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Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type 2 Diabetes

Educational 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).
1 Credit CME
Key Points

Question  What is the association between the use of sodium-glucose cotransporter 2 inhibitors and lower extremity amputation, peripheral arterial disease, osteomyelitis, and venous ulceration among patients with type 2 diabetes?

Findings  In this population-based cohort study of commercially insured patients, the length of follow-up was relatively short, and amputations were rare. There was no statistically significantly increased risk of amputations associated with new use of sodium-glucose cotransporter 2 inhibitors compared with new use of dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 agonists, although the hazard ratios were elevated, while new use of sodium-glucose cotransporter 2 inhibitors was associated with a statistically significant increased risk of amputation compared with use of metformin, sulfonylureas, and thiazolidinediones.

Meaning  Sodium-glucose cotransporter 2 inhibitors may be associated with increased risk of amputation compared with some oral treatments for type 2 diabetes.

Abstract

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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Article Information

Accepted for Publication: April 20, 2018.

Corresponding Author: G. Caleb Alexander, MD, MS, Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St W6035, Baltimore, MD 21205 (galexand@jhsph.edu).

Published Online: August 13, 2018. doi:10.1001/jamainternmed.2018.3034

Author Contributions: Drs Chang and Alexander had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Chang, Singh, Baksh, Alexander.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Chang, Singh, Mansour, Baksh.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Chang, Singh.

Obtained funding: Alexander.

Administrative, technical, or material support: Mansour, Baksh, Alexander.

Supervision: Alexander.

Conflict of Interest Disclosures: Dr Alexander reported serving as Chair of the US Food and Drug Administration’s Peripheral and Central Nervous System Advisory Committee, serving as a paid consultant to QuintilesIMS, serving on the Advisory Board of MesaRx Innovations, holding equity in Monument Analytics, and serving as a member of OptumRx’s Pharmacy and Therapeutics Committee. This arrangement has been reviewed and approved by the Johns Hopkins Bloomberg School of Public Health. Dr Singh reported attending advisory board meetings on the safety of diabetic drugs hosted by Janssen Pharmaceuticals (manufacturer of canagliflozin) and Eli Lilly & Co (manufacturer of dulaglutide) and was compensated for his time.

Funding/Support: This work was supported in part through contract number U01 FD004977-03 from the Johns Hopkins Center of Excellence in Regulatory Science and Innovation (Dr Alexander).

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study, analysis or interpretation of the data, and preparation or final approval of the manuscript prior to publication.

