by Prof. Francesco Giorgino, MD

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of a first hospitalization for heart failure (HHF).The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial was designed to evaluate the effect of dapagliflozin on the incidence of worsening heart failure or cardiovascular (CV) death in patients with chronic heart failure with reduced ejection fraction (HFrEF).Initial results from the study published in 2019 indicated that the risk of worsening heart failure or death from CV causes was lower among patients with HFrEF who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. Based on these and other results, dapagliflozin was approved by the Food and Drug Administration in May 2020 for treatment of HFrEF.

A new analysis presented at ADA 2020 showed a reduction of a composite endpoint that also included new or augmented treatment for HF (e.g. diuretics). The benefit on the primary endpoint occurred regardless of the presence of diabetes, in patients with eGFR (estimated glomerular filtration rate) below or above 60, regardless of use of MRA (mineralocorticoid receptor antagonist) or neprilisin/valsartan, and also regardless of baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) status (i.e. severe, moderate, light).

The KCCQ investigates the symptoms related to HF and was used in DAPA-HF. Dapagliflozin was better than placebo for the primary endpoint in all KCCQ quartiles: indeed, it was associated with KCCQ total symptom score improvement as well as clinically meaningful improvements in all key domains of the KCCQ. Dapagliflozin improved all major components of the KCCQ, with effects that were more evident over time.Fewer patients treated with dapagliflozin showed significant deterioration, and more experienced small, moderate, and large clinically meaningful improvements across all key domains of the KCCQ.The effects were substantial, with anumber needed to treat ranging from 12-18 vs. placebo after 8 months of treatment.It should be noted that not all therapies effective for HF outcomes improve the symptoms of HF (e.g. beta-blockers).

The renal composite endpoint was tendentially reduced with dapagliflozin, but this difference was not statistically significant, perhaps due to the small number of events.The change in eGFR over time was, however, statistically significant.This is reminiscent of other trials: e.g., in VERTIS-CV, where a renal composite endpoint was not achieved even though the change in eGFR over time was apparently affected favorably.

DAPA-HF also showedsome interesting metabolic results. Higher body mass index and HbA_1c, and lower eGFR rate were all associated with a greater risk of new onset type 2 diabetes (T2D). However, the incidence of new onset T2D was 32% lower in the 2605 participants in the DAPA-HF trial without T2D at baseline who received dapagliflozin vs. placebo. The effect was principally driven by participants with prediabetes. This is important since patients with new onset T2D had greater mortality during the trial. Decreasing incident T2D could be considered as an additional benefit of dapagliflozin, even though we do not know whether this is simply masking hyperglycemia or favorably and persistently affecting beta-cell function. Another interesting result is that the HF benefits occurred independently of metformin use or use of glucose-lowering medications in the diabetic cohort, lending support to the possibility of using cardioprotective therapies independently of metformin as first-line agent.

There is considerable debate as to how SGLT2 inhibitors improve CV outcomes.SGLT2 inhibitors have clear diuretic effects and improve volume status without many of the traditional adverse effects of diuretics.Even if SGLT2 inhibitors may be added late to the medication regimen in patients with HF, clinical adoption is likely to be extensive and facilitated due to the good safety profile of these drugs, which was also confirmed in DAPA-HF.