Dapagliflozin remains safe, effective for HF irrespective of diuretic use
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Dapagliflozin for worsening HF was both safe and efficacious regardless of diuretic use or dose, according to findings from the DAPA-HF trial published in Circulation.
“Our findings show that combining the SGLT2 inhibitor dapagliflozin with a conventional diuretic in patients with HF and reduced ejection fraction (HFrEF) is effective and well-tolerated,” Alice M. Jackson, MBChB, clinical research fellow in the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, U.K., told Healio. “We found that in the DAPA-HF trial, the majority of patients remained on the same dose of furosemide-equivalent loop diuretic throughout trial follow-up, and that the mean dose of diuretic did not differ between randomized groups. These data suggest that, for most patients, combining dapagliflozin with conventional diuretics is safe and will not necessitate adjustment of their conventional diuretic regime.”
For this analysis of 4,744 participants in DAPA-HF, of whom 3,880 were on some dosage of a diuretic at baseline (35.2% on 40 mg; 31% on more than 40 mg; 33.8% on less than 40 mg or non-loop diuretic), investigators determined whether combination dapagliflozin (Farxiga, AstraZeneca) and diuretic use was associated with the composite endpoint of CV death, worsening HF event, its components, all-cause death and symptoms. Participants were one-to-one matched with the DAPA-HF placebo group.
Diuretic dose did not change among most participants during follow-up, and mean diuretic dose was similar between dapagliflozin and placebo groups.
Researchers observed that dapagliflozin reduced the risk for the composite endpoint across every strata of diuretic use (P = .61):
- on no diuretic (HR = 0.57; 95% CI 0.36-0.92);
- diuretic dose less than 40 mg (HR = 0.83; 95% CI, 0.63-1.1);
- diuretic done of 40 mg (HR = 0.77; 95% CI, 0.6-0.99); and
- diuretic dose more than 40 mg (HR = 0.78; 95% CI, 0.63-0.97).
Adverse events linked to volume depletion were infrequent but more common among patients on higher diuretic dose in the placebo group, researchers reported, ranging from 5.3% in participants receiving the lowest-dose diuretic to 8.9% in those receiving the highest dose.
Moreover, events were numerically more common among participants who received dapagliflozin compared with patients assigned to placebo (0.2% on less than 40 mg; 3.1% on 40 mg; 1.6% on more than 40 mg), according to the study.
“In addition to confirming that treatment with both loop diuretics and dapagliflozin is safe and effective, our findings suggest that SGLT2 inhibitors may have effects other than hemoconcentration in patients with HFrEF,” Jackson said in an interview. “For example, the rise in hematocrit with dapagliflozin occurred irrespective of whether the diuretic dose increased, decreased or remained the same; one explanation for this finding might be an increase in the production of erythropoietin.
“Exactly how SGLT2 inhibitors exert their benefits in patients with HFrEF remains unclear, despite signals that mechanisms other than natriuresis and diuresis are likely to be involved,” Jackson told Healio. “Future research should focus on better understanding these mechanisms.”
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