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Life sciences · Journal article
Frontiers in Endocrinology · September 21, 2026
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Objective To evaluate the longitudinal associations of early insulin combined with metformin therapy, compared with metformin monotherapy, with subsequent risks of stroke, heart failure, chronic kidney disease, and cancer among adults with newly diagnosed type 2 diabetes using real-world data. Methods We conducted an active-comparator new-user cohort study using the Cheeloo LEAD electronic health record database (Shandong, China; 2014–2021). Adults aged 40–85 years who initiated early insulin combined with metformin therapy or metformin monotherapy during 2014–2017 were included in the common parent cohort (n=19,908; 4,304 [21.6%] and 15,604 [78.4%], respectively). Follow-up began at each treatment strategy initiation date (t0). Four independent outcome-specific subcohorts excluded patients with the corresponding pre-existing outcome and those with the outcome recorded within 30 days after t0. The combination group required at least 14 days of overlapping insulin and metformin use. L1-regularized propensity score matching and Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) over up to 1,500 days. Sensitivity analyses used a 180-day outcome-exclusion window. Results Compared with metformin monotherapy, early insulin combined with metformin therapy was associated with a lower hazard of stroke (HR 0.88, 95% CI 0.78–0.99) and higher hazards of heart failure (HR 1.18, 95% CI 1.02–1.36), chronic kidney disease (HR 1.37, 95% CI 1.03–1.83), and cancer (HR 1.37, 95% CI 1.14–1.66). Exploratory subgroup estimates varied by age and sex; no formal interaction tests were performed. Results were broadly consistent in sensitivity analyses. Conclusion Early insulin combined with metformin therapy and metformin monotherapy showed different longitudinal associations with the four outcomes. These findings should be interpreted in light of residual confounding by baseline disease severity and treatment indication and may inform risk monitoring in routine care.