Sodium–Glucose Cotransporter 2 Inhibitors and The

2444 Diabetes Care Volume 43, October 2020

Sodium–Glucose Cotransporter 2 Oriana Hoi Yun Yu,1,2 Sophie Dell’Aniello,1 Baiju R. Shah,3,4,5 Vanessa C. Brunetti,1,6 Inhibitors and the Risk of Below- Jean-Marc Daigle,7 Michael Fralick,3,8 Antonios Douros,1,9,10,11 Nianping Hu,12 Knee Amputation: A Multicenter Silvia Alessi-Severini,13,14 Anat Fisher,15 Shawn C. Bugden,13,16 Paul E. Ronksley,17 Observational Study Kristian B. Filion,1,9 Pierre Ernst,1,9 and Lisa M. Lix,18 for the Canadian Network Diabetes Care 2020;43:2444–2452 | https://doi.org/10.2337/dc20-0267 for Observational Drug Effect Studies (CNODES) Investigators*

OBJECTIVE Reports of amputations associated with sodium–glucose cotransporter 2 (SGLT2) 1Center for Clinical Epidemiology, Lady Davis inhibitors have been inconsistent. We aimed to compare the risk of below-knee Institute, Jewish General Hospital, Montreal,´ amputation with SGLT2 inhibitors versus dipeptidyl peptidase 4 (DPP-4) inhibitors Quebec,´ Canada among patients with type 2 diabetes. 2Division of Endocrinology, Department of Med- icine, Jewish General Hospital, Montreal,´ Quebec,´ Canada RESEARCH DESIGN AND METHODS 3

EPIDEMIOLOGY/HEALTH SERVICES RESEARCH Department of Medicine, University of Toronto, This multicenter observational study used administrative health care databases Toronto, Ontario, Canada from seven Canadian provinces and the U.K. Incident SGLT2 inhibitor users were 4Institute for Clinical Evaluative Sciences (ICES), matched to DPP-4 inhibitor users using a prevalent new-user design and time- Toronto, Ontario, Canada 5Sunnybrook Health Sciences Centre, Toronto, conditional propensity scores. Cox proportional hazards models were used to Ontario, Canada estimate site-specific adjusted hazard ratios (HR) and corresponding 95% CIs of 6Department of Epidemiology, Biostatistics and incident below-knee amputation for SGLT2 inhibitor versus DPP-4 inhibitor users. Occupational Health, McGill University, Mon- Random effects meta-analyses were used to pool the site-specific results. treal,´ Quebec,´ Canada 7Institut national d’excellence en santeeten´ ´ ´ RESULTS services sociaux (INESSS), Quebec City, Quebec, Canada The study cohort included 207,817 incident SGLT2 inhibitor users matched to 8Sinai Health System, Toronto, Ontario, Canada 207,817 DPP-4 inhibitor users. During a mean exposed follow-up time of 11 months, 9Departments of Medicine and of Epidemiology, the amputation rate was 1.3 per 1,000 person-years among SGLT2 inhibitor users Biostatistics, and Occupational Health, McGill University, Montreal,´ Quebec,´ Canada and 1.5 per 1,000 person-years among DPP-4 inhibitor users. The adjusted HR of 10Institute of Clinical Pharmacology and Toxicol- below-knee amputations associated with SGLT2 inhibitor use compared with DPP-4 ogy, Charite-Universit´ atsmedizin¨ Berlin, corporate inhibitor use was 0.88 (95% CI 0.71–1.09). Similar results were obtained in stratified member of Freie Universitat¨ Berlin, Humboldt- ¨ analyses by specific SGLT2 inhibitor molecule. Universitat zu Berlin, Berlin, Germany 11Berlin Institute of Health, Berlin, Germany 12The Health Quality Council, Saskatoon, Sas- CONCLUSIONS katchewan, Canada In this large multicenter observational study, there was no association between 13College of Pharmacy, Rady Faculty of Health SGLT2 inhibitor use and incident below-knee amputations among patients with Sciences, University of Manitoba, Winnipeg, Man- type 2 diabetes compared with DPP-4 inhibitor use. While these findings provide itoba, Canada 14Manitoba Centre for Health Policy, Rady Fac- some reassurance, studies with a longer duration of follow-up are needed to assess ulty of Health Sciences, University of Manitoba, potential long-term effects. Winnipeg, Manitoba, Canada 15Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Sodium–glucosecotransporter 2(SGLT2) inhibitors are the newest antidiabetic agents Vancouver, Canada for type 2 diabetes management (1). They inhibit the SGLTs on renal proximal tubules, 16School of Pharmacy, Memorial University of leading to glucosuria. This effect not only lowers glycemia but also induces weight loss Newfoundland, St. John’s, Newfoundland and Labrador, Canada and blood pressure reduction (2). Indeed, randomized placebo-controlled trials have 17Department of Community Health Sciences, shown that SGLT2 inhibitors also decrease the risk of cardiovascular outcomes (3,4) Cumming School of Medicine, University of Cal- and heart failure (3–5). Current guidelines from the American Diabetes Association gary, Calgary, Alberta, Canada care.diabetesjournals.org Yu and Associates 2445

