceutical name, is beneficial. And at this meeting, we’re at the ACC (American College of Cardiology) meeting in March of 2019 in New Orleans, Dr. Bhatt is going to present some more data on sub- sequent follow-on analyses, which I think will reinforce this idea. I don’t know the answers because he hasn’t presented it yet, but stay tuned. Now, we’re very fortunate because there is another properly designed trial with another pharmaceutical grade omega-3 fatty acid preparation and that is the STRENGTH trial, which will not report out maybe until 2020 or maybe even beyond, but that’s using a different mix of omega-3 fatty acids. It’s using a mixture of eicosapentaenoic acid and docosahexaenoic acid, two fish oil- derived omega-3 fatty acids. So, it’ll be very interesting to see the results of that trial comparing with REDUCE-IT. So, we’re on a very exciting time. Dr. Shah: That is interesting. Dr. Libby: And I would hasten to say that we don’t know the mechanism of the ben- efit seen in the REDUCE-IT trial. Yes, the omega-3 fatty acids do lower triglycerides

Dr. Shah is Executive Publisher, Online Content at Elsevier.

Go to www.practiceupdate.com/c/81213 to watch this interview with Dr. Libby.

VOL. 3 • NO. 2 • 2019