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Randomized Controlled Trial
. 2023 May 1;46(5):967-977.
doi: 10.2337/dc22-1238.

Cardiovascular Safety in Type 2 Diabetes With Sulfonylureas as Second-line Drugs: A Nationwide Population-Based Comparative Safety Study

Huan Wang  1 , Ruth L M Cordiner  1 , Yu Huang  1   2 , Louise Donnelly  1 , Simona Hapca  3 , Andrew Collier  4 , John McKnight  5 , Brian Kennon  6 , Fraser Gibb  7 , Paul McKeigue  7 , Sarah H Wild  7 , Helen Colhoun  7 , John Chalmers  8 , John Petrie  9 , Naveed Sattar  9 , Thomas MacDonald  10 , Rory J McCrimmon  11 , Daniel R Morales  1 , Ewan R Pearson  1 ; Scottish Diabetes Research Network Epidemiology Group
Collaborators, Affiliations
Randomized Controlled Trial

Cardiovascular Safety in Type 2 Diabetes With Sulfonylureas as Second-line Drugs: A Nationwide Population-Based Comparative Safety Study

Huan Wang et al. Diabetes Care. .

Abstract

Objective: To assess the real-world cardiovascular (CV) safety for sulfonylureas (SU), in comparison with dipeptidyl peptidase 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 composite major adverse cardiovascular events (MACE), including hospitalization for myocardial infarction, ischemic stroke, heart failure, and CV death. Secondary outcomes were each individual end point 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.

Results: Comparing SU to non-SU (DPP4i/TZD), the hazard ratio (HR) for MACE was 1.00 (95% CI: 0.91-1.09) 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).

Conclusions: 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.

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Conflict of interest statement

Duality of Interest. R.L.M.C. has received honoraria from Sanofi, J.M. has received speaker fees from Napp Pharmaceuticals and has been involved in CV outcome trials funded by Novo Nordisk, Eli Lilly, Boehringer, GlaxoSmithKline, and Medimmune Ltd. H.C. has received grants or institutional fees from Eli Lilly and Company, AstraZeneca LP, Pfizer, and Novo Nordisk. N.S. has consulted for Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceutical, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi, and received grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. R.J.M. has received royalties or licenses from Elsevier and honoraria from Sanofi and Novo Nordisk, and institutional fees from National Health Services Tayside and Medical Reserve Corps. E.R.P. has received honoraria from Sanofi and Eli Lilly. No other potential conflicts of interest relevant to this article were reported.

Figures

None
Graphical abstract
Figure 1
Figure 1
Forest plot summarizing the comparison of outcome rates between SU and non-SU agents (DPP4i or TZD) as second-line treatment in addition to metformin between 2010 and 2017.
Figure 2
Figure 2
Forest plot summarizing the comparison of outcome rates between SU and DPP4i as second-line treatment in addition to metformin between 2010 and 2017.
Figure 3
Figure 3
Forest plot summarizing the comparison of outcome rates between SU and TZD as second-line treatment in addition to metformin between 2010 and 2017.
See this image and copyright information in PMC

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