Effects of empagliflozin on skeletal muscle degradation in patients with heart failure: a prospective observational study

Background Sodium–glucose cotransporter-2 inhibitors (SGLT2i) are a cornerstone of contemporary heart failure (HF) therapy and provide consistent prognostic benefit, including in older, frail, and underweight patients. However, whether SGLT2i adversely affect skeletal muscle through accelerated muscle degradation remains insufficiently characterized. Urinary titin N-fragment (U-titin) is a non-invasive biomarker of skeletal muscle breakdown and may help quantify longitudinal changes in muscle degradation after SGLT2i initiation. Purpose To evaluate the effect of empagliflozin on skeletal muscle degradation, assessed by changes in U-titin over 6 months, and to identify clinical correlates and predictors of U-titin increase in patients with stable HF. Methods In this prospective, single-centre observational study, 93 consecutive patients with stable HF were enrolled between February 2023 and October 2024 and initiated on empagliflozin 10 mg once daily. Nutritional, quality-of-life, and frailty-related indices were assessed, including the Geriatric Nutritional Risk Index (GNRI), Controlling Nutritional Status (CONUT) score, Mini Nutritional Assessment (MNA), Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12; overall and clinical summary scores), Barthel Index, and Clinical Frailty Scale. U-titin (pmol/mg creatinine) was measured at baseline and at 6 months. Associations between baseline U-titin and clinical indices were examined, and predictors of a >50% increase in U-titin at 6 months were assessed using multivariable logistic regression. Results Median age was 79 years (IQR 72–83), 40% were women, and baseline body mass index was 22.8 kg/m² (IQR 19.8–26.2). Heart failure with preserved ejection fraction (LVEF ≥50%) was present in 46%. Baseline U-titin was modestly but significantly correlated with GNRI, MNA, and KCCQ-12 overall and clinical summary scores (all p<0.05). Median U-titin was 1.7 pmol/mg Cr (IQR 1.1–3.5) at baseline and 2.4 pmol/mg Cr (IQR 1.3–4.2) at 6 months, with no significant change (p=0.629). In contrast, GNRI, MNA, KCCQ-12 overall and clinical summary scores, body mass index, and NT-proBNP improved significantly over 6 months, whereas CONUT, Barthel Index, and Clinical Frailty Scale did not show significant changes. In multivariable analysis, HFpEF (LVEF ≥50%) independently predicted a >50% rise in U-titin at 6 months (OR 3.31, 95% CI 1.23–9.52; p=0.017). Conclusion In stable HF, empagliflozin initiation was not associated with a significant overall increase in U-titin at 6 months, despite improvements in nutritional and patient-reported health status and NT-proBNP. However, patients with preserved ejection fraction may be more susceptible to U-titin elevation during therapy, warranting further investigation in larger prospective studies.