SGLT2 inhibitors may be a better treatment option for some older, frail patients hospitalized with heart failure, according to a study presented at the 2025 annual meeting of the Heart Failure Society of America.

Results linked SGLT2 inhibitors to significantly lower mortality and fewer heart failure-related readmissions when compared with angiotensin receptor-neprilysin inhibitors (ARNIs) in frail, older adults with heart failure with preserved ejection fraction (HFpEF).

The real-world analysis adds to mounting evidence for SGLT2 inhibitors in HFpEF and sheds light on outcomes in a vulnerable group for whom clinical guidance remains limited.

“Older adults with HFpEF and frailty represent a complex and understudied population,” said study author Miranda Huebner, DO, an internist at UnityPoint Health in Des Moines, Iowa, who presented the findings during a late-breaking poster session. “In this population, I would initiate SGLT2 inhibitors before considering ARNIs. Across the board, SGLT2 inhibitors were associated with lower all-cause mortality and fewer heart failure-related admissions.”

Real-World Comparison in a Frail Population

The retrospective analysis used data from the TriNetX Research Network to identify adults aged 65 years and older who were hospitalized with HFpEF and had at least one frailty-related diagnosis, such as cachexia, sarcopenia, or recurrent falls, between January 2019 and December 2023. Researchers included patients if they started an SGLT2 inhibitor or an ARNI during the hospitalization period and had not previously received the comparator drug. Those with systolic heart failure or end-stage renal disease were excluded.

After propensity score matching, 623 patients remained in each treatment group. Outcomes were assessed at 30 days, 90 days, 6 months, and 1 year after treatment initiation.

SGLT2 inhibitor use was associated with a 24% lower risk for all-cause mortality at 90 days (HR, 0.76; 95% CI, 0.62-0.93), a 19% lower risk at 6 months (HR, 0.81; 95% CI 0.68-0.95), and a 16% risk reduction at 1 year (HR, 0.84; 95% CI 0.73-0.97) compared with ARNI use. Patients receiving SGLT2 inhibitors also experienced fewer heart failure-related hospital readmissions at each follow-up point, with consistent benefit across age, sex, and comorbidity subgroups.

Consistent With Guidelines, but Caution Warranted

Paul Heidenreich, MD, a professor of medicine and vice chair for quality in the Department of Medicine at Stanford University School of Medicine in California, said the results align with existing treatment guidelines but warrant careful interpretation.

“The guidelines — and randomized trial data — suggest SGLT2 inhibitors should be first-line treatment for HFpEF,” Heidenreich told Medscape Medical News. “These findings are consistent with that, though the observational nature of the data makes the results uncertain and in need of confirmation with a randomized trial.” Heidenreich was not involved with the study.

He noted several possible sources of residual confounding inherent to real-world analyses. 

“Patients with more severe heart failure may have been preferentially treated with ARNIs, while some patients with minimal heart failure may have been put on SGLT2 inhibitors for treatment of diabetes or prediabetes, ” he said. “Thus, SGLT2 inhibition treatment may be a marker of mild heart failure while ARNI treatment may be a marker of worse heart failure, and available patient data may be inadequate for complete risk adjustment.”

At the same time, he added, the results are consistent with current standards of care.

“Since the guidelines already indicate SGLT2 inhibitors should be first-line therapy, these results are practice-reinforcing rather than practice-changing,” he said.

Implications for Practice and Research 

Frailty is common among older adults with HFpEF but underrepresented in randomized trials, leaving uncertainty about optimal treatment. This analysis sought to address that gap by comparing real-world outcomes among older adults with clinical markers of frailty.

The findings support the current emphasis on SGLT2 inhibitors in HFpEF management while highlighting the need for data specific to frail patients.

Heidenreich emphasized that, given the study’s observational design, the results should be interpreted with caution. Randomized trials that include frail older adults are still needed to confirm whether the apparent advantage of SGLT2 inhibitors reflects a true treatment effect rather than residual confounding.

Huebner and Heidenreich report no relevant financial relationships. 

Meg Barbor is a freelance writer for Medscape.