Risk of major adverse cardiovascular events and all-cause mortality in type 2 diabetic patients receiving insulin versus non-insulin treatment intensification

The optimal timing for initiating insulin therapy in patients with type 2 diabetes (T2D) remains uncertain and varies among clinical guidelines. This retrospective cohort study analyzed claims data to include insulin-naïve T2D patients aged ≥ 20 years who intensified treatment using either insulin or non-insulin therapies between 2012 and 2021. Cox proportional hazards models were applied to estimate hazard ratios (HRs) for major adverse cardiovascular events (MACE) and all-cause mortality, with adjustments for sex, age interval, index year interval, number of outpatient visits, number of inpatient admissions, diabetes duration, Charlson Comorbidity Index (CCI), Diabetes Complication Severity Index (DCSI), the number of prior antidiabetic medications, medications for hypertension, hyperlipidemia, antiplatelets, and anticoagulants. Subgroup analyses stratified by sex, age, the number of prior antidiabetic medications and types of insulin were also performed. Compared to non-insulin intensification, insulin therapy was associated with significantly higher risks of MACE and all-cause mortality. The adjusted HRs (95% confidence intervals [CIs]) were 2.78 (2.64-2.92) for MACE and 4.74 (4.63-4.85) for all-cause mortality. Subgroup analyses revealed consistently elevated risks across all patient groups, with the smallest risk increases observed in patients who had previously used three non-insulin drugs before initiating insulin therapy (HRs for MACE: 2.62 [2.13-3.22]; all-cause mortality: 3.05 [2.68-3.49]). Among insulin types, long-acting insulin was associated with the lowest risk increases (MACE HR: 1.34 [1.19-1.51]; all-cause mortality HR: 1.90 [1.78-2.03]). In conclusion, treatment intensification with insulin was linked to increased risks of MACE and all-cause mortality. The lowest risks were observed in patients initiating long-acting insulin following prior therapy with three non-insulin drugs. These findings highlight the need for careful patient evaluation and individualized decision-making when initiating insulin therapy in T2D management.