SGLT-2 Inhibitors in Heart Failure

James Januzzi, MD: Let’s circle back to the newer drugs. We talked about sacubitril/valsartan.It’s a learning curve. It’s a little more challenging to use because of blood pressure effects. But internists and endocrinologists know SGLT2 inhibitors, so there’s a greater opportunity for us to lead and educate on this. They’ve gone from a diabetes therapy to a cardio prevention drug to a standard-of-care therapy. Can you review some of the top-line results from the trials that led us to this point?

Javed Butler, MD, MPH, MBA: It’s interesting because most of the heart failure therapies were developed and started from the cardiovascular and then went to primary care. This is the opposite.

James Januzzi, MD: The opposite. In fact, all the therapies we use in heart failure were not developed for heart failure. They found their way here. What about SGLT2 inhibitors?

Javed Butler, MD, MPH, MBA: We can make this discussion as complicated or as simple as we want. There’s a ton of trials in the type 2 diabetes space, in the heart failure space, in the chronic kidney disease [CKD] space. The top line is that wherever we’ve tried, these drugs have worked. In the heart failure space, if you look at patients with type 2 diabetes or CKD, these drugs prevent the development of heart failure. If you take patients with heart failure and reduced ejection fraction, these drugs reduce the risk of cardiovascular death and heart failure hospitalization and total heart failure hospitalization. If you look at heart failure with preserved ejection fraction [HFpEF], with these drugs, it’s the same thing. The primary endpoint of cardiovascular death and heart failure hospitalization was met for both trials. If you look at acute heart failure or worsening heart failure, there were a couple of trials in that space. They were also positive in a relatively short timeframe. Those outcomes were better. The interesting thing is that we were sweating a little when we were designing these studies because it’s tough to convince people that we should give these diabetes drugs to all patients with heart failure. We were sweating a little that even if they work in diabetes, what about patients without diabetes? There’s no difference.

James Januzzi, MD: No difference at all.

Javed Butler, MD, MPH, MBA: No difference. You can dichotomize diabetes or no diabetes. You can trichotomize diabetes, prediabetes, or no glycemic abnormalities. Or you can simply look at hemoglobin A as a continuous measure from 4 to 12 g/dL, with no difference in benefits.

James Januzzi, MD: They don’t cause hypoglycemia.

Javed Butler, MD, MPH, MBA: No. If you’re taking insulin or secretagogues like sulfonylureas for type 2 diabetes, there may be a bit of a risk. But for the other patient populations, there’s almost nonexistent risk. If you look at quality-of-life scores, they get better uniformly in all these patient populations as well. In HFpEF, if you look across the spectrum of ejection fraction, you’ll see the benefit. Lastly, is the speed with which you get the benefit. With all these trials, we’re finding that once the trial ends, statistically speaking, you can go back and see when this Kaplan-Meier curve separated and reach statistical significance. Invariably, it’s less than 4 weeks for all these therapies.

James Januzzi, MD: In fact, SGLT2s but also sacubitril/valsartan, MRAs [mineralocorticoid receptor antagonists], and even beta-blockers. It’s interesting: the focus on the time to first benefit, as a way of putting it, has bothered some classical trialists because it’s not the way they like to look at the statistics in these studies. For us clinicians, it makes sense to look at it this way. Of course, it doesn’t detract from the long-term benefits in these studies, and it helps to provide urgency for initiation and sequencing of how these drugs are started.

Transcript edited for clarity