In this MDBriefCase conversation is Dr. Sara Stafford an endocrinologist in Surrey, BC, and Dr. Jeff Winterstein, a specialist in diabetes and peri-operative medicine in Edmonton, AB.

“I think we are looking at a new standard of care for our heart failure patients.”

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Summary

There is a strong association between patients with diabetes and heart failure. We know that diabetes and cardiovascular disease are intimately related. Two-thirds of deaths in patients with diabetes are directly attributed to cardiovascular disease. The worse your diabetes is, the higher your cardiovascular risk. And chief among those risks is heart failure, which is a highly prevalent condition.

At least 26 million adults are living with heart failure. Of those, about 670,000 Canadians live with heart failure. As many as one in five adults over the age of 40 will develop heart failure during their lifetime. 

It’s a significant amount, and it’s associated with poor outcomes. The mortality for patients who are hospitalized with heart failure is upward of 17 percent. Approximately 50 percent of patients with heart failure die within five years of diagnosis. We’re dealing with a condition that has a relatively poor prognosis and unfortunately, it’s very intimately associated with diabetes. 

Over the years, we have not recognized the importance of heart failure in patients who have diabetes. We have many patients with diabetes who come to our clinic complaining of fatigue or dyspnea, or impaired exercise tolerance. Data shows that in people who have type two diabetes, up to 14 percent have underlying heart failure. It’s just as common as atherosclerosis, strokes, or peripheral arterial disease. We need to move heart failure top of mind when we’re taking care of patients who have diabetes.

Not all heart failure is created equal. Most of us would recognize a heart failure with reduced ejection fraction. That’s the patient with symptoms of pitting edema, reduced ejection fraction that you can easily see when looking at an ultrasound. Diastolic dysfunction or heart failure with preserved ejection fraction is a little harder to diagnose. Patients are not usually symptomatic, it usually goes undiscovered or it’s a harder diagnosis to make.

Heart failure with reduced ejection fraction is usually categorized if your left ventricular ejection fraction is less than 40 percent. There is an intermediary stage or heart failure with mildly reduced ejection fraction. And that is typically diagnosed with a left ventricular ejection fraction between 41 to 49 percent. And then the heart failure with preserved ejection fraction, which we typically reserved for patients who still have a left ventricular ejection fraction greater than 50 percent.

Using an echocardiogram to assess left ventricular ejection fraction is one of the important keys in assessment and diagnosis, as well as using BNP. There are a number of different ways we can diagnose heart failure. And I think that we’ll be getting more guidance on how to assess for heart failure and diagnose heart failure in our patients as we get new diabetes and heart failure guidelines over the next year or so.

Prior to this new trial that we’re going to talk about, we were recognizing that heart failure with preserved ejection fraction is that sort of underlying condition that isn’t as easy to diagnose. So in my clinic, I was sending my patients for a yearly BNP if they were over 40 years old, just to make sure that they didn’t have any kind of heart failure. And if their BNP was positive, which I would then confirm with a transthoracic echocardiogram.

What chance does a diabetes drug have against PEF, or preserved ejection fraction if a hardened heart failure drug doesn’t do anything?

The cardiovascular outcome trials of the STLT-2 inhibitors, which were done, you know, now several years ago, in the secondary analysis of those trials, each of the  STLT-2 inhibitors showed a reduction in hospitalization for heart failure. And these were in patients who had atherosclerotic cardiovascular disease, but really were not a strongly enriched population for heart failure. But those early signals from the CBO T’s led to the initiation of heart failure trials specifically to explore the efficacy of the STLT-2 inhibitors for heart failure specifically. We have data already from the DAPA HF study, and the study looked at heart failure with reduced ejection fraction.

This was the first trial that we have that was aimed to investigate the safety and efficacy of a medication, or of an STLT-2 inhibitor, this one being empagliflozin versus placebo in patients with heart failure with preserved ejection fraction, and it looked at patients with diabetes and patients without diabetes. Patients are randomized to either the 10-milligram dose of epic or frozen, or the placebo, and these patients were followed for about 26 months. Patients included in this trial had to have a left ventricular ejection fraction of greater than 40 percent, have an NT pro BNP greater than 300, and patients without atrial fibrillation, and greater than 900 in patients with atrial fibrillation. And they had to have had structural changes in the heart, or hospitalization for heart failure within 12 months of screening.

