Metformin-based glucose-lowering regimens, circulating biomarkers, and exploratory muscle outcomes in type 2 diabetes: a cross-sectional study

Резюме

Background To compare three stable metformin-based regimens—metformin alone, metformin plus dulaglutide, and metformin plus empagliflozin—in relation to muscle phenotypes and circulating insulin-like growth factor 1 (IGF-1) and tumor necrosis factor alpha (TNF-α) in adults with type 2 diabetes mellitus (T2DM). Methods This single-center cross-sectional study included 161 patients. Bioelectrical impedance analysis-derived skeletal muscle index (BIA-SMI), maximum handgrip strength, 6-m gait speed, five-times chair stand time, sarcopenia status, serum IGF-1, and serum TNF-α were assessed. Primary models adjusted for age, sex, diabetes duration, and the most recent body mass index, glycated hemoglobin, and estimated glomerular filtration rate recorded before regimen initiation, using HC3 heteroskedasticity-robust standard errors. IGF-1 and TNF-α were primary biomarker outcomes; BIA-SMI and handgrip strength were secondary exploratory outcomes. Holm correction, pairwise propensity score overlap weighting, restriction and log-transformation sensitivity analyses, and false discovery rate-adjusted Spearman correlations were used. Results The metformin, dulaglutide, and empagliflozin groups included 52, 54, and 55 patients, respectively. BIA-SMI, handgrip strength, physical performance, and sarcopenia prevalence did not differ significantly among groups. Compared with metformin, empagliflozin was associated with IGF-1 higher by 7.50 ng/mL (95% CI 1.66 to 13.34; Holm-adjusted P = 0.035) and TNF-α lower by 3.09 pg/mL (95% CI −4.95 to −1.24; Holm-adjusted P = 0.004). The overall handgrip-strength test was not significant ( P = 0.137); the empagliflozin-versus-metformin coefficient was 2.11 kg (nominal P = 0.047; Holm-adjusted P = 0.189) and was interpreted as exploratory. BIA-SMI was not associated with regimen (overall P = 0.739). After overlap weighting, the association with lower TNF-α persisted, whereas the IGF-1 difference was attenuated. Biomarker associations retained the same directions in log-transformed models. TNF-α was directionally consistent across restriction analyses, whereas the IGF-1 association weakened after exclusion of patients with chronic kidney disease. Conclusion Lower circulating TNF-α concentrations were observed in the empagliflozin group in the primary analyses, although this association was attenuated after additional adjustment for cardiovascular and renal comorbidities and statin use. The IGF-1 association was uncertain and may reflect kidney-related differences. No statistically significant differences were detected in the objective muscle outcomes, whereas SARC-F scores differed across groups, with the highest median score in the empagliflozin group. The patient-reported and performance-based findings did not provide consistent evidence of better or worse muscle-related function attributable to any regimen. Sarcopenia comparisons were exploratory and limited by the small number of cases. Treatment-selection differences, residual confounding, and potential hydration-related bias in BIA estimates limit interpretation. These findings are hypothesis-generating and do not establish independent drug effects on IGF-1, comparative treatment benefits, or equivalent muscle mass.