Sodium/glucose cotransporters 2 inhibitors but not other antidiabetic drugs improve frailty in older adults with diabetes and heart failure with preserved ejection fraction

Time of primary review: 30 days Heart failure with preserved ejection fraction (HFpEF) is a prevailing entity in patients with comorbidities. Frailty represents a multi-dimensional syndrome characterized by decreased physiological reserve and increased vulnerability to stressors, commonly observed in older adults with chronic conditions.1 Diabetes mellitus (DM, both Types 1 and 2) impairs endothelial function triggering inflammation, atherosclerosis, and oxidative stress, potentially driving the onset of HFpEF. In fact, patients with DM have a higher risk of developing frailty.2,3 Sodium/glucose cotransporters 2 inhibitors (SGLT2-Is) are useful drugs for both DM and HFpEF4 and have been proposed as anti-frailty drugs.5–7 To test the hypothesis that SGLT2-I could have beneficial effects on physical/cognitive impairment and on frailty levels in a population of older adults with DM and HFpEF, we conducted a prospective 1 year study enrolling consecutive frail older adults with a diagnosis of DM and HFpEF, admitted (as outpatients) between March 2021 and March 2023 at the Local Health Authority of Avellino and Casa di Cura Montevergine, Mercogliano (Italy). Inclusion criteria were as follows: age >65 years; confirmed diagnoses of DM, frailty, and HFpEF; a Montreal Cognitive Assessment (MoCA) score <26; and antidiabetic monotherapy (at enrolment) with SGLT2-I, glucagon-like peptide-1 receptor agonist (GLP-1 RA), metformin, or insulin (pre-specified analysis). Exclusion criteria included history of stroke, acute myocardial infarction, coronary revascularization, cancer, or pacemaker implantation, sequential use of antidiabetic drugs, and estimated glomerular filtration rate <30 mL/min/1.73 m2. A pre-specified statistical analysis plan was developed for the trial, and the sample size was estimated using G*Power software. Written informed consent was obtained from all participants or their legally authorized representatives. The study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and was approved by the Ethics Committee of Campania Nord.