These patients, on average, were 72 years old, they had a BMI of 30, and they on average had a left ventricular ejection fraction of 54 percent. In their NYHA class, most of them were class two. And they were very well-treated patients on you know, appropriate pharmacotherapy for the treatment of heart failure. Many of them had diabetes, about half of them. And they had a baseline GFR of about 60. 

It’s exciting now to see the results of this study. So again, they were randomized to flows in 10 milligrams versus placebo. And the combined primary outcome of cardiovascular death or hospitalization for heart failure. The results showed a hazard ratio of point seven nine, which was a 21 percent reduction in the primary outcome, which translated into a number needed to treat 31 over the 26 months of the trial. Now, this is really an impressive outcome, and very important that it is statistically significant in this composite primary outcome. It was driven primarily by a reduction in hospitalization for heart failure, and cardiovascular death trended downwards but wasn’t independently statistically significant. But of course, isn’t powered for those sub endpoints, and the composite primary outcome was strongly positive. 

Remarkably, these benefits are similar in patients with diabetes. And in those without diabetes. We’ve seen this in a trial, I think, with flows in which was, which is a combined  STLT-1 and STLT-2 inhibitor, which improves clinical outcomes after episodes of heart failure, and both patients with reduced ejection fraction, and in patients with preserved ejection fraction, but this is the first dedicated trial that we have, that actually shows benefit in preserved ejection fraction across the board.

In all of the prespecified subgroups, there was really no difference in the benefit of empagliflozin, independent of age, gender, baseline, left ventricular ejection fraction, whether it was lower than 50, or between 50 and 60, or over 60, independent of baseline GFR, independent baseline diabetes status, independent that because of heart failure, or medication use. All different populations within this study benefited similarly from empirical flows.

The data we get for the STLT-2 inhibitors has probably been the most consistent across the class of any of the classes of medications that I’ve seen when we look at the STLT-2 inhibitors for their benefits for cardiovascular outcomes for heart failure outcomes with reduced ejection fraction for the renal outcomes.

We’re excited about the dapagliflozin evaluation to improve the lives of patients with preserved ejection fraction heart failure. And that will further clarify whether this is the class effect, or if there’s something specific to empagliflozin. Having seen the results of this trial, it’s definitely going to be a game-changer for the cardiologists, this will probably change a lot of things. I see this medication being used in patients, again, without diabetes with half PEF. 

I anticipate that STLT-2 inhibitors will become standard of care for all patients with heart failure with preserved ejection fraction, independent of their diabetes status, just like it is now standard of care for all patients with heart failure with reduced ejection fraction based on our newest updates to our guidelines. We should see that this is really a practice-changing study.

We should also touch on the fact that there was another pre-specified secondary endpoint looking at a decline in GFR. And also empagliflozin in this population, also so that it reduced the decline in GFR. In this patient population of urine and blood flows in versus placebo, it was renal protective, based on EGFR slope. So again, consistency across the STLT-2 inhibitors data, but I think it did show a little bit more benefit for patients who had worse ejection fraction across the board. And as your ejection fraction improved, we did see slightly less benefit. That is consistent with what we’ve seen in that the sicker the patient, the more benefit that they will get from this type of medication.

To summarize prior to the last half of August, we did not have a medication that demonstrated consistent benefit for heart failure with preserved ejection fraction. And now we have an STLT-2 inhibitor, specifically empagliflozin, which demonstrated a significant 21 percent relative risk reduction in the primary endpoint of cardiovascular death or hospitalization or heart failure. And again, that was on top of background therapy, which makes it even more impressive, and the benefit was independent of ejection fraction and consistent across all the pre-specified subgroups. And again, independent of whether a patient had diabetes or did not, which again, is just impressive across the board.

I think we are looking at a new standard of care for our heart failure patients.

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The views Information and opinions expressed in this podcast are solely those of the individuals involved and do not represent those of Think Research, MDBriefCase, or Novo Nordisk. This podcast does not constitute medical advice. It is only meant to educate and inform the listener. This podcast is available at MDBriefCase.com and has been developed by MDBriefCase and supported by educational funding from Novo Nordisk.