This exploratory analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) randomised controlled trial demonstrated that the sodium–glucose cotransporter 2 inhibitor dapagliflozin, added to contemporary therapies, for the treatment of heart failure with reduced ejection fraction (HFrEF) significantly reduced the risk of a first episode of worsening heart failure (HF) or cardiovascular (CV) death compared with placebo in people with or without type 2 diabetes. The magnitude of benefit was similar in those with type 2 diabetes and in those without.
The study enrolled 4744 individuals with HFrEF, of whom 2139 (45%) were living with type 2 diabetes, and demonstrated a significant absolute risk reduction of 4.9% with dapagliflozin in the primary composite endpoint of worsening HF or CV death. This translated into a number needed to treat (NNT) of 21 over 1.5 years. Notably, an early divergence in Kaplan–Meier survival curves was observed at around 4 weeks both for the primary endpoint and for the individual endpoint of HF events.
Diabetes status at baseline was one of the prespecified exploratory analysis subgroups. The statistical analysis plan also stated that study outcomes would be analysed among those without diabetes according to baseline HBA1c: <39 mmol/mol (normoglycaemic) or 39–47 mmol/mol (pre-diabetes according to American Diabetes Association criteria). The key findings from this exploratory analysis was that the effect of dapagliflozin on the primary and secondary outcomes did not differ in those with or without diabetes. Among those without diabetes, the primary outcome occurred in 13.2% of the dapagliflozin group and 17.7% of the placebo group. In those with type 2 diabetes, the primary outcome occurred in 20% of the dapagliflozin group and 25.5% of the placebo group. Moreover, in those without diabetes, there was a similar magnitude of effect in those with pre-diabetes or with HbA1c <39 mmol/mol. Unsurprisingly, dapagliflozin was found to reduce HbA1c in those with type 2 diabetes but had no effect in those without diabetes. Interestingly, dapagliflozin resulted in improvements in weight, blood pressure, estimated glomerular filtration rate and NT-proBNP in both those with and without type 2 diabetes, suggesting that these beneficial effects are independent of the drug’s glucose-lowering properties.
Finally, the rate of pre-specified adverse effects, including volume depletion, adverse renal events, fracture and amputation, were low overall and did not differ by diabetes status. There were no episodes of major hypoglycaemia or diabetic ketoacidosis observed in those without diabetes.
In conclusion, while this was an exploratory subgroup analysis with its inherent statistical limitations, dapagliflozin significantly reduced the risk of worsening HF or CV death compared with placebo, regardless of diabetes status. This paves the way for dapagliflozin to be considered as a new therapeutic option for HFrEF independent of diabetes status.
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PCDS Chair, Clare Hambling, pays tribute to Pam Brown, winner of the 2022 PCDS Lifetime Achievement Award.
29 Mar 2023