American Diabetes Association
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Cardiovascular safety in type 2 diabetes with sulfonylureas as second-line drugs: a nation-wide population based comparative safety study

Version 2 2023-03-27, 20:48
Version 1 2023-03-21, 19:21
posted on 2023-03-27, 20:48 authored by HUAN WANGHUAN WANG, Ruth L. M. Cordiner, Yu HuangYu Huang, Louise Donnelly, Simona HapcaSimona Hapca, Andrew Collier, John McKnight, Brian Kennon, Fraser Gibb, Paul McKeigue, Sarah H Wild, Helen Colhoun, John Chalmers, John Petrie, Naveed Sattar, Thomas MacDonald, Rory J McCrimmon, Daniel R. Morales, Ewan R. Pearson, the Scottish Diabetes Research Network Epidemiology Group



To assess the real-world cardiovascular (CV) safety for SU, in comparison with dipeptidylpeptidase-4 inhibitors (DPP4i) and thiazolidinediones (TZD) through development of robust methodology for causal inference in a whole nation study. 

Research Design and Methods

A cohort study was performed including people with type 2 diabetes diagnosed in Scotland before 31 December 2017, who failed to reach HbA1c 48 mmol/mol despite metformin monotherapy and initiated second-line pharmacotherapy (SU/DPP4i/TZD) on or after 1 January 2010.

The primary outcome was the composite major adverse cardiovascular events (MACE), including hospitalization for myocardial infarction (MI), ischemic stroke, heart failure, and CV death. Secondary outcomes were each individual endpoint and all-cause death. Multivariable Cox proportional hazards regression and an instrumental variable (IV) approach were used to control confounding in a similar way to the randomization process in a randomized control trial.  


Comparing SU to non-SU (DPP4i/TZD), the hazard ratio (HR) for MACE was 1.00 (95% CI: 0.91 to 1.09) from the multivariable Cox regression and 1.02 (0.91  - 1.13) and 1.03 (0.91- 1.16) using two different IVs. For all-cause death, the HR from Cox regression and the two IV analyses was 1.03 (0.94 - 1.13), 1.04 (0.93 - 1.17), and 1.03 (0.90 - 1.17). 


Our findings contribute to the understanding that second-line SU for glucose lowering are unlikely to increase CV risk or all-cause mortality. Given their potent efficacy, microvascular benefits, cost effectiveness and widespread use, this study supports that SU should remain a part of the global diabetes treatment portfolio.Article  


British Heart Foundation (BHF)


HDR-5012 Public Health Agency (Northern Ireland)

Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government)

the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government

Wellcome Trust 102820/Z/13/Z