recommend the use of SGLT2 inhibitors been conducted to assess the association which contains full hospitalization data as second- or third-line treatment in ad- between SGLT2 inhibitor use and the risk of from 1997 to the present. Hospital Epi- dition to metformin in the management of amputation, with most of the studies using sodes Statistics linkage for this study was type 2 diabetes (1). Owing to the cardio- the same employment insurance database from 1 April 1997 to 31 December 2017. vascular and renal benefits conferred by in the U.S.; however, their findings have The study protocol was registered at these agents, SGLT2 inhibitors are recom- been inconsistent (7,12–18). ClinicalTrials.gov (NCT04017221). Ethics ap- mended as one of the preferred second-line In light of the findings from the CAN- proval was obtained at each participating agentsforpatientswhohavehighriskfactors VAS Program trial and the inconsistent site. The study protocol received ethical and or known cardiovascular disease, heart fail- results of previous observational studies, scientific approval from the Independent ure,andchronicrenaldisease(i.e.,estimated further studies are needed to address Advisory Scientific Committee of the CPRD glomerular filtration rate [eGFR] of 30– whether SGLT2inhibitor useis associated (protocol number: 19_007A2). 60 mL/min/1.73 m2 or urine albumin-to- withan increased riskof amputation.This Individuals aged $18 years with type 2 creatinine ratio of 30 mg/g). Given the study used data from Canada and the diabetes were identified by prescrip- cardiovascular benefits of SGLT2 inhibitors U.K. with the aim of determining whether tions for an antidiabetic medication (a- andtheemphasisonthesebenefitsinrecent SGLT2 inhibitor use compared with DPP-4 glucosidase inhibitors, DPP-4 inhibitors, treatment guidelines, the use of SGLT2 inhibitor use, is associated with an in- glucagon-like peptide [GLP]-1 receptor inhibitors has increased substantially creased risk of below-knee amputation agonists, insulin, meglitinides, metfor- among patients with type 2 diabetes (6). among patients with type 2 diabetes in a min, SGLT2 inhibitors, sulfonylureas, thia- Despite the cardiovascular benefits as- real-world setting. zolidinediones, or combinations of these sociated with SGLT2 inhibitor treatment, drugs) between 1 January 2006 and 30 June there are several safety concerns asso- RESEARCH DESIGN AND METHODS 2018 or the most recent date of data ciated with their use, including a reported Source Population availability at each site. Potentially eligible increased risk of below-knee amputations We used administrative health care data- subjects were identified as of 2006 to cover (3,7). Concerns regarding this adverse event bases from the Canadian provinces of the period of general availability of DPP-4 stem from the Canagliflozin Cardiovas- Alberta,BritishColumbia,Manitoba,Nova inhibitors and SGLT2 inhibitors. In Nova cular Assessment Study (CANVAS) Program Scotia, Ontario, Quebec,´ and Saskatch- Scotia, due to limitations in prescription trial, in which participants randomized to ewan and the U.K. Clinical Practice Re- drug data availability, individuals who re- the SGLT2 inhibitor canagliflozin had a search Datalink (CPRD). The Canadian ceived antidiabetic medications between twofold increased risk compared with databases contain population-level data on 1 November 2017 and 30 June 2018 were participants randomized to placebo (haz- physician claims, hospitalization records, eligible to be included in the study cohort. ard ratio [HR] 1.97; 95% CI 1.41–2.75) (3). and prescription drug claims. Prescription From this source population, we con- As a result of this finding, the U.S. Food drug data are only available for individuals structed the study cohort of users of and Drug Administration issued a black- aged $18 years in Alberta, aged $65 years SGLT2 inhibitors and users of DPP-4 box warning of amputation risk for can- in Ontario, and those $65 years receiving inhibitors with a prescription after the agliflozin (8). However, there was no social assistance and without access to date of introduction of SGLT2 inhib- increased risk of amputation associated private drug insurance in Quebec.´ itors at each study site (Supplementary with canagliflozin use among patients The CPRD is a large primary care da- Table 1). Identifiable information was not with type 2 diabetes and chronic renal tabase containing medical information accessible, and we complied with all disease compared with patients treated documented by primary care physicians privacy requirements of the data custo- with placebo in the Canagliflozin and on ;13 million patients enrolled in .680 dians at each site. A prevalent new-user Renal Events in Diabetes with Established general practices in the U.K. (19,20). This design (22) was used to match each user Nephropathy Clinical Evaluation (CRE- database documents demographic char- of an SGLT2 inhibitor to a user of a DPP-4 DENCE) trial, which assessed canagliflo- acteristics, diagnoses, laboratory test results, inhibitor. Study cohort entry among zin use and renal outcomes (HR 1.11; procedures, prescriptions, medical history, SGLT2 inhibitor users was defined by 95% CI 0.79–1.56) (9). Nevertheless, two administrative information, and clinical data, thedateofthefirst SGLT2 dispensing pharmacovigilance analyses found an in- including smoking, BMI, and alcohol use. (or prescription in CPRD). Study cohort creased reporting of amputation among The CPRD is regularly audited, and the entry for DPP-4 inhibitor users was the individuals treated with SGLT2 inhibitors data have been shown to be valid and of date of the matched (see below) DPP-4 compared with other antidiabetic agents high quality (19,21). CPRD data were linked inhibitor prescription during the pe- (10,11