References
1.
Centers for Disease Control and Prevention.  National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, US Dept of Health and Human Services; 2017.
2.
US Food and Drug Administration. FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). https://www.fda.gov/downloads/Drugs/DrugSafety/UCM558427.pdf. Updated May 16, 2017. Accessed October 17, 2017.
3.
Fulcher  G, Matthews  DR, Perkovic  V,  et al.  Efficacy and safety of canagliflozin used in conjunction with sulfonylurea in patients with type 2 diabetes mellitus: controlled trial.  Diabetes Ther. 2015;6(3):289-302. doi:10.1007/s13300-015-0117-zPubMedGoogle ScholarCrossref
4.
Fulcher  G, Matthews  DR, Perkovic  V,  et al; CANVAS Trial Collaborative Group.  Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes.  Diabetes Obes Metab. 2016;18(1):82-91. doi:10.1111/dom.12589PubMedGoogle ScholarCrossref
5.
Neal  B, Perkovic  V, de Zeeuw  D,  et al; CANVAS Trial Collaborative Group.  Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes.  Diabetes Care. 2015;38(3):403-411. doi:10.2337/dc14-1237PubMedGoogle ScholarCrossref
6.
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(7):644-657. doi:10.1056/NEJMoa1611925PubMedGoogle ScholarCrossref
7.
Lee  S.  Update on SGLT2 inhibitors—new data released at the American Diabetes Association.  Crit Pathw Cardiol. 2017;16(3):93-95. doi:10.1097/HPC.0000000000000125PubMedGoogle ScholarCrossref
8.
Liu  J, Lee  TW, DeFronzo  RA.  Why do SGLT2 inhibitors inhibit only 30-50% of renal glucose absorption in humans?  Diabetes. 2012;61:2199-2204. doi:10.2337/db12-0052PubMedGoogle ScholarCrossref
9.
Chang  CC, Chen  YT, Hsu  CY,  et al.  Dipeptidyl peptidase-4 inhibitors, peripheral arterial disease, and lower extremity amputation risk in diabetic patients.  Am J Med. 2017;130(3):348-355. doi:10.1016/j.amjmed.2016.10.016PubMedGoogle ScholarCrossref
10.
Newton  KM, Wagner  EH, Ramsey  SD,  et al.  The use of automated data to identify complications and comorbidities of diabetes: a validation study.  J Clin Epidemiol. 1999;52(3):199-207. doi:10.1016/S0895-4356(98)00161-9PubMedGoogle ScholarCrossref
11.
Bekwelem  W, Bengtson  LG, Oldenburg  NC,  et al.  Development of administrative data algorithms to identify patients with critical limb ischemia.  Vasc Med. 2014;19(6):483-490. doi:10.1177/1358863X14559589PubMedGoogle ScholarCrossref
12.
Chang  HY, Weiner  JP, Richards  TM, Bleich  SN, Segal  JB.  Predicting costs with Diabetes Complications Severity Index in claims data.  Am J Manag Care. 2012;18(4):213-219.PubMedGoogle Scholar
13.
Chang  HY, Weiner  JP, Richards  TM, Bleich  SN, Segal  JB.  Validating the adapted Diabetes Complications Severity Index in claims data.  Am J Manag Care. 2012;18(11):721-726.PubMedGoogle Scholar
14.
Singh  S, Chang  HY, Richards  TM, Weiner  JP, Clark  JM, Segal  JB.  Glucagonlike peptide 1–based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study.  JAMA Intern Med. 2013;173(7):534-539. doi:10.1001/jamainternmed.2013.2720PubMedGoogle ScholarCrossref
15.
Chang  HY, Hsieh  CF, Singh  S, Tang  W, Chiang  YT, Huang  WF.  Anti-diabetic therapies and the risk of acute pancreatitis: a nationwide retrospective cohort study from Taiwan.  Pharmacoepidemiol Drug Saf. 2015;24(6):567-575. doi:10.1002/pds.3770PubMedGoogle ScholarCrossref
16.
Tseng  YH, Tsan  YT, Chan  WC, Sheu  WH, Chen  PC.  Use of an α-glucosidase inhibitor and the risk of colorectal cancer in patients with diabetes: a nationwide, population-based cohort study.  Diabetes Care. 2015;38(11):2068-2074. doi:10.2337/dc15-0563PubMedGoogle ScholarCrossref
17.
Ou  SM, Shih  CJ, Chao  PW,  et al.  Effects on clinical outcomes of adding dipeptidyl peptidase-4 inhibitors versus sulfonylureas to metformin therapy in patients with type 2 diabetes mellitus.  Ann Intern Med. 2015;163(9):663-672. doi:10.7326/M15-0308PubMedGoogle ScholarCrossref
18.
Chang  HY, Zhou  M, Tang  W, Alexander  GC, Singh  S.  Risk of gastrointestinal bleeding associated with oral anticoagulants: population based retrospective cohort study.  BMJ. 2015;350:h1585. doi:10.1136/bmj.h1585PubMedGoogle ScholarCrossref
19.
Casadaban  L, Rauscher  G, Aklilu  M, Villenes  D, Freels  S, Maker  AV.  Adjuvant chemotherapy is associated with improved survival in patients with stage II colon cancer.  Cancer. 2016;122(21):3277-3287. doi:10.1002/cncr.30181PubMedGoogle ScholarCrossref
20.
Harder  VS, Stuart  EA, Anthony  JC.  Propensity score techniques and the assessment of measured covariate balance to test causal associations in psychological research.  Psychol Methods. 2010;15(3):234-249. doi:10.1037/a0019623PubMedGoogle ScholarCrossref
21.
Kurth  T, Walker  AM, Glynn  RJ,  et al.  Results of multivariable logistic regression, propensity matching, propensity adjustment, and propensity-based weighting under conditions of nonuniform effect.  Am J Epidemiol. 2006;163(3):262-270. doi:10.1093/aje/kwj047PubMedGoogle ScholarCrossref
22.
Austin  PC.  An introduction to propensity score methods for reducing the effects of confounding in observational studies.  Multivariate Behav Res. 2011;46(3):399-424. doi:10.1080/00273171.2011.568786PubMedGoogle ScholarCrossref
23.
Lin  DY, Wei  LJ.  The robust inference for the Cox proportional hazards model.  J Am Stat Assoc. 1989;84:1074-1078. doi:10.1080/01621459.1989.10478874Google ScholarCrossref
24.
Lin  DY, Wei  LJ, Ying  Z.  Checking the Cox model with cumulative sums of martingale-based residuals.  Biometrika. 1993;80:557-572. doi:10.1093/biomet/80.3.557Google ScholarCrossref
25.
European Medicines Agency. Pharmacovigilence Risk Assessment Committee (PRAC): PRAC assessment report. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors_Canagliflozin_20/European_Commission_final_decision/WC500227102.pdf. Published February 9, 2017. Accessed October 23, 2017.
26.
US Food and Drug Administration. Sodium-glucose cotransporter-2 (SGLT2) inhibitors. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm446852.htm. Updated May 16, 2017. Accessed October 27, 2017.
27.
Fadini  GP, Avogaro  A.  SGLT2 inhibitors and amputations in the US FDA Adverse Event Reporting System.  Lancet Diabetes Endocrinol. 2017;5(9):680-681. doi:10.1016/S2213-8587(17)30257-7PubMedGoogle ScholarCrossref
28.
Yuan  Z, DeFalco  FJ, Ryan  PB,  et al.  Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: a retrospective cohort study.  Diabetes Obes Metab. 2018;20(3):582-589. doi:10.1111/dom.13115PubMedGoogle ScholarCrossref
29.
Hsu  CY, Chen  YT, Su  YW, Chang  CC, Huang  PH, Lin  SJ.  Statin therapy reduces future risk of lower-limb amputation in patients with diabetes and peripheral artery disease.  J Clin Endocrinol Metab. 2017;102(7):2373-2381. doi:10.1210/jc.2016-3717PubMedGoogle ScholarCrossref
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