U-titin levels increased significantly during empagliflozin treatment in heart failure patients, 'suggesting a possible association with skeletal muscle degradation' despite improvements in nutritional and cardiac markers.
Key Findings
Results
Median urinary titin N-fragment (U-titin) increased significantly after 6 months of empagliflozin treatment in heart failure patients.
Median U-titin increased from 1.7 (IQR 1.1–3.5) at baseline to 2.4 (IQR 1.3–4.2) pmol/mg Cr at 6 months (p = 0.040).
93 patients were analyzed after exclusions from an initial cohort of 117 patients with stable congestive heart failure.
All patients received 10 mg of empagliflozin daily for 6 months.
Median patient age was 79 years; 40% were women.
U-titin is described as 'a biomarker of skeletal muscle degradation.'
Results
Baseline U-titin levels showed weak but statistically significant correlations with nutritional and functional status measures in heart failure patients.
Baseline U-titin correlated weakly with GNRI (Geriatric Nutritional Risk Index), MNA (Mini Nutritional Assessment), and KCCQ-12 scores (all p < 0.05).
The authors state that 'baseline U-titin levels seem to reflect nutritional and functional status in patients with heart failure.'
Correlations were characterized as 'weak,' indicating modest but statistically detectable associations.
Results
Left ventricular ejection fraction ≥50% independently predicted a ≥50% increase in U-titin levels during empagliflozin treatment.
LV ejection fraction ≥50% was an independent predictor of ≥50% U-titin increase (OR 3.31, 95% CI 1.23–9.52, p = 0.017).
This suggests that patients with preserved ejection fraction heart failure may be at greater risk for skeletal muscle degradation during SGLT2 inhibitor therapy.
This finding was identified via multivariable logistic regression analysis.
Results
Nutritional and cardiac markers improved significantly over the 6-month empagliflozin treatment period despite the increase in U-titin.
GNRI, MNA, KCCQ-12, body mass index, and NT-proBNP levels all improved significantly during follow-up.
CONUT score, Barthel index, and clinical frailty scores remained unchanged.
The improvement in these markers occurred concurrently with the rise in the skeletal muscle degradation biomarker U-titin.
This dissociation between improved nutritional/cardiac indices and increased muscle degradation marker is a central finding of the paper.
Methods
The study was designed as a prospective single-centre observational study of heart failure patients initiating empagliflozin.
117 patients with stable congestive heart failure were enrolled between February 2023 and October 2024.
After exclusions, 93 patients were analyzed.
Assessments were conducted at baseline and again at 6 months.
Outcome measures included nutritional indices (GNRI, CONUT, MNA), quality-of-life (KCCQ-12), functional status (Barthel index), frailty (clinical frailty scale), and U-titin.
The study was conducted at a single centre, which limits generalizability.
Background
SGLT2 inhibitors have demonstrated prognostic benefits in heart failure including in older adults, frail, and underweight patients, but potential adverse effects on skeletal muscle are a concern motivating this study.
The authors note that 'their prognostic benefits are consistent across older adults, frail, and underweight patients, but there may be potential adverse effects on the skeletal muscle.'
This potential adverse effect on skeletal muscle formed the primary rationale for measuring U-titin as the study's key biomarker.
SGLT2 inhibitors are described as having 'become essential in the management of heart failure.'
What This Means
This research suggests that a diabetes and heart failure medication called empagliflozin (an SGLT2 inhibitor) may be associated with increased breakdown of skeletal muscle in heart failure patients, even when other health markers are improving. In a study of 93 older heart failure patients (median age 79) who took empagliflozin for 6 months, a urine-based marker of muscle breakdown called urinary titin (U-titin) rose significantly over the treatment period. At the same time, measures of nutrition, heart function, and quality of life all improved, creating a mixed picture of benefit and potential harm.
The study also found that patients whose hearts pump with preserved strength (ejection fraction ≥50%) were more than three times as likely to experience a large increase in this muscle breakdown marker compared to those with reduced pumping strength. Additionally, baseline U-titin levels reflected patients' nutritional and physical condition before treatment began, suggesting this biomarker could be useful for monitoring vulnerable patients.
This research matters because SGLT2 inhibitors like empagliflozin are now widely used in heart failure management and have proven benefits, but the patients who benefit most — older, frail, and underweight individuals — may also be the most vulnerable to muscle loss. The findings suggest that monitoring skeletal muscle health during treatment may be important, particularly in older heart failure patients, though the study's observational design means it cannot prove that empagliflozin directly causes the muscle breakdown.
Nishikawa T, Nakanishi N, Osawa K, Mizuno J, Ono Y, Shirahata A, et al.. (2026). Association between empagliflozin exposure and skeletal muscle degeneration in patients with heart failure.. BMC cardiovascular disorders. https://doi.org/10.1186/s12872-026-06003-4