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

Heart failure with preserved ejection fraction (HFpEF) is a prevailing entity in patients with comorbidities. Frailty represents a multidimensional 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.

We assessed global cognitive function via MoCA test⁸ and physical function via 5-metre gait speed (5mGS).⁹ We performed a physical frailty assessment applying the Fried criteria.¹⁰

Data are shown as mean ± standard deviation (SD) for normally distributed continuous data (compared via Mann–Whitney or Kruskal–Wallis test) and n (%) for categorical data (compared using Fisher’s exact test). To adjust for potential confounders, we performed a linear regression analysis with the MoCA score or 5mGS test as dependent variables.

We evaluated a total of 548 patients; 399 patients successfully completed the study (Figure 1A): SGLT2-I: 101, glucagon-like peptide-1 receptor agonists (GLP-1 RA; 98), metformin: 105, and insulin: 95. Baseline clinical, metabolic, and demographic characteristics are presented in Figure 1B; no statistically significant differences were observed among the groups at enrolment, ensuring comparability of the cohorts.

Figure 1.

(A) Study flow chart. (B) Baseline clinical characteristics of our population; data are means ± SD or n (%); *P < 0.05. Effects of antidiabetic treatment on frailty levels (C, Fisher’s exact test), on physical (D) and cognitive impairment (E) and at 1 year follow-up (**P = 0.0095; ****P < 0.0001; Kruskal–Wallis test). BMI, body mass index; BNP, brain natriuretic peptide; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; HbA_1c, glycated hemoglobin; SBP, systolic blood pressure.

The difference in frailty under each treatment was assessed in our clinics after 1 year of follow-up by investigators blinded to the treatments. Patients treated with SGLT2-I displayed a significant reduction in frailty severity compared with baseline (P < 0.0001; Figure 1C), while no meaningful changes were detected in the groups receiving GLP-1 RA, metformin, or insulin. This finding suggests a potential disease-modifying effect of SGLT2-I on the frailty trajectory in older adults with DM and HFpEF.

Physical function markedly improved in the SGLT2-I group (baseline: 0.67 ± 0.09 vs. follow-up: 0.79 ± 0.10; P < 0.0001; Figure 1D), whereas no significant differences were observed in the other treatment groups. Cognitive performance also improved significantly in patients receiving SGLT2-I (baseline: 19.49 ± 3.5 vs. follow-up: 21.09 ± 3.9; P = 0.0019; Figure 1E), indicating a favourable impact on both physical and cognitive domains. These findings support the hypothesis that SGLT2-I can exert multifaceted protective effects extending beyond glycaemic control, potentially mitigating frailty progression and enhancing overall functional status in older patients with HFpEF and DM.

In this prospective study conducted in frail older adults with DM and HFpEF, treatment with SGLT2-I was associated with significant improvements in frailty status, physical performance, and cognitive function over a 1-year follow-up. The interplay between metabolic dysregulation, endothelial dysfunction, inflammation, and mitochondrial impairment contributes to both frailty and cardiovascular disease progression.¹¹ In this context, the observed benefits of SGLT2-I on frailty and function may reflect their ability to simultaneously target several of these pathophysiological mechanisms.

Mechanistically, SGLT2-I can induce mild osmotic diuresis and natriuresis, reducing cardiac preload and afterload, thereby improving haemodynamic efficiency and left ventricular compliance, an especially relevant mechanism in HFpEF. Beyond their cardiovascular benefits, these agents also improve endothelial function, mitigate oxidative stress, and promote favourable shifts in substrate utilization, favouring ketone oxidation and mitochondrial efficiency. Such metabolic remodelling may enhance skeletal muscle bioenergetics and perfusion, leading to improved physical performance. Furthermore, the anti-inflammatory and neuroprotective effects of SGLT2-I, possibly mediated by reductions in systemic cytokines, uric acid, and neuroinflammation, may contribute to the observed gains in cognitive function.

The improvement in both physical and cognitive domains underscores the potential of SGLT2-I to act as geroprotective agents, attenuating the biological processes underpinning ageing and frailty. Unlike other antidiabetic agents, SGLT2-I can influence multiple organ systems simultaneously, integrating cardiac, renal, vascular, and neurocognitive pathways. This pleiotropy may explain why, in our study, improvements were not observed in patients treated with metformin, GLP-1 receptor agonists, or insulin, despite similar baseline characteristics.

Our findings are consistent with recent observations suggesting that SGLT2-I might reduce hospitalizations, improve quality of life, and enhance exercise capacity in HFpEF patients, including those without DM.^12–15 Importantly, the extension of these benefits to frailty-related outcomes supports the notion of a broader, integrative physiological effect, indicating that SGLT2-I may modulate systemic pathways implicated in aging and functional decline. Mechanistically, these effects likely reflect coordinated improvements in mitochondrial efficiency, reduction in systemic inflammation, optimization of endothelial function, and favorable shifts in substrate utilization toward ketone bodies and fatty acids. Such pleiotropic actions reinforce the emerging paradigm that SGLT2 inhibition functions as a metabolic and vascular stabilizer, exerting multi-organ protective effects that transcend traditional glucose-lowering properties and instead target fundamental processes underlying cardiometabolic and geriatric vulnerability.

This study is not exempt from limitations. For instance, the observational design precludes causal inference, and although groups were balanced at baseline, unmeasured confounders may have influenced outcomes. The 1 year follow-up period, although clinically meaningful, may not capture the long-term sustainability of the observed benefits. Future randomized controlled trials specifically designed to evaluate frailty trajectories in older adults treated with SGLT2-I are warranted.

In conclusion, our study provides novel and strong evidence supporting the anti-frailty and anti-ageing effects of SGLT2-I in older adults with DM and HFpEF. By improving both physical and cognitive domains of frailty, these agents may redefine therapeutic strategies in geriatric cardiometabolic care. SGLT2 inhibition thus emerges not only as a cornerstone of cardiometabolic protection but also as a promising approach to promote healthy ageing and functional independence in a rapidly expanding elderly population.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.