COMMENTARY

SGLT2 Inhibitors to Prevent HF: Time to Get More Proactive?

Interviewer: Ileana L. Piña, MD, MPH; Interviewee: Javed Butler, MD, MPH, MBA

Disclosures

February 04, 2019

Ileana L. Piña, MD, MPH: Hello. I am Ileana Piña, from Albert Einstein College of Medicine and Montefiore Medical Center. I am here at the American Heart Association (AHA) Scientific Sessions in Chicago. I often use this opportunity to do some of my blogs because I have some excellent faculty accessible to me, and we can discuss some really important issues.

Today, I want to welcome my friend Javed Butler, who is now the chair of medicine in Jackson, Mississippi, after having left us in New York recently. I congratulate him on this new position.

Javed Butler, MD, MPH, MBA: Thank you very much. Great to be here.

Reducing Heart Failure Risk in Patients With Diabetes

Piña: You are playing a very important role in some of our clinical trials having to do with diabetes. Due to the fact that the AHA has a new relationship with the American Diabetes Association (ADA), diabetes is a hot topic at this meeting, and it's very pertinent to the patient population that you and I see. You did a commentary on the DECLARE-TIMI 58 trial,[1] and you made a very strong statement about how we need to start using these drugs on our patients for prevention. Why would you say that?

Butler: I want to give a brief historical background of how these trials came into being, because that becomes pretty important. Remember when rosiglitazone and myocardial infarction (MI) was a big story? Because of that, these trials were designed to look at cardiovascular safety. Because MI was the concern, the primary endpoint was a three-point major adverse cardiovascular event (MACE): cardiovascular mortality, stroke, and MI. It was very atherosclerosis-focused.

We know that patients with diabetes have a lot of risk factors, but three big things happen to them that lead to cardiovascular mortality: chronic kidney disease (CKD), heart failure (HF), and atherosclerosis (ie, MI, stroke, and cardiovascular disease). Because these trials were focused on atherosclerosis, HF and CKD were kind of looked at as secondary endpoints. I put it to you that [the composite endpoint of hospitalization for HF or CV death] was not a primary endpoint in any of these trials, including EMPA-REG[2] or CANVAS.[3] In DECLARE, originally it was not a primary endpoint, but the analytic plan was changed and it became a co-primary endpoint with CV mortality, MACE, and others.

My passion derives from the fact that we think about coronary artery disease prevention all the time. We think about risk, and we have the Framingham Risk Score. When it comes to HF, we never think about prevention. We know from hypertension trials that with control of hypertension, you control the risk for stroke and MI. But the number one risk you control is HF. Patients with diabetes are at such a higher risk of developing HF, and once they develop HF, they are at a particularly higher risk for adverse outcomes.

When I look at these trials, there is some degree of difference in MACE benefit and primary versus secondary prevention benefit. But when you look at HF prevention and renal function, you see [significant reduction of risk] across the entire population in all three trials. On top of that, we now have two large studies with real-world evidence: CVD-REAL[4] (six different countries, 300,000 patients) and EMPRISE,[5] which was presented in this meeting.

If we can prevent HF, how much better is that than trying to reverse the course when somebody does develop HF? I realize that the trial design did not have HF prevention as the primary endpoint. There is a historical reason for that which is not rooted in biological importance, but on regulatory guidance related to safety.

Piña: That is what they looked at in the old trials. With diabetics, we all worry about making them sicker because of what we are giving them. I go back to the original CHARM trial[6] that showed a reduction in onset of new diabetes. I think one of the losartan trials found the same thing. We have had HF drugs, but they were never moved upon. Nobody ever said, "Maybe these are the drugs that we want to give our patients." Now we are doing the opposite. We are looking at the diabetics for the incidence of HF.

HFpEF Versus HFrEF

Piña: What kind of HF do you think you prevent? Is it ischemic?

Butler: I will give you two answers, the first being from an epidemiologic perspective. HF with preserved ejection fraction (HFpEF) is more common in patients with diabetes than HF with reduced ejection fraction (HFrEF), so it stands to reason that probably more HFpEF is prevented. I would also argue with you that it absolutely does not matter, because treatment of HF is intricately dependent on your ejection fraction, whether you have HFrEF or HFpEF. We have quite a lot of epidemiologic data that once you develop HF, your prognosis is equally bad whether you have HFrEF or HFpEF. Whether you are preventing HFrEF or HFpEF, you are still doing your patients a lot of good.

