Case-Based Evidence for Cardiovascular Risk Reduction - Episode 12
Deepak Bhatt, MD, MPH: There was a press release stating that the STRENGTH trial—a cardiovascular outcome trial with a particular type of omega-3 fatty acid mixture of EPA [eicosapentaenoic acid] and DHA [docosahexaenoic acid] at a high dose of 4 g per day—was stopped because it did not indicate a high likelihood of benefit. Matt, do you have any thoughts about why that is? Of course, that’s a different drug from what was studied in the REDUCE-IT trial, which was 4 g per day of a highly purified ethyl ester EPA, icosapent ethyl. It’s essentially a different drug, but a high dose of an EPA-DHA mixture. Why didn’t it provide a significant benefit?
Matthew J. Budoff, MD, FACC, FAHA: The difference was that the STRENGTH trial was larger and had a higher-risk population than the REDUCE-IT trial, which also used 4 g of a combination of DHA-EPA this time. I believe DHA has an adverse effect on our LDL [low-density lipoprotein] and likely is not the best cardiovascular protective therapy. We have seen that from a lot of the smaller trials, and STRENGTH is proof of that concept because there are no other great reasons based on study design or dose of therapy being given.
It’s a 13,000-person trial, so it was more than 50% larger than REDUCE-IT. It should have had the power to show a benefit if there was going to be a benefit from a combination of an EPA-DHA product. Additionally, as Preston Mason and Harvard Medical School have shown several times, the effect of DHA is significantly different from EPA or icosapent ethyl on the lipid membrane.
Deepak Bhatt, MD, MPH: That’s a great explanation. We’ll see what the trial shows when it’s presented ultimately. Matt, what are you excited about in this therapeutic area? We have talked about bempedoic acid, but what else are you interested in?
Matthew J. Budoff, MD, FACC, FAHA: I share Jamie’s enthusiasm with all the new studies that are coming out now. It’s really an exciting time in lipids. Moreover, we talked about bempedoic acid, specifically pemafibrate, which is being studied in the PROMINENT trial, a large outcome study looking at a new fibrate for patients with high triglycerides and low HDL [high-density lipoprotein], which may be an improved targeted population for fibrates.
Perhaps that will be the first of the fibrates to show real cardiovascular benefit in the age of statins. There is inclisiran, possibly the next generation of PCSK9 inhibition, working at a 3- to 6-month interval rather than twice a month or monthly injections. Of course, like bempedoic acid, the outcome study is several years away so we will have to wait to see how well inclisiran works when it is available. Additionally, the price point of inclisiran will also be of great interest as we see how that is introduced to the market. Finally, the last thing I am excited about in the lipid world—and I would love to hear more from others regarding this topic—is the antisense therapies coming out for LP(a) [lipoprotein(a)].
We previously spoke of the benefits of PCSK9 inhibition on lowering LP(a) by 30%, 35%. These antisense therapies look as though they’re going to lower LP(a) by up to 80%. For patients with isolated elevations of lipoprotein(a), this is potentially a great new therapy for them as a targeted population.
Deepak Bhatt, MD, MPH: Yes, that’s good thinking. Bob, what are you excited about as far as emerging therapies? Specifically, it doesn’t have to just be in the lipid space. It can be in the diabetes space too.
Robert Busch, MD: All the drugs that Matt had mentioned excite me as well. In the diabetes space there are the GLP1-GIPs, which are a combination of the GIP and GLP1 receptor agonists. These drugs have better weight-loss effects and compare very favorably with semaglutide, which are best in class for A1C [glycated hemoglobin] and weight. The oral semaglutide has a big cardiovascular trial for MI [myocardial infarction] stroke deaths, so that will be exciting as an oral agent, besides the SGLT2 inhibitors that might lower heart disease with the combinations of SGLT2s and GLP1 agonists. Regarding having more of our cardiologists widely embrace these drugs, it’s 1 thing to put it in that note, but it’s another thing to write it. Writing that these drugs don’t cause hypoglycemia will teach you the dose of Diflucan [fluconazole] to treat yeast infections if you aren’t comfortable with it, but just do it. These drugs are phenomenal, and we get all the hugs. You could get the hugs too if your patients lose weight and drop some of their other drugs for diabetes as well.
Deepak Bhatt, MD, MPH: Yes, we could use some hugs in cardiology. How bad an issue is the infection you mentioned earlier regarding the fungal infections?
Robert Busch, MD: Choose the appropriate patient. It may not be the 1 woman who’s had 5 yeast infections and comes into you on an antibiotic, or an uncircumcised size man who was at balanitis. You must choose the right patient. The same goes with frequent urination: If you have a man with BPH [benign prostatic hyperplasia] who is urinating every hour at night that is not a great patient to give an SGLT2 inhibitor. Perhaps, you could sneak it in every other day or every third day in the beginning and then get it on board? As a result, many of your colleagues are starting to put it in the note, which is great.
Some don’t because they do not want to step on the primary care physician’s toes. I use PCSK9 inhibitors as much as all of you do. In fact, if my patients aren’t an injectable, there is no injectable objection that the patient must giving an injectable because they’re already on injectables. As such, I have no problem writing the lipid drugs in the beyond-lipid therapy or beyond-LDL therapy for my patients, just as cardiologists should have no problem writing these drugs either.
Deepak Bhatt, MD, MPH: Those are great points. I believe there really is a need for more education in the cardiology community to really gain comfort with SGLT2 inhibitors. Although with the heart failure data that are coming out, that comfort is going to grow rapidly with SGLT2 inhibitors. Regarding the GLP1 agonists, having oral availability might change their perception and utilization for the better. Brett, is there anything you’re particularly excited about in terms of emerging therapies in this space?
Brett Nowlan, MD, FACC, RPVI: Most of what I’m interested in and what I have been keeping my eye on has been mentioned. Again, I’m someone that follows lipoprotein(a) levels in all my patients. I have some patients who have tremendously elevated numbers. In fact, I have some patients who even supersede the range that the lab I send to measures at somewhere up there in the stratosphere. There is very little we can offer these patients right now. We have patients currently on antiplatelet therapy.
I try to get them on PCSK9 inhibitors, but it’s not very much. What is also very intriguing about these antisense agents, and the lowering of LP(a), is that they might also give us the first medical therapy as a prevention against aortic stenosis. A whole fascinating idea came up from that analysis of the FOURIER data, that there was a separation of curves after a year of aortic stenosis events.
This was lowering that LP(a) by 20% to 30%. If we had an agent that was lowering 80% plus and doing it persistently, we might be in a whole different realm when it comes to aortic stenosis and being able to prevent aortic stenosis, which is very fascinating to me right now.
Deepak Bhatt, MD, MPH: Well, terrific.
Transcript Edited for Clarity