Study Summary

The DAPA-HF trial1 demonstrated that the sodium-glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, reduced mortality and hospitalizations for heart failure (HF) in patients with HF with reduced ejection fraction (HFrEF) irrespective of diabetes status. Given concerns regarding the safety and efficacy of dapagliflozin in the elderly, the investigators conducted a subgroup analysis2 to examine the effects of this drug according to age. Patients receiving optimal medical therapy for symptomatic HF (left ventricular EF ≤40%) were included. Patients were randomly assigned to receive 10 mg of dapagliflozin daily or placebo (n = 4,744). Patient ages were as follows: 636 (13.4%) were <55 years; 1,242 (26.2%) were 55–64 years; 1,717 (36.2%) were 65–74 years; and 1,149 (24.2%) were ≥75 years.

The incidence of the primary composite outcome of first episode of worsening HF (defined as hospitalization or an urgent care visit for HF) or cardiovascular death was lower in the dapagliflozin group than in the placebo group for each age range. Hazard ratios were as follows: 0.87 (95% CI 0.6–1.28) for <55 years; 0.71 (95% CI 0.55–0.93) for 55–64 years; 0.76 (95% CI 0.61–0.95) for 65–74 years; and 0.68 (95% CI 0.53–0.88) for ≥75 years (P for interaction = 0.76). There were no differences in treatment discontinuation or adverse events — including volume depletion, renal dysfunction, and hypoglycemia — between the treatment groups for each age range.

Commentary

Study Strengths: This study is the first evaluation of the safety and efficacy of dapagliflozin according to age in patients with established HF regardless of diabetes status.

Study Limitations: This is a post hoc subgroup analysis and, therefore, susceptible to selection bias due to lack of randomization by age group. The DAPA-HF trial was not powered to detect differences by age. Additionally, the age categories were chosen arbitrarily.

Next Steps/Clinical Perspective: The benefits and safety of dapagliflozin in different age groups are not known, and there is concern that the drug might be poorly tolerated in the elderly owing to advanced age and polypharmacy2. This subgroup analysis provides evidence that dapagliflozin is efficacious regardless of age and thus associated with improved outcomes in the HF population independent of age and diabetes status. Furthermore, there were no significant differences in tolerability or safety between dapagliflozin and placebo when stratified by age, including in the elderly.

References

1. +
McMurray,  J. J. V. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. doi: 10.1056/NEJMoa1911303.
2. +
Martinez,  F. A. et al. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age: insights from DAPA-HF. Circulation doi: 10.1161/CIRCULATIONAHA.119.044133.
3. +
Sztramko,  R., Chau,  V., & Wong,  R. Adverse drug events and associated factors in heart failure therapy among the very elderly. Can. Geriatr. J.14:79–92 (2011).