Could a Diabetic Drug Improve Outcomes in Heart Failure?

Dawn O'Shea

December 01, 2021

The results of a systematic review and meta-analysis published in the European Journal of Preventive Cardiology suggest SGLT2 inhibitors could be the long sought-after Holy Grail in the management of LVEF >50% heart failure (HFpEF). It would make SGLT2 inhibitors the first drugs to provide a real benefit in terms of improving outcomes for these patients. The study authors say the findings "will revolutionise treatment options" for this group.

A team from the Norfolk and Norwich University Hospitals, Imperial College London, Cambridge University Hospitals, and the University of East Anglia, carried out a systematic search of PubMed, Embase, Cochrane and the Web of Science databases from inception to August 27, 2021, to identify studies containing the terms 'SGLT2' or 'sodium-glucose cotransporter-2 inhibitors' or 'canagliflozin', 'dapagliflozin', 'empagliflozin', 'ertugliflozin' or 'heart failure'. Only studies with a follow-up period of at least six months were included. The primary endpoint was cardiovascular (CV) death and hospitalisation for heart failure (HHF).

From 9493 articles identified, 167 studies underwent full-text screening, after which a total of five studies and 9726 participants were included. Of these, 5046 patients received an SGLT2i, and 4680 received placebo.

Analysis of the studies showed that the use of SGLT2 inhibitors was associated with a significant reduction in CV death or HHF (HR 0.78; 95% CI 0.69 to 0.87; I2 0%) or HHF (HR 0.71; 95% CI 0.61 to 0.84; I2 0%), compared with placebo. However, there were no significant differences between the two groups in terms of CV death (HR 1.01; 95% CI 0.80 to 1.28; I2 23%) and all-cause mortality (HR 1.01; 95% CI 0.89 to 1.14; I2 0%).

Since some studies included patients with left ventricular ejection fraction (LVEF) 40 to 50%, which does not meet the definition of HFpEF set out in the recent ESC heart failure guidelines, the researchers undertook a focused pre-specified sub-analysis of studies with available data on patients with LVEF>50%, which comprised 5928 patients. Based on this data, SGLT2 inhibitors were associated with a 23% reduction in CV death or HHF (HR 0.77; 95% CI 0.66 to 0.91; I2 22%), and this remained significant after sensitivity analysis.

This is first meta-analysis reviewing SGLT2 inhibitors for HFpEF. The finding that SGLT2 inhibitors show benefit in this cohort suggests SGLT2 inhibitors could be the first medications with potential for prognostic benefit in HFpEF, but further large trials are needed to evaluate the effect of the SGLT2 inhibitors in a sufficient number of patients with HFpEF.

Commenting on the results, lead author Professor Vass Vassiliou from the University of East Anglia Norwich Medical School and honorary consultant cardiologist at the Norfolk and Norwich University Hospital, said HFpEF has proved to be a challenging condition to treat, as every medicine tested has failed to show benefit in terms of outcomes.

While previous studies have shown that SGLT2 inhibitors are beneficial in HF with reduced ejection fraction, the current study found that these therapies can also help heart failure patients with preserved ejection fraction, he pointed out.

Presenting the findings, the authors say: "The various sub-phenotypes of HFpEF and its management have puzzled physicians for several years. The high rates of morbidity and mortality that it carries, along with the diagnostic and treatment challenges, have transformed it into one of the most challenging clinical entities. SGLT2 inhibitors appear to provide some light and positivity, as their cardiometabolic profile impacts favourably on the complex pathophysiological mechanisms involved in HFpEF.

However, the quest to untangle the complexity of treating HFpEF is certainly not over" and they caution that "the journey for an optimal and effective medication for HFpEF still continues". However, they say, it could be argued that with SGLT2 inhibitors, "the target destination is now visible, and Ithaca is closer than it has even been".

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