What is the comparative effectiveness of sodium-glucose cotransporter 2 inhibitors vs sulfonylureas associated with the risk of all-cause mortality among individuals using metformin for treatment of type 2 diabetes?
In this comparative effectiveness study analyzing data from the US Department of Veterans Affairs and including 128 293 individuals with type 2 diabetes receiving metformin, use of sodium-glucose cotransporter 2 inhibitors was associated with reduced risk of all-cause mortality compared with sulfonylureas, regardless of cardiovascular disease status, estimated glomerular filtration rate category, and albuminuria status. Use of sodium-glucose cotransporter 2 inhibitors with metformin therapy was associated with a reduced risk of all-cause mortality compared with sodium-glucose cotransporter 2 inhibitors without metformin therapy.
The results of this cohort study provide real-world data on the risk of all-cause mortality associated with sodium-glucose cotransporter 2 inhibitors vs sulfonylureas, which may help guide the choice of antihyperglycemic therapy in people with type 2 diabetes.
In the treatment of type 2 diabetes, evidence of the comparative effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors vs sulfonylureas—the second most widely used antihyperglycemic class after metformin—is lacking.
To evaluate the comparative effectiveness of SGLT2 inhibitors and sulfonylureas associated with the risk of all-cause mortality among patients with type 2 diabetes using metformin.
Design, Setting, and Participants
A cohort study used data from the US Department of Veterans Affairs compared the use of SGLT2 inhibitors vs sulfonylureas in individuals receiving metformin for treatment of type 2 diabetes. A total of 23 870 individuals with new use of SGLT2 inhibitors and 104 423 individuals with new use of sulfonylureas were enrolled between October 1, 2016, and February 29, 2020, and followed up until January 31, 2021.
New use of SGLT2 inhibitors or sulfonylureas.
Main Outcomes and Measures
This study examined the outcome of all-cause mortality. Predefined variables and covariates identified by a high-dimensional variable selection algorithm were used to build propensity scores. The overlap weighting method based on the propensity scores was used to estimate the intention-to-treat effect sizes of SGLT2 inhibitor compared with sulfonylurea therapy. The inverse probability of the treatment adherence weighting method was used to estimate the per-protocol effect sizes.
Among the 128 293 participants (mean [SD] age, 64.60 [9.84] years; 122 096 [95.17%] men), 23 870 received an SGLT2 inhibitor and 104 423 received a sulfonylurea. Compared with sulfonylureas, SGLT2 inhibitors were associated with reduced risk of all-cause mortality (hazard ratio [HR], 0.81; 95% CI, 0.75-0.87), yielding an event rate difference of −5.15 (95% CI, −7.16 to −3.02) deaths per 1000 person-years. Compared with sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of death, regardless of cardiovascular disease status, in several categories of estimated glomerular filtration rate (including rates from >90 to ≤30 mL/min/1.73 m2) and in participants with no albuminuria (albumin to creatinine ratio [ACR] ≤30 mg/g), microalbuminuria (ACR >30 to ≤300 mg/g), and macroalbuminuria (ACR >300 mg/g). In per-protocol analyses, continued use of SGLT2 inhibitors was associated with a reduced risk of death compared with continued use of sulfonylureas (HR, 0.66; 95% CI, 0.60-0.74; event rate difference, −10.10; 95% CI, −12.97 to −7.24 deaths per 1000 person-years). In additional per-protocol analyses, continued use of SGLT2 inhibitors with metformin was associated with a reduced risk of death compared with SGLT2 inhibitor treatment without metformin (HR, 0.70; 95% CI, 0.50-0.97; event rate difference, −7.62; 95% CI, −17.12 to −0.48 deaths per 1000 person-years).
Conclusions and Relevance
In this comparative effectiveness study analyzing data from the US Department of Veterans Affairs, among patients with type 2 diabetes receiving metformin therapy, SGLT2 inhibitor treatment was associated with a reduced risk of all-cause mortality compared with sulfonylureas. The results provide data from a real-world setting that might help guide the choice of antihyperglycemic therapy.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: April 14, 2021.
Published Online: June 28, 2021. doi:10.1001/jamainternmed.2021.2488
Correction: This article was corrected on September 13, 2021, to fix errors in Figure 2 and the Supplement.
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Xie Y et al. JAMA Internal Medicine.
Corresponding Author: Ziyad Al-Aly, MD, Clinical Epidemiology Center, Research and Development Service, VA St Louis Health Care System, 915 N Grand Blvd, 151-JC, St Louis, MO 63106 (firstname.lastname@example.org).
Author Contributions: Dr Al-Aly had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Xie, Bowe, Maddukuri, McGill, Al-Aly.
Acquisition, analysis, or interpretation of data: Xie, Bowe, Gibson, Al-Aly.
Drafting of the manuscript: Xie, Al-Aly.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Xie, Bowe, Al-Aly.
Obtained funding: Al-Aly.
Administrative, technical, or material support: Al-Aly.
Conflict of Interest Disclosures: Dr McGill reported receiving grants from Dexcom, Medtronic, and Novo Nordisk, and personal fees from Bayer, Boehringer Ingelheim, Lilly, Metavant, and Salix outside the submitted work. No other disclosures were reported.
Funding/Support: Support for Veterans Affairs/Centers for Medicare & Medicaid Services data was provided by the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, VA Information Resource Center (project number/data use agreement ID Al-Aly-01-A-1). This research was funded by the United States Department of Veterans Affairs and the Institute for Public Health at Washington University, St Louis, Missouri (Dr Al-Aly), an American Society of Nephrology and KidneyCure predoctoral fellowship award (Mr Xie), and an American Society of Nephrology and KidneyCure predoctoral fellowship award (Mr Bowe).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The contents do not represent the views of the US Department of Veterans Affairs or the US government.
Additional Contributions: Miguel Hernan, MD, PhD (Harvard T. H. Chan School of Public Health), provided input on this manuscript without financial compensation.
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