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. 2025 Mar 1;48(3):361-370.
doi: 10.2337/dc24-1546.

Use of SGLT2i Versus DPP-4i as an Add-on Therapy and the Risk of PAD-Related Surgical Events (Amputation, Stent Placement, or Vascular Surgery): A Cohort Study in Veterans With Diabetes

Katherine E Griffin  1 , Kathryn Snyder  1   2 , Amir H Javid  1   3 , Amber Hackstadt  1   3 , Robert Greevy  1   3 , Carlos G Grijalva  1   4 , Christianne L Roumie  1   2   4
Affiliations

Use of SGLT2i Versus DPP-4i as an Add-on Therapy and the Risk of PAD-Related Surgical Events (Amputation, Stent Placement, or Vascular Surgery): A Cohort Study in Veterans With Diabetes

Katherine E Griffin et al. Diabetes Care. .

Abstract

Objective: To compare the risk of composite peripheral artery disease (PAD) surgical outcome, including peripheral revascularization and amputation procedures, between new users of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP-4is).

Research design and methods: This retrospective cohort study of U.S. veterans age ≥18 years with diabetes who received care from the Veterans Health Administration was performed from 1 October 2000 to 31 December 2021. Data were linked to Medicare, Medicaid, and the National Death Index. New use of SGLT2i or DPP-4i medications as an add-on to metformin, sulfonylurea, or insulin treatment alone or in combination was evaluated for an association with PAD surgical procedure for peripheral revascularization and amputation. A Cox proportional hazards model for time-to-PAD event analysis compared the risk of a PAD event between SGLT2is and DPP-4is in a propensity score-weighted cohort with a competing risk of death and allowance for events to occur up to 90 days or 360 days after stopping SGLT2is.

Results: The weighted cohort included 76,072 SGLT2i vs. 75,833 DPP-4i use episodes. The median age was 69 years, HbA1c was 8.4% (interquartile range [IQR] 7.5-9.4%), and the median diabetes duration was 10.1 (IQR 6.6-14.6) years. There were 874 and 780 PAD events among SGLT2i and DPP-4i users, respectively, for an event rate of 11.2 (95% CI 10.5-11.9) and 10.0 (9.4-10.6) per 1,000 person-years (adjusted hazard ratio [aHR] 1.18 [95% CI 1.08-1.29]). When PAD events were allowed for 360 days after SGLT2i use ended, the aHR was 1.16 (95% CI 1.06-1.26).

Conclusions: SGLT2i as an add-on diabetes therapy was associated with an increased cause-specific hazard of PAD surgeries compared with DPP-4i.

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Conflict of interest statement

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Figures

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Graphical abstract
Figure 1
Figure 1
Flowchart of eligible patient episodes for analysis. Ref., reference.
Figure 2
Figure 2
Cumulative probability of surgical PAD events (composite of time to amputation or surgical revascularization) in the SGLT2i vs. DPP-4i cohort using propensity score weighting. A: PAD events up to 90 days after stopping medications. B: PAD events up to 90 days after stopping medications with death as a competing event. C: PAD events up to 360 days after stopping medications. D: PAD events up to 360 days after stopping medications with death as a competing event.
See this image and copyright information in PMC

References

    1. Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr 2010;8:29. - PMC - PubMed
    1. McCullough KP, Morgenstern H, Saran R, Herman WH, Robinson BM. Projecting ESRD Incidence and Prevalence in the United States through 2030. J Am Soc Nephrol 2019;30:127–135 - PMC - PubMed
    1. American Diabetes Association . Cardiovascular disease. Accessed 21 January 2024. Available from https://diabetes.org/about-diabetes/complications/cardiovascular-disease
    1. U.S. Food and Drug Administration. FDA removes boxed warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Published 17 September 2020. Accessed 21 January 2024. Available from https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed...
    1. Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS Program Collaborative Group . Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–657 - PubMed

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