Piña: You don't really know which one it is that you're preventing? The way the information is picked up from the patient is symptomatology.

Butler: It's the same. A perfect comparator would be hypertension, right? I mean, nobody would argue there is a 50% reduction in HF. We don't know whether it's HFrEF or HFpEF.

[On] the basis of all these data for prevention, we need to get more proactive.

Being Proactive

Piña: Should we still do EMPA-REG [Editor's Note: The speaker meant to say "EMPEROR"]? You've been very involved in empagliflozin.

Butler: Absolutely. If you look at these trials, about 10% of the patients had prevalent HF. Here, we are talking about treatment of HF (not prevention) in about 700-800 patients, which would be size of a good, robust phase 2 study. We have all seen that phase 2 studies may or may not pan out in phase 3 studies.

A statin is a perfect example. If you look at the statin data in high-risk atherosclerotic patients (carotid disease, aortic disease, peripheral vascular disease, coronary disease), it all works. But when you try it in HF, it does not work. There is a precedent for that. In those patients who already have HF, yes, we really need to do EMPEROR-Reduced and EMPEROR-Preserved.

My argument is that on the basis of all these data for prevention, we need to get more proactive.

Piña: Do you think it would make the guidelines?

Butler: It's interesting. The latest iteration of the guideline from the American College of Cardiology/AHA/ Heart Failure Society of America[7] is the first time ever that they had a recommendation for prevention of HF based on biomarker screening from the STOP-HF[8] and [PONTIAC][9] trials. They looked at patients with high N-terminal pro–B-type natriuretic peptide (NT-proBNP) and disease management strategies that reduce the risk. It is a class IIa recommendation; this is a really forward-thinking way in which the organizations are thinking. Except that these are small studies, and both studies combined had less than 100 events.

We are getting close to 1000 events now, so there is such a robust data set.

Piña: It has been consistent. If you give it a higher level of recommendation, you have several trials with the same consistency.

Butler: I struggle, as I'm sure a lot of people struggle, with what hat do you wear? If you wear a purist trialist statistician hat, you can say it was not primary end point, et cetera, but when I wear my clinical hat and I see these consistent data with 1000 events that have accumulated and the fact that I know that the secondary endpoint is not rooted in biology but because of the regulatory guidelines, I am really hard pressed to say that we are not going to have a recommendation for prevention. But we will see.

Initiating Sodium Glucose Cotransporter 2 Inhibitor Therapy

Piña: I'm sending patients back to their primary care physicians to start the drugs, because I don't consider myself a diabetologist and I recognize that it needs to be cared for. For the first time, I've been able to tell my diabetic patients, "I've never truly had any information to tell you that it was important to control your diabetes. But now I do. I want you to see your primary care physician." Are you starting the drugs yourself?

Butler: I do, but you can go either way and have your primary care physician or your endocrinologist start it. You then have that partnership whichever way. The bigger thing is to give these drugs to the patient.

Again, if you look at the side-effect profile, you are not giving an injection and you are not managing insulin and fine-tuning the glucose. If a patient is not taking a secretagogue or an insulin, the chance of developing hypoglycemia is very low. It's an oral pill, and you are not dose-titrating. I would suggest that it's a pretty easy drug to use.

A common issue is volume depletion. Obviously, if you your patient is on a diuretic, you need to check that.

Piña: I see a lot of reports about dehydration and then renal function bumping up. It's because a patient is dehydrated.

Butler: Cardiologists are sort of used to thinking about hypotension and hypovolemia. We are not used to thinking about genital infection. In men and women both, there is higher risk for genital infection but not urinary tract infection. Genital hygiene is something that we need to talk to our patients about.

Piña: Do you think it's glucose being in the genital area? That is how I've interpreted it. I've told my coordinator the same thing—that we need to talk to the patients about their personal hygiene and how important that is. We will see what the next iteration of the guidelines say.

I want to thank you, Javed. It's always fun to sit and chat with you. Thank you for your time. Signing off.

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