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.

NM receives grant funding from the National Institutes of Health, Breakthrough T1D, and Samsung Research America. MAS and GH have received contracts from the US Food and Drug Administration and Janssen Research & Development. MAS also receives contracts from Gilead Sciences, Inc. AO is an employee of Johnson & Johnson. These relationships are outside the scope of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

https://ohdsi-studies.github.io/LegendT2dm/Protocol.html

This study was partially funded through the National Institutes of Health grants R01LM006910, R01DK125780, R01DK134955, R01HL169954, R01HL167858, R35GM160458, T15LM007079-34, R01AG089981, and K23HL153775; the Doris Duke Charitable Foundation (award 2022060); the Blavatnik Family Foundation; and Breakthrough T1D. The funders had no role in the design and conduct of the protocol; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All data partners received institutional approval or exemption for their participation. For CCAE, MDCR, MDCD, Optum Cliniformatics, and OptumEHR, New England IRB determined the study as exempt from broad IRB approval. For Open Claims and GermanyDA, approval is provided for OHDSI network studies. For the VA database, use of VA-OMOP was reviewed by the VA Salt Lake City Health Care System Research and Development Committee and was determined to meet the criteria for exemption under Exemption Category 4 (3) and approved the request for Waiver of HIPAA Authorization (IRBnet #1875081-3).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The patient-level raw data used in this study cannot be publicly shared due to strict data privacy regulations, ethical considerations, and commercial Data Use Agreements. The underlying databases (e.g., Merative MarketScan, Optum, IQVIA, VA, SIDIAP) are subject to licensing restrictions and institutional governance. Researchers interested in accessing the raw patient-level data must apply directly to the respective data custodians for access or licensing. However, the comprehensive aggregated summary statistics, baseline characteristics, propensity score diagnostics, and full comparative effectiveness analysis results are publicly available through interactive online repositories. Cohort characteristics analysis results can be accessed at: https://data.ohdsi.org/LegendT2dmClassCohortExplorer/ and comparative effectiveness analysis results at: https://data.ohdsi.org/LegendT2dmClassEvidenceExplorer/.

https://data.ohdsi.org/LegendT2dmClassCohortExplorer/

https://data.ohdsi.org/LegendT2dmClassEvidenceExplorer/