Antidiabetic Drug Associations With Heart Failure Outcomes: Real-World Evidence Study Using Electronic Health Records

Abstract Background Patients with type 2 diabetes mellitus (T2D) have a higher risk of cardiovascular disease, including heart failure (HF), leading to health care burden including hospitalization and mortality. Among multiple T2D therapies, there are inadequate head-to-head comparisons of their effects on HF in the real-world patient population. Objective This study aims to compare the time-to-HF among patients treated with different T2D drugs following metformin. Methods We conducted a retrospective data analysis on electronic health records of 5000 patients with T2D. The inclusion criteria were previous treatment with metformin and initiation of glucagon-like peptide-1 receptor agonists (GLP1 RAs), dipeptidyl peptidase-4 inhibitors (DPP4i), sulfonylureas, or insulin. We grouped patients by the mechanism of their subsequent therapies and focused on 2 pairs of comparisons classified by insulin resistance: sulfonylureas versus insulin (increased resistance) and GLP1 RA versus DPP4i (decreased resistance). The outcomes were 5-year HF status and the HF-free survival time, which was verified manually by examining clinical notes. We applied doubly robust causal estimation and accounted for confounding by adjusting for coded and natural language processing electronic health record features identified through medical knowledge networks. Results The study included 939 patients, of whom 204 (21.7%) received insulin, 482 (51.3%) received sulfonylureas, 90 (9.6%) received GLP1 RA, and 163 (17.4%) received DPP4i. Patients in the sulfonylureas group had a significantly higher 5-year HF-free survival compared to the insulin group (survival ratio of insulin/sulfonylureas 0.902, 95% CI 0.840‐0.976; P= .01). There was no significant difference between the DPP4i versus GLP1 RA group in 5-year HF-free survival (survival ratio of GLP1 RA/DPP4i was 0.953, 95% CI 0.849‐1.067; P= .40). For the occurrence of a HF-related hospitalization within 5 years, there were no significant differences between the sulfonylureas and insulin groups (risk difference 0.057, 95% CI –0.011 to 0.132; P= .11), and between the GLP1 RA and DPP4i groups (risk difference 0.010, 95% CI –0.096 to 0.129). Conclusions We evaluated real-world evidence on 2 head-to-head comparisons of second-line T2D therapies on 5-year HF outcomes. Patients on sulfonylureas were associated with lower 5-year HF risks than those treated with insulin when measured by risk ratio, but no significant difference was detected when measured by the risk difference. Limitations of this study included potentially inadequate adjustment of confounding in the observational study and a limited sample size with validated HF outcomes.