Evolution of SGLT2 Inhibitors in Treatment Regimens


Javed Butler, MD, MPH, MBA, reviews the historical background of using SGLT2 inhibitors and the impact on patients with heart failure with reduced ejection fraction.

James Januzzi, MD: Javed, we’ve had a big change in the heart failure space in the last few years with respect to sodium-glucose cotransporter-2 inhibitors, or SGLT2 inhibitors, for the treatment of patients with heart failure. This is a therapy that was initially discovered by accident during clinical trials for the treatment of type 2 diabetes. We could probably give a complete hour on the discovery and mechanisms of action of SGLT2 inhibitors, but I’m going to ask you to give the 10,000-foot view of how we got here with SGLT2 inhibitors and your point of view about how they may work. Then we can talk about how we weave them into the care of our patients with heart failure.

Javed Butler, MD, MPH, MBA: That’s the story of serendipity on steroids. These were developed for diabetes. They help make you urinate glucose and decrease the absorption of glucose, so it’s a diabetes drug. Then in 2008, the United States FDA mandated that all newer therapies for diabetes should be assessed for their cardiovascular benefit. It was still a diabetes drug and it was tested for cardiovascular safety—not even benefit. Trials were done. And then with SGLT2 inhibitors, we were suddenly seeing substantial reductions in heart failure hospitalizations. We’re talking about 30% relative risk reduction, irrespective of any other characteristics. It doesn’t matter what your starting A1C [glycated hemoglobin] was, what your ending A1C was. There was no association with glycemic control. It doesn’t matter whether you have a history of heart failure. It doesn’t matter whether you have atherosclerotic cardiovascular disease or just risk factors. No matter how you slice and dice the data, there was a reduction in heart failure hospitalization. That was one realization that these drugs should maybe be used for heart failure as well.

The second realization was that, by that time, we had started to understand the pharmacodynamic effect beyond glycemic control. Most of the major organ systems that are associated with pathophysiology of development or progression of heart failure are beneficially impacted by SGLT2 inhibitors. Vascular function, aortic stiffness, endothelial function, cardiac structure and function, hypertrophy regression, diastolic function, fibrosis, renal function preservation, metabolism, and ATP [adenosine triphosphate] generation, no matter how you slice it, all benefit. Then there are a lot of more nuanced, subtle mechanisms of action as well, like lysosomal activity and autophagy.

The bottom line is that when they took a step back and looked at the pharmacodynamic effects of this drug, the question completely changed. The question was not how they improve cardiovascular outcomes. The question was, what does any of this have to do with diabetes? Perhaps we should look into all of these things, and these are cardiovascular risk-modifying agents, which are great diabetes drugs that you should absolutely use for glycemic control. But perhaps in the cardiovascular setting, we should test it irrespective of diabetes. So we started doing chronic kidney disease trials, heart failure with reduced ejection fraction [HRrEF], post-MI [post-myocardial infarction], and heart failure with preserved ejection fraction, without focusing on whether a person has diabetes.

James Januzzi, MD: Yes, it’s a remarkable story. The multitude of potential mechanisms of action remain so compelling, and yet still unanswered. There are more review articles on the mechanisms of action than mechanistic papers explaining what the most plausible candidates may be. These therapies preserve kidney function and lead to a certain degree of nature-resistant diuresis without activating the renin-angiotensin-aldosterone system [RAAS], but they’re much more than just a so-called smart diuretic. In fact, as you pointed out, there are now randomized data showing an impact on reverse cardiac remodeling. Earlier on I mentioned that therapies that improve ejection fraction in HFrEF are beneficial. Javed, what do we know about the impact of SGLT2 inhibitors on patients with heart failure with reduced EF? Let’s put the diabetes question completely aside. Let’s talk about them as a heart failure drug.

Javed Butler, MD, MPH, MBA: There are 2 large trials that have been published. DAPA-HF was dapagliflozin 10 mg vs placebo on standard of care, and EMPEROR-Reduced with empagliflozin. Both trials had baseline therapy that was excellent: 90%-plus use of diuretics, RAAS inhibitors, and β-blockers, and 70%-plus use of MRAs [mineralocorticoid receptor antagonists]. The beneficial effect that we’re seeing was on top of really good baseline medical therapies, so we can be rest assured that this is incremental benefit on top of that.

The primary end point of reduction in cardiovascular death and heart failure hospitalization, was positive in both trials. Recurrent heart failure hospitalizations, total heart failure hospitalization, renal function preservation, and quality of life scores were all improved in both of the trials. Then there were 2 big questions. Did this gamble of giving SGLT2 inhibitors to patients without diabetes pan out? Absolutely. Not only do patients without diabetes benefit from these agents, the magnitude of benefit and relative risk reduction is interchangeable in those with or without diabetes. One of my colleagues said, “Well, prediabetes, diabetes is a continuum. What about low glycemic epidemiology?” So DAPA-HF looked at it in 3 ways: diabetes, prediabetes, or no glycemic imbalance. Again, all 3 groups benefited.

James Januzzi, MD: On top of that, they also have data showing that being on dapagliflozin prevented onset of diabetes among people who didn’t have the diagnosis before. You’re talking about almost a 360-degree win. It’s quite remarkable. This experience has been one of the victories in recent heart failure therapy development. The observation in the diabetes trials was made, then the outcomes trials were rapidly developed, executed, and successful. Now we have a fourth major category of therapy in our armamentarium. That term is used all the time. We like to call them weapons. We now have a fourth major category of drug, the fourth pillar, that blocks a unique set of biological pathways to improve outcomes in our patients with heart failure with reduced ejection fraction.

Transcript Edited for Clarity

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