Revisiting Glycemic Control Targets: Survival Outcomes by Glycated Hemoglobin Levels Among Patients With Diabetes Under Contemporary Antidiabetic Therapy

BACKGROUND: Optimal glycated hemoglobin (HbA1c) targets for type 2 diabetes remain controversial. Given the evolution of modern antidiabetic therapies, this study aims to reevaluate optimal glycemic targets among patients receiving contemporary glucose-lowering treatments. METHODS: We conducted a retrospective cohort study using the National Taiwan University Hospital Integrated Medical Database, including 16 604 patients with type 2 diabetes who initiated dipeptidyl peptidase-4 inhibitors between 2009 and 2019, with follow-up through December 2021. Patients were categorized by long-term mean HbA1c quintiles. Outcomes included major adverse cardiovascular events (including ischemic stroke, myocardial infarction, cardiovascular death), renal outcomes (progression to dialysis, ≥50% estimated glomerular filtration rate decline, or doubling serum creatinine), hospitalization for heart failure, and safety outcomes. Associations were assessed using Cox proportional hazards models and restricted cubic spline analyses. RESULTS: Compared with the third quintile as reference, the fourth (hazard ratio [HR], 1.22 [95% CI, 1.01-1.47]) and fifth quintiles (HR, 1.36 [95% CI, 1.12-1.64]) were associated with a significantly higher risk of major adverse cardiovascular events. Restricted cubic spline modeling identified significant J-shaped relationships for both major adverse cardiovascular events and renal outcomes, with the lowest risk observed around an HbA1c of 7%. In contrast, hospitalization for heart failure risk increased linearly with rising HbA1c levels. Notably, sex differences were identified: men showed a linear decrease in cardiovascular risk with lower HbA1c, whereas women exhibited a J-shaped relationship, indicating increased risks at both glycemic extremes. CONCLUSION: Optimal glycemic targets among patients receiving contemporary therapies differ by outcome and sex. Individualized HbA1c management strategies are essential to balance cardiovascular and renal benefits against potential risks.