Heart failure with preserved ejection fraction – do SGLT2 inhibitors help?

9th September 2021, Dr Chee L Khoo

heart failure and SGLT2 inhibitors

You already know that SGLT2 inhibitors, as a class, have been shown to reduce the development and progression of heart failure in patients with diabetes (1-3). Incidentally, it has also been shown to do the same in patients with heart failure but without diabetes. Life used to be simple. You just have heart failure. With better understanding about the dynamics of the ventricular function, we now have heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fracture (HFrEF) according to whether the ejection fracture is preserved or reduced. Do SGLT2 inhibitors work for both HFrEF and HFpEF? Well, specific heart failure outcome trials (DAPA-HF and EMPEROR-Reduced) have demonstrated benefits for patients with HFrEF (4-6). Data on the effects of SGLT2 inhibitors on patients with HFpEF is limited. Until now.

The original cardiovascular outcome trials (CVOTs) involving the SGLT2 inhibitors were really safety trials designed to prove that anti-diabetic medications did not increase major adverse cardiovascular events (MACE). Surprisingly, not only did they showed SGLT2 inhibitors to be not harmful but pleasantly, showed they significantly improve MACE (superiority). However, although they were shown to reduce hospitalisation for heart failure (hHF), hHF was not in their primary outcomes. So, subsequent specific heart failure outcome trials (DAPA-HF, EMPEROR-Reduced and Soloist-WHF) (4-6) enrolled patients with known heart failure with reduced ejection fraction in the trials and indeed, they confirm that SGLT2 inhibitors do reduce death from heart failure or worsening of heart failure in patients with HFrEF.

All well and good but what about patients with HFpEF? It was only a matter of time before trials involving patients with HFpEF. The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) was carried out to evaluate the effects of SGLT2 inhibition with empagliflozin on major heart failure outcomes in patients with heart failure and a preserved ejection fraction (7). Participants were men or women, ≥ 18 years old older, who had New York Heart Association functional class II–IV chronic heart failure and a left ventricular ejection fraction of > 40%. The protocol required patients to have an N-terminal pro–B-type natriuretic peptide (NT-proBNP) level of more than 300 pg per milliliter or, for patients with atrial fibrillation at baseline, an NT-proBNP level of more than 900 pg per milliliter.

The primary outcome was a composite of cardiovascular death or hospitalisation for heart failure. The first secondary outcome was the occurrence of all hospitalisations for heart failure, including first and recurrent events. The second secondary outcome was the rate of decline in the eGFR during double-blind treatment.

5988 patients were randomly assigned to receive either empagliflozin (2997 patients) or placebo (2991 patients). Nearly half the patients had diabetes and half had an eGFR of less than 60 ml per minute per 1.73 m2. The median duration of follow-up for the primary outcome was 26.2 months.

The Results

Heart failure benefits

In patients with HFpEF, empagliflozin led to a 21% lower relative risk in the composite of cardiovascular death or hospitalisation for heart failure. The reduction in composite outcomes were seen in patients with or without diabetes. As part of the secondary outcomes, empagliflozin also led to a lower total number of hospitalisations for heart failure and a longer time to first hospitalisation for heart failure. This benefit from empagliflozin is similar to that reported with empagliflozin in patients with HFrEF (EMPEROR-Reduced) which suggests that SGLT2 inhibition benefits heart failure events irrespective of the heart failure phenotype.

The results from EMPEROR-Preserved is particular important because most trials till now have focussed on patients with reduced ejection fraction. In PARAGON-HF trial, candesartan, spironolactone, and sacubitril–valsartan reduced cardiovascular death and hospitalisations for heart failure by a modest 10-15% but subgroup analyses suggested that the benefit may have been preferentially seen in patients with an ejection fraction of 40 to 49% (8).

In EMPEROR-Preserved, participants’ ejection fracture had to be >40%. Two thirds of the patients had a left ventricular ejection fraction of ≥50%. The median left ventricular ejection fraction was 54%.

Mortality benefits

Now, in EMPEROR-Preserve, most of the reduction of the composite outcomes came from a 29% lower risk of hospitalisation for heart failure. In fact, empagliflozin did not appear to affect the number of deaths from cardiovascular or other causes in the trial. It is noteworthy that the percentage of patients who discontinued treatment for reasons other than death was 23% overall and was similar in the two treatment groups; this high rate of discontinuation may have driven the effect size toward the null hypothesis. The lack of effect on cardiovascular mortality is not that dissimilar in the PARAGON-HF trials which was conducted in a similar population for a similar period of time. Perhaps, the duration of the trials were not long enough.

Implications for general practice

Remember, these are dedicated heart failure trials which means all participants already have heart failure. In the original cardiovascular outcome trials (EMPAREQ, DECLARE-TIMI57, CANVAS), subanalysis of the data showed that most of the benefits were in patients with established cardiovascular disease although the definition of “established” included participants who had not had an event but were at high risk of having an event. Patients included were those with peripheral arterial disease and angiogram proven coronary stenosis of >50%.

Nonetheless, this trial remind us that in patients with diabetes and cardiovascular disease, an SGLT2 inhibitor with proven cardiovascular benefit should be considered. Now, heart failure is common in patients with diabetes but is not always symptomatic. Often, we have to refer patients for echocardiograph but it is not easy to decipher the echocardiograph report as to whether your patient have HFrEF or HFpEF. It is comforting to know that SGLT2 inhibitors will benefit these patients irrespective of the heart failure phenotype with a caveat. So far, only empagliflozin has shown the benefit in HFpEF. More trials will be reporting soon…

References:

  1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17. PMID: 26378978.
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