Dr Mikhail Kosiborod Discusses the Clinical Importance of the Latest DELIVER Data on Dapagliflozin

The DELIVER trial is the largest trial to date of SGLT2 inhibitor use in heart failure, and these latest data on dapagliflozin in heart failure with mildly reduced or preserved ejection fraction show an extensive benefit on health status, which includes symptom burden, function, and quality of life, emphasized Mikhail N. Kosiborod, MD, cardiologist at St. Luke's Mid America Heart Institute in Kansas City, Missouri; vice president of research at Saint Luke's Health System; and director of cardiometabolic research and co-director of the Saint Luke’s Michael & Marlys Haverty Cardiometabolic Center of Excellence.

He presented, “The Effects of Dapagliflozin on Symptoms, Function and Quality of Life in Patients With Heart Failure and Mildly Reduced or Preserved Ejection Fraction: Results From the DELIVER Trial,” during the A Second Look at Practice-Changing Heart Failure Trials session on the final day of the American Heart Association’s Scientific Sessions.

Transcript

What do these latest DELIVER data add to knowledge of dapagliflozin in heart failure?

Well, we already know that SGLT2 inhibitors improve clinical outcomes in patients with mildly reduced and preserved ejection fraction. We knew that from the EMPEROR-Preserved trial and now from the DELIVER trial. We also had earlier data suggesting that SGLT2 inhibitors, including dapagliflozin, improve symptoms, physical limitations, quality of life in patients with heart failure, which is, of course, a very important goal of management. Patients with heart failure, especially those with mildly reduced or preserved ejection fraction experience a very significant burden of symptoms, physical limitations, and a poor quality of life. And finding treatments that improve those important outcomes is critically important.

We had some data suggesting that SGLT2 inhibitors improve these important outcomes, but that came from trials that were generally modest in size, had a relatively short follow-up. or did not specifically focus on patients with mildly reduced or preserved ejection fraction. We also had data from EMPEROR-Preserved showing modest benefits of empagliflozin on these outcomes, but there was also suggestion from EMPEROR-Preserved that the benefit of SGLT2 inhibitors may be attenuated in patients with heart failure and completely normal ejection fraction above 65%.

So there were still some remaining uncertainties about the magnitude of benefit of SGLT2 inhibitors on health status, which collectively encompasses symptoms, function, quality of life, and also whether there are certain subgroups of patients, such as those with completely normal ejection fraction, where perhaps those benefits are attenuated. And that's exactly what we try to address in this presentation here at the American Heart Association, using the data from DELIVER trial, which is the largest SGLT2 inhibitor trial in heart failure that's ever been conducted.

With there being few treatments approved to treat HFpEF, and none proven to reduce mortality, how can your latest data help to close that this gap?

Well, we have a triple goal of care in patients with heart failure, including those with heart failure and mildly reduced or preserved ejection fraction. That's to make our patients live longer, reduce mortality; try to keep them out of the hospital, try to reduce hospitalization rates, and emergency room visits; and a third and equally important goal is to improve symptoms, physical limitations, and quality of life.

We had data from SGLT2 inhibitor trials, large trials, that they reduce the risk of cardiovascular death or hospitalization for heart failure in this patient population. A large part of that benefit was in reducing hospitalization, but actually if you combine the data from EMPEROR-Preserved and DELIVER, we actually see borderline significant mortality reduction in cardiovascular mortality. And when you combine all of the SGLT2 inhibitor trials, there is actually a reduction in all-cause mortality—so it's across the range of ejection fraction.

So, yes, each individual trial of SGLT2 inhibitors did not show a cardiovascular death reduction, but they were not powered for that outcome either; they're not independently powered for reduction in cardiovascular death. And when you combine the data in a meta analysis, there is actually about a 12% relative risk reduction, cardiovascular death that's borderline significant.

With that acknowledged now, the real contribution of the studies that we have presented, as well as other studies of our leading health status, is that it's not enough just to reduce deaths in this patient population or reduce hospitalizations. As if not more importantly, it's also critical to improve symptoms and function and quality of life. Why is that? Because these patients really suffer from a great burden of the disease and a large part of that burden is symptomatic burden.

And in fact, there are well-conducted surveys of patients, especially older patients with heart failure, including heart failure with preserved ejection fraction, where many of them actually would trade better quality of life for a shorter longevity. So for many of these patients, feeling better is actually more important than living longer. I think that's what's the real contribution of our data is: It clearly demonstrates when collectively put together with the data we've had in the past, these agents clearly impact this important treatment goal in a positive direction.

What of dapagliflozin’s mechanism of action makes it effective against heart failure symptom burden, and how do SGLT2 inhibitors compare with other treatments?

We clearly saw that patients who were the most symptomatic at baseline appeared to derive the greatest benefit when it comes to clinical events like reduction in cardiovascular deaths or worsening heart failure. And that's one of the important conclusions. The second one is that patients experienced greater improvements in symptoms, as well as aspects of health status, physical limitations, quality of life, with dapagliflozin vs placebo, and we saw absolutely no evidence of any attenuation of that symptomatic benefit, even in patients with completely normal ejection fraction. If anything, it appears that those patients on the higher range of ejection fraction numerically actually did even better. So I think that's a critical important point, because we now have that evidence that SGLT2 inhibitors are beneficial in clinical events, regardless of ejection fraction. We now can also say that there are beneficial terms of symptoms in patients with heart failure, regardless of ejection fraction as well. That's very clinically important.

Now, your other question, which is why is that, what makes dapagliflozin or SGLT2 inhibitors different from other medications we've had in heart failure that clearly are effective maybe in the lower range, but not a higher range of ejection fraction, and, of course, we’re still working on trying to understand the mechanisms of how SGLT2 inhibitors provide heart failure benefit. Without a doubt, they are multifactorial. But of course, what drives most of the symptoms and physical limitations in heart failure is congestion. That's a final common pathway of all heart failure regardless of ejection fraction.

We know very clearly that SGLT2 inhibitors do improve congestion. We have well-conducted multiple mechanistic clinical trials, placebo-controlled trials, that show that they reduced filling pressures, pulmonary pressures, effectively in a very short period of time. We know that they increase the fractional sodium excretion and provide effective reduction in total blood volume, in plasma volume, and improve diuretic efficiency. And of course, the metabolic effects and nephroprotective effects of these agents are also highly relevant to all heart failure, regardless of ejection fractions. They are completely different.

Whatever all the mechanisms may be, they're clearly different from neurohormonal drugs, like beta-blockers and renin angiotensin blockers and neprilysin inhibitors, and minerlaocorticoid receptor antagonists. So I think that's the reason we see for the first time that we have consistent effectiveness across the entire range of ejection fraction.