Beyond glycemic control: differential effects of empagliflozin and sitagliptin on insulin sensitivity and a shared increase in adropin in type 2 diabetes

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by metabolic and inflammatory disturbances beyond hyperglycemia. Hepatokines such as adropin have emerged as regulators of insulin resistance and vascular function, yet the comparative metabolic effects of sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase 4 (DPP-4) inhibitors on adropin remain unclear. This study compared the effects of empagliflozin versus sitagliptin, each added to metformin, on serum adropin, insulin resistance, glycemic control, lipid profile, and inflammation in adults with T2DM. METHOD: In this single-center, randomized, open-label, parallel-group superiority trial with blinded outcome assessment and blinded statistical analysis, 100 adults with inadequately controlled type 2 diabetes mellitus (HbA1c ≥ 7.5%) receiving stable metformin therapy were allocated in a 1:1 ratio to receive empagliflozin 10 mg once daily or sitagliptin 100 mg once daily for a 12-week intervention period. The co-primary outcomes were changes in circulating adropin concentrations and insulin resistance, assessed by the homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes included changes in HbA1c, fasting insulin, lipid parameters, body weight, and tumor necrosis factor-α (TNF-α). All analyses were conducted according to the intention-to-treat principle. RESULT: Ninety‑four participants completed the intervention; all were included in analyses. Serum adropin increased from 291 ± 133 to 362 ± 124 pg/mL with empagliflozin and from 299 ± 98 to 358 ± 126 pg/mL with sitagliptin (time effect: F = 19.67, p < .001). HOMA‑IR declined from 10.08 ± 4.44 to 6.65 ± 2.50 with empagliflozin and from 9.28 ± 2.97 to 7.15 ± 1.80 with sitagliptin (interaction: F = 4.85, p = .032, partial η² = 0.09). HbA1c decreased from 8.10 ± 0.53 to 7.04 ± 1.18 with empagliflozin and from 8.29 ± 0.66 to 7.62 ± 0.68 with sitagliptin (interaction: F = 4.30, p = .043, η² = 0.081). TNF‑α fell from 44.12 ± 21.52 to 30.78 ± 15.93 in empagliflozin and from 43.93 ± 21.33 to 37.65 ± 17.96 in sitagliptin (time effect: F = 37.09, p < .001). Empagliflozin produced greater reductions in fasting insulin (- 3.43 ± 2.34 µIU/mL vs. - 2.13 ± 1.17 µIU/mL, interaction p = .036), triglycerides (- 42.5 ± 23.9 mg/dL vs. - 21.9 ± 14.5 mg/dL, interaction p = .005), and a larger HDL‑C increase (+ 5.8 ± 3.1 mg/dL vs. + 3.3 ± 2.5 mg/dL, interaction p = .017). Body weight and BMI decreased similarly in both groups (time effect p < .001, no interaction). No serious adverse events occurred. CONCLUSION: Both empagliflozin and sitagliptin improved metabolic and inflammatory markers and were associated with comparable increases in circulating adropin. Empagliflozin conferred broader metabolic benefits, particularly in insulin resistance, glycemic control, and lipid profile. The parallel rise in adropin across treatment groups highlights its potential role as a treatment-responsive biomarker rather than a drug-specific effect. TRIAL REGISTRATION: This trial was prospectively registered with the Iranian Registry of Clinical Trials (IRCT ID: IRCT20160625028627N8) on May 27, 2025 (Trial ID: 83720). The complete trial record is accessible at https://irct.behdasht.gov.ir/user/trial/83720/view.