Repurposing doxycycline as an adjunct to sitagliptin in type 2 diabetes mellitus: a randomized controlled study on glycemic, inflammatory, and cardiometabolic outcomes

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, β-cell dysfunction, and chronic low-grade inflammation. Doxycycline exhibits anti-inflammatory properties, suggesting potential benefit as an adjunctive therapy in T2DM. To evaluate the efficacy and safety of adjunctive doxycycline in patients with T2DM receiving sitagliptin. In this randomized controlled trial, 57 patients with T2DM were assigned to receive sitagliptin alone (n = 29) or sitagliptin plus doxycycline (n = 28) for 12 weeks. Glycemic indices, insulin sensitivity measures, lipid profile, cardiometabolic risk indices, and inflammatory markers were assessed before and after treatment. Parametric outcomes were analyzed using analysis of covariance (ANCOVA) adjusted for baseline values, while non-parametric biomarkers were analyzed using Hodges-Lehmann estimators. Multivariable linear regression identified independent determinant of treatment response. Between-group comparisons for secondary outcomes were adjusted using the Benjamini-Hochberg false discovery rate. Both groups showed significant within-group improvements in body weight, glycemic indices, lipid profile, and inflammatory markers (p < 0.05). However, the combination therapy demonstrated superior outcomes. Significant reductions were observed in fasting blood glucose (adjusted mean difference: - 6.20 mg/dL, p = 0.034), fasting insulin (- 2.02 μIU/mL, p = 0.008), HOMA-IR (- 0.83, p < 0.001), and HbA1c (- 1.25%, p < 0.001), along with increased insulin sensitivity (QUICKI: + 0.0086, p < 0.001). Cardiometabolic parameters were also significantly improved, including total cholesterol (- 14.0 mg/dL, p = 0.030), triglycerides (- 11.6 mg/dL, p = 0.007), LDL-C (- 14.4 mg/dL, p < 0.001), and HDL-C (+ 4.8 mg/dL, p = 0.030). Risk indices (AI, CVRI, CRR) showed marked reductions (all p < 0.05). Inflammatory biomarkers were associated with improvements with combination therapy, including reductions in MMP-9 (p = 0.030) and CRP (p = 0.002). Regression analysis identified doxycycline treatment as an independent determinant of improvement in most outcomes, including HbA1c, HOMA-IR, QUICKI, lipid indices, and MMP-9. FDR correction confirmed the robustness of these findings. Correlation analyses revealed strong associations between insulin resistance markers and cardiometabolic indices. Adverse events were mild and comparable between groups. The addition of doxycycline to sitagliptin appears to improve glycemic control, insulin sensitivity, cardiometabolic risk profile, and inflammatory status in T2DM, without increasing adverse effects. These findings are exploratory and should be confirmed in larger trials with longer follow-up. CLINICAL TRIAL IDENTIFIER: NCT06329882.