Anu Lala, MD

We have all been waiting for a therapy to show efficacy in HFpEF. Even though many of us interpret the results of the TOPCAT trial of spironolactone and the PARAGON-HF trial of sacubitril/valsartan as applicable to certain subgroups of patients with HFpEF, the fact that the overall trials still failed to meet significance for their primary endpoint caused a lot of confusion and trepidation, leading to variable implementation in clinical practice. To have a study that is positive in achieving its primary endpoint makes the conversation cleaner. I am excited about that.

It is important to note that the primary endpoint was a composite of CV mortality and HF hospitalization, and though it was a significant reduction with empagliflozin, it was driven by the reduction in HF hospitalizations. It is also important to mention that the study population was 45% women. It is high time that we pay attention to sex-specific analyses. Women are more likely to have HFpEF than men. Forty-five percent is a much larger proportion of women than we’ve seen in HF clinical trials but still, I’d like to see even more, especially given the increased prevalence of HFpEF amongst women.

It is now a question of what treatment does one implement first. For example, do you use an SGLT2 inhibitor, sacubitril/valsartan or spironolactone first in a woman with an EF of 50% and elevated natriuretic peptides and the clinical syndrome of HFpEF? For a patient with hypertension, I would still be inclined to use sacubitril/valsartan in the appropriate setting. I also believe in the efficacy of spironolactone. EMPEROR-Preserved adds to our armamentarium. I do not think we can speculate the order in which these drugs should be offered.

From an insurance coverage perspective, because this is a clear-cut trial that met its primary endpoint, it will lend credibility to starting empagliflozin. We know we can use it in our patients with type 2 diabetes. The question is, in the patients without diabetes, dapagliflozin is approved by the FDA in patients at risk for worsening chronic kidney disease. One could argue that all patients with HFpEF are at risk for worsening CKD. This is an incredibly important discovery, and I would think about an SGLT2 inhibitor for any patient we are seeing in clinic with HFpEF.

The questions clinicians should be asking is why is this patient not on an SGLT2 inhibitor, why is this patient not on spironolactone, why is this patient not on a sacubitril/valsartan, as opposed to is this patient a candidate for these medications. Taking this approach will help in the implementation of these drugs. What remains to be seen is how expensive and accessible these medicines are to our patients.

Carlos G. Santos-Gallego, MD

For the first time in the study of HFpEF, we finally have a drug that is effective and safe that improves clinical outcomes.

Many drugs have failed in this population, and two drugs, spironolactone and sacubitril/valsartan, were borderline and had some promising results. The TOPCAT trial of spironolactone was negative, but if patients from Russia and The Republic of Georgia are excluded — many of those patients were truly not taking spironolactone or truly did not have HFpEF — the trial is positive. So many cardiologists have been treating patients with HFpEF with spironolactone because they consider TOPCAT to be positive. The PARAGON-HF trial of sacubitril/valsartan was neutral, with a P value of .059, but the FDA recently approved the drug for some patients with HFpEF due to lack of other options.

Another key message is that empagliflozin is effective in HF independent of classification and is appropriate for all types of HF. We do not yet have the results from the DELIVER trial of dapagliflozin, but I suspect that this is a class effect that will be extended to all SGLT2 inhibitors.

Also encouraging is the tolerability of SGLT2 inhibitors; we want a drug that is safe as well as effective. About 5 years ago, there was fear about worsening renal function, hypotensive events, dehydration, urinary infections, ketoacidosis and hypoglycemic events with SGLT2 inhibitors. All the clinical trials have confirmed that these fears were unwarranted. In EMPEROR-Preserved, the rates of hypotension, hypoglycemia and ketoacidosis were similar in both arms. Regarding worsening renal function, we now know that there is an initial dip in estimated glomerular filtration rate, but in the long term, SGLT2 inhibitors are nephroprotective. The nephrologists have taken to prescribing them with even more enthusiasm than the cardiologists.

After many years, we are finally seeing something positive for patients with HFpEF. There is an overwhelming sense of joy and relief in the cardiology community. This is truly something revolutionary.

Christopher M. O’Connor, MD, MACC, FESC, FHFSA, FHFA

This is a terrific day for the HF field. We have known that SGLT2 inhibitors are very effective at improving outcomes in HFrEF, but the world had been waiting for this trial and the DELIVER trial of dapagliflozin (which will be coming in the spring), and we are very pleased this this trial showed empagliflozin conferred a significant reduction in the primary endpoint of HF hospitalization or CV death, driven by HF hospitalization, in patients with HFpEF. It was a big win for patients.

We had signals with spironolactone, but TOPCAT was a very complicated trial that was left to interpretation. Based on PARAGON-HF, sacubitril/valsartan was approved by the FDA to include certain patients with normal EF, becoming the first approved therapeutic in this population. Now empagliflozin has a very strong signal for reducing HF hospitalizations in HFpEF, and this moves it to the top of therapeutic options with sacubitril/valsartan.

This is a big difference from 5 years ago, when there were no specific therapies for HFpEF, and we focused on the comorbidities such as hypertension, atrial fibrillation and ischemic heart disease. Now we have two classes of therapies that specifically target patients with HFpEF and should make a real impact on the course and burden of the disease.

However, we still do not have a signal on mortality, so there is some open space for additional therapeutics.

This is a great step, but it is not the last step. We need to take some time to understand this dataset so we can see where the stronger and weaker signals are and be more targeted in our approach in the future.

Manesh Patel, MD

I am impressed by the consistency of the benefit of empagliflozin across the EMPEROR-Preserved and EMPEROR-Reduced trials. Patients with HF even with an EF greater than 40% had a 21% reduction in CV death and HF hospitalization. The HR of 0.79 seems to be present early. This consistency is powerful. Also important is the consistency across LVEF, sex and diabetes status, which are questions that have been raised about other therapeutics.

Importantly, there is now a therapy for patients with HFpEF with or without diabetes for reducing clinical events, which we have not had before.

Patients with HFpEF represent a large portion of patients with HF around the world. Many of them have conditions such as hypertension and diabetes that lead to HFpEF. To date, we had been using therapies that had been studied in patients with reduced EF, hoping that we would get similar beneficial effects. The implication is that empagliflozin is likely going to be one of the initial therapies that we provide patients with HFpEF to keep them out of the hospital and prevent CV events.