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Diabetes Distilled: Signed, sealed and DELIVERed

Kevin Fernando
While current guidelines recommend the use of SGLT2 inhibitors in people with chronic heart failure and a reduced ejection fraction, several gaps remain in the evidence. The DELIVER trial aimed to establish the effectiveness of dapagliflozin in those with a higher left-ventricular ejection fraction (LVEF). Participants with an LVEF 40% were randomised to receive dapagliflozin (10 mg once daily) or placebo, in addition to usual therapy, and followed for 2.3 years. The primary endpoint of a composite of worsening heart failure or cardiovascular death was significantly reduced with dapagliflozin, driven by a reduction in worsening heart failure. The benefits were not affected by diabetes status. A separate analysis found a consistent benefit of dapagliflozin across all frailty statuses, with early improvements in quality of life. These findings establish the fundamental role of SGLT2 inhibitors in heart failure therapy, regardless of ejection fraction or diabetes status.

The present trial, DELIVER, explored the effect of dapagliflozin in people living with mildly reduced or preserved ejection fraction, irrespective of diabetes status (Solomon et al, 2022). It recruited 6263 individuals with an ejection fraction >40% to receive either dapagliflozin 10 mg or placebo. Of note, individuals with improved ejection fraction were also included (i.e. individuals whose ejection fraction was below 40% but subsequently rose above 40% at time of recruitment). This a previously understudied group.

Mean ejection fraction of the whole population was 54%. Overall, 43.6% of participants were women who, it has been well established, carry a higher burden of heart failure with preserved ejection fraction (HFpEF). Non-white ethnicities, however, comprised only 30% of participants, so were under-represented. The primary endpoint was a composite of worsening heart failure (unplanned hospitalisation for heart failure or an urgent visit for heart failure) or cardiovascular death.

After a median follow-up of 2.3 years, the primary endpoint was significantly reduced by 18% with dapagliflozin compared to placebo (absolute risk reduction, 3.1%; number needed to treat, 32). This was driven by a significant reduction in worsening heart failure. There was no statistically significant reduction in cardiovascular or all-cause death. Total events and symptom burden were lower in the dapagliflozin group.

These benefits were observed irrespective of diabetes status. Importantly, results were similar in those with left-ventricular ejection fraction ≥60% and <60%. This suggests no decline in benefit even in those with an ejection fraction in the normal range, which has been observed in previous HFpEF studies.

The incidence of adverse events did not differ significantly between the dapagliflozin and placebo groups.

Helpfully, given our ageing population, a pre-specified post hoc analysis of the DELIVER trial investigated the efficacy and tolerability of dapagliflozin according to frailty status in people living with mildly reduced or preserved ejection fraction (Butt et al, 2022). Unsurprisingly, frailty was found to be common in those with heart failure and was associated with worse outcomes. Reassuringly, the benefit of dapagliflozin was consistent across all frailty statuses, and improvements in quality of life occurred early and were particularly apparent in those with more severe frailty. Age and functional status should not, therefore, be a barrier to consideration of SGLT2 inhibitor therapy and, as always, we should assess goals of heart failure management and risk/benefit ratios on an individual basis.

DELIVER has sealed the role of SGLT2 inhibitors as a fundamental pillar of heart failure therapy and a new standard of care, irrespective of ejection fraction or diabetes status. The challenge now is to translate this seminal trial data into a change in practice in primary and secondary care.

Click here to read the full article.

Kevin Fernando’s previous Diabetes Distilled article, “The EMPEROR really does have new clothes”, provides an overview of the effect of empagliflozin in people living with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial.

REFERENCES:

Butt JH, Jhund PS, Belohlávek J et al (2022) Efficacy and safety of dapagliflozin according to frailty in patients with heart failure: a prespecified analysis of the deliver trial. Circulation 27 Aug [Epub ahead of print]; https://doi.org/10.1161/CIRCULATIONAHA.122.061754

Solomon SD, McMurray JJV, Claggett B et al; DELIVER Trial Committees and Investigators (2022) Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 387: 1089–98; https://doi.org/10.1056/NEJMoa2206286

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