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Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type 2 Diabetes
Open accessAbstract
Importance: Results of clinical trials suggest that canagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor for treating type 2 diabetes, may be associated with lower extremity amputation. Objective: To quantify the association between the use of oral medication for type 2 diabetes and 5 outcomes (lower extremity amputation, peripheral arterial disease, critical limb ischemia, osteomyelitis, and ulcer). Design, Setting, and Participants: A retrospective cohort study was conducted using Truven Health MarketScan Commercial Claims and Encounters data on new users between September 1, 2012, and September 30, 2015. The study focused on 2.0 million commercially insured individuals and used propensity score weighting to balance baseline differences among groups. Sensitivity analyses varied statistical models, assessed the effect of combining dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists as a single referent group, adjusted for baseline use of older oral agents, and included people with baseline amputation. Exposures: New use of SGLT-2 inhibitors alone, DPP-4 inhibitors alone, GLP-1 agonists alone, or other antidiabetic agents (sulfonylurea, metformin hydrochloride, or thiazolidinediones). Main Outcomes and Measures: Foot and leg amputation, defined by validated International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes. Results: Among 2.0 million potentially eligible individuals, a total of 953 906 (516 046 women and 437 860 men; mean [SD] age, 51.8 [10.9] years) were included in the final analyses, including 39 869 new users of SGLT-2 inhibitors (4.2%), 105 023 new users of DPP-4 inhibitors (11.0%), and 39 120 new users of GLP-1 agonists (4.1%). The median observation time ranged from 99 days for new users of GLP-1 agonists to 127 days for those using metformin, sulfonylureas, and thiazolidinediones, while the crude incident rates ranged from 4.90 per 10 000 person-years for those using metformin, sulfonylureas, and thiazolidinediones to 10.53 per 10 000 person-years for new users of SGLT-2 inhibitors. After propensity score weighting and adjustment for demographics, severity of diabetes, comorbidities, and medications, there was a nonstatistically significant increased risk of amputation associated with new use of SGLT-2 inhibitors compared with DPP-4 inhibitors (adjusted hazard ratio, 1.50; 95% CI, 0.85-2.67) and GLP-1 agonists (adjusted hazard ratio, 1.47; 95% CI, 0.64-3.36). New use of SGLT-2 inhibitors was statistically significantly associated with amputation compared with sulfonylureas, metformin, or thiazolidinediones (adjusted hazard ratio, 2.12; 95% CI, 1.19-3.77). These results persisted in sensitivity analyses. Conclusions and Relevance: Use of SGLT-2 inhibitors may be associated with increased risk of amputation compared with some oral treatments for type 2 diabetes. Further observational studies are needed with extended follow-up and larger sample sizes.
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“Observational data have been inconclusive.”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [114]
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Austin, P. C. (2011) · Multivariate Behavioral Research · doi:10.1080/00273171.2011.568786 · Cited by 12,242
Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes
Neal, B., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Erondu, N., Shaw, W., Law, G., Desai, M., & Matthews, D. R. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1611925 · Cited by 7,830
The Robust Inference for the Cox Proportional Hazards Model
Lin, D. Y., & Wei, L. J. (1989) · Journal of the American Statistical Association · doi:10.1080/01621459.1989.10478874 · Cited by 2,695
Checking the Cox model with cumulative sums of martingale-based residuals
LIN, D. Y., WEI, L. J., & YING, Z. (1993) · Biometrika · doi:10.1093/biomet/80.3.557 · Cited by 1,432
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Singh, S., Chang, H.-Y., Richards, T. M., Weiner, J. P., Clark, J. M., & Segal, J. B. (2013) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2013.2720 · Cited by 467
Self-citationNeal, B., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Ways, K., Desai, M., Shaw, W., Capuano, G., Alba, M., et al. (2015) · Diabetes Care · doi:10.2337/dc14-1237 · Cited by 233
Why Do SGLT2 Inhibitors Inhibit Only 30–50% of Renal Glucose Reabsorption in Humans?
Liu, J., Lee, T. W., & DeFronzo, R. A. (2012) · Diabetes · doi:10.2337/db12-0052 · Cited by 227
Adjuvant chemotherapy is associated with improved survival in patients with stage II colon cancer
Casadaban, L. C., Rauscher, G. H., Aklilu, M., Villenes, D., Freels, S. A., & Maker, A. V. (2016) · Cancer · doi:10.1002/cncr.30181 · Cited by 152
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2 of the 28 references couldn’t be matched to a known paper.
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- Chang, 2012, Validating the adapted Diabetes Complications Severity Index in claims data., Am J Manag Care, 18, 721
- Centers for Disease Control and Prevention, 2017, National Diabetes Statistics Report, 2017
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Zelniker, T. A., Wiviott, S. D., Raz, I., Im, K., Goodrich, E. L., Bonaca, M. P., Mosenzon, O., Kato, E. T., Cahn, A., Furtado, R. H. M., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(18)32590-x · Cited by 2,845
KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease
Rossing, P., Caramori, M. L., Chan, J. C. N., Heerspink, H. J. L., Hurst, C., Khunti, K., Liew, A., Michos, E. D., Navaneethan, S. D., Olowu, W. A., et al. (2022) · Kidney International · doi:10.1016/j.kint.2022.06.008 · Cited by 1,373
An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors
Salvatore, T., Galiero, R., Caturano, A., Rinaldi, L., Martino, A. D., Albanese, G., Salvo, J. D., Epifani, R., Marfella, R., Docimo, G., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073651 · Cited by 279
Lower Extremity Peripheral Artery Disease Without Chronic Limb-Threatening Ischemia
Polonsky, T. S., & McDermott, M. M. (2021) · JAMA · doi:10.1001/jama.2021.2126 · Cited by 211
Lower extremity arterial disease in patients with diabetes: a contemporary narrative review
Nativel, M., Potier, L., Alexandre, L., Baillet‐Blanco, L., Ducasse, E., Velho, G., Marre, M., Roussel, R., Rigalleau, V., & Mohammedi, K. (2018) · Cardiovascular Diabetology · doi:10.1186/s12933-018-0781-1 · Cited by 207
Metadata
- Authors
- Chang, H.-Y., Singh, S., Mansour, O., Baksh, S., & Alexander, G. C.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Alexander, G. Caleb
- Venue
- JAMA Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2018-09-01
- Volume
- 178
- Issue
- 9
- Pages
- 1190
- ISSN
- 2168-6106 (ISSN-L)
- PMC
- PMC6142968
- OpenAlex
- W2886009800
- Cited by
- 163
- References
- 28
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 18 · 2023: 25 · 2022: 20 · 2021: 19 · 2020: 32 · 2019: 23 · 2018: 5
- FWCI
- 15.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Internal Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL139426)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetic Foot Ulcer Assessment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- SGLT2 inhibitors, canagliflozin, lower limb amputation, type 2 diabetes, DPP-4 inhibitors, GLP-1 receptor agonists, peripheral arterial disease, critical limb ischemia, osteomyelitis, foot ulcer, drug safety, commercially insured patients, propensity score weighting, metformin
- MeSH terms
- Canagliflozin, Sodium-Glucose Transporter 2 Inhibitors, Amputation, Surgical, Blood Glucose, Diabetes Mellitus, Type 2, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Male, Middle Aged, Population Surveillance, Retrospective Studies, United States, Incidence, Lower Extremity, Glucagon-Like Peptide 1, Dipeptidyl-Peptidase IV Inhibitors, Propensity Score, Peripheral Arterial Disease
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