Sex Differences in Comparative Effectiveness and Safety of Second-line Antidiabetic Agents: Real-world Evidence from Large-scale Multinational Study

Importance Women have been under-represented in clinical trials of type 2 diabetes mellitus (T2D), and evidence on sex differences in effectiveness of T2D treatments remains limited. Objective To assess sex differences in comparative effectiveness and safety of four second-line antidiabetic agents: glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), and sulfonylureas (SU). Design Retrospective cohort study using an active-comparator new-user design, following each participant till treatment discontinuation or end of data. Setting Multinational study across ten real-world databases from the Observational Health Data Sciences and Informatics (OHDSI) network in the United States, United Kingdom, Germany, and Spain. Participants 5.15 million adults with T2D who initiated one of the four second-line therapies following metformin during 1992-2021. Exposures GLP-1RA, SGLT2i, DPP4i, or SU. Main Outcomes and Measures Cardiovascular effectiveness as measured through 7 outcomes (major adverse cardiovascular events and glycemic control) and safety through 18 outcomes as highlighted by ADA guideline. Hazard ratios (HRs) are estimated separately for women and men using propensity score-stratified Cox models with empirical calibration. Sex differences were tested using Z-tests on log-HR differences. Results Drug initiation rates differed by sex with 9.28% of women initiating on GLP-1RA, 11.91% SGLT2i, 27.81% DPP4i, and 50.99% SU; the rates among the men were 5.41%, 12.84%, 24.64%, and 57.10%. No significant sex differences were observed for cardiovascular effectiveness outcomes. Several safety outcomes showed significant sex differences that are consistent across drug comparisons. Focusing on GLP-1RA compared to SGLT2i for brevity, GLP-1RA users experienced the following comparative benefits and risks: higher risk of acute pancreatitis among women (HR 1.39 [1.13, 1.70]) while non-differential risk among men (HR 0.91 [0.74, 1.12]) with p = 0.005 for the test of difference; non-differential risk of hypotension among women (HR 1.08 [0.98, 1.19]) while lower risk among men (HR 0.87 [0.78, 0.96]) with p = 0.003. Where no sex differences were found, our findings were consistent with existing evidence. Conclusions and Relevance This large-scale multinational study on antidiabetic agents identified clinically relevant sex differences, which are biologically plausible but previously lacked clinical evidence. Our findings reinforce the importance of tailoring T2D management according to sex.