Empagliflozin and Assessment of Lower-Limb Amputations in the EMPA-REG OUTCOME Trial
Abstract
Sodium–glucose cotransporter 2 (SGLT2) inhibitors are oral glucose-lowering agents indicated for the treatment of type 2 diabetes. In the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, the SGLT2 inhibitor canagliflozin was associated with an increased risk for lower-limb amputation (LLA) (including minor and major amputation) versus placebo (hazard ratio [HR] 1.97 [95% CI 1.41, 2.75]) in patients with type 2 diabetes and high cardiovascular risk (1). In the EMPA-REG OUTCOME trial in patients with type 2 diabetes and established cardiovascular disease (2), the proportion of patients with LLA was similar between those treated with empagliflozin and placebo (3). We report further analyses of LLA in the EMPA-REG OUTCOME trial. Any hospital admission during the EMPA-REG OUTCOME trial was to be reported as a serious adverse event. Investigators were asked to provide a detailed narrative with additional medical information for each serious adverse event. From the EMPA-REG OUTCOME trial database, we identified LLA via a systematic search of serious adverse event narratives, from events reported as adverse events, and from those reported as a “medical procedure” under “concomitant therapy” in electronic case report forms or in investigator comments describing adverse events. All cases identified were medically reviewed to confirm an LLA event. Time to first LLA was analyzed using a …
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The similar rates of amputation and fracture are consistent with trials of other SGLT2 inhibitors but differ from the CANVAS Program findings.
“The similar rates of amputation and fracture that we observed with canagliflozin and placebo are reassuring and consistent with trials of other SGLT2 inhibitors 6,7,20 but differ from the CANVAS Program findings.5”
From Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (2019) · cites this paper as [20]
Cites
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., Devins, T., Johansen, O. E., Woerle, H. J., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504720 · Cited by 12,315 · see citing works
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Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy
Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. J. L., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1811744 · Cited by 6,189 · see citing works
Self-citationBaigent, C., Emberson, J., Haynes, R., Herrington, W. G., Judge, P., Landray, M. J., Mayne, K. J., Ng, S. Y. A., Preiss, D., Roddick, A. J., et al. (2022) · The Lancet · doi:10.1016/s0140-6736(22)02074-8 · Cited by 1,020 · see citing works
Self-citationSGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review
Verma, S., & McMurray, J. J. V. (2018) · Diabetologia · doi:10.1007/s00125-018-4670-7 · Cited by 999 · see citing works
Das, S. R., Everett, B. M., Birtcher, K. K., Brown, J. M., Januzzi, J. L., Kalyani, R. R., Kosiborod, M., Magwire, M., Morris, P. B., Neumiller, J. J., et al. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2020.05.037 · Cited by 466 · see citing works
Renoprotective effects of sodium-glucose cotransporter-2 inhibitors
Heerspink, H. J. L., Kosiborod, M., Inzucchi, S. E., & Cherney, D. Z. I. (2018) · Kidney International · doi:10.1016/j.kint.2017.12.027 · Cited by 393 · see citing works
Self-citationDas, S. R., Everett, B. M., Birtcher, K. K., Brown, J. M., Cefalu, W. T., Januzzi, J. L., Kalyani, R. R., Kosiborod, M., Magwire, M. L., Morris, P. B., et al. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.09.020 · Cited by 300 · see citing works
Pharmacotherapy of obesity: available medications and drugs under investigation.
Pilitsi, E., Farr, O. M., Polyzos, S. A., Perakakis, N., Nolen-Doerr, E., Papathanasiou, A.-E., & Mantzoros, C. S. (2019) · Metabolism · doi:10.1016/j.metabol.2018.10.010 · Cited by 248 · see citing works
Cardiac and Renal Effects of Sodium-Glucose Co-Transporter 2 Inhibitors in Diabetes
Zelniker, T. A., & Braunwald, E. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.06.040 · Cited by 236 · see citing works
A safety update on sodium glucose co-transporter 2 inhibitors
Fitchett, D. (2019) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13611 · Cited by 99 · see citing works
Staplin, N., Roddick, A. J., Emberson, J., Reith, C., Riding, A., Wonnacott, A., Kuverji, A., Bhandari, S., Baigent, C., Haynes, R., et al. (2021) · eClinicalMedicine · doi:10.1016/j.eclinm.2021.101163 · Cited by 74 · see citing works
Landgraf, R., Aberle, J., Birkenfeld, A. L., Gallwitz, B., Kellerer, M., Klein, H., Müller-Wieland, D., Nauck, M. A., Reuter, H.-M., & Siegel, E. (2019) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-1018-9106 · Cited by 62 · see citing works
Lower extremity artery disease in patients with type 2 diabetes
Buso, G., Aboyans, V., & Mazzolai, L. (2019) · European Journal of Preventive Cardiology · doi:10.1177/2047487319880044 · Cited by 48 · see citing works
Landgraf, R., Aberle, J., Birkenfeld, A. L., Gallwitz, B., Kellerer, M., Klein, H., Müller-Wieland, D., Nauck, M. A., Wiesner, T., & Siegel, E. (2022) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-1624-3449 · Cited by 12 · see citing works
- Authors
- Inzucchi, S. E., Iliev, H., Pfarr, E., & Zinman, B.
- Affiliations
- Yale University (US)
- Boehringer Ingelheim (Germany) (DE)
- Mount Sinai Hospital (CA)
- Corresponding author
- Inzucchi, Silvio E.
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2017-11-13
- Volume
- 41
- Issue
- 1
- Pages
- e4-e5
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- OpenAlex
- W2769721741
- Cited by
- 162
- References
- 1
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 10 · 2023: 6 · 2022: 19 · 2021: 12 · 2020: 27 · 2019: 37 · 2018: 37 · 2017: 2
- FWCI
- 22.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes Care (publishedVersion)
- PubMed (publishedVersion)
- 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
- empagliflozin, lower limb amputation, SGLT2 inhibitors, type 2 diabetes, EMPA-REG OUTCOME trial, serious adverse events, cardiovascular disease, drug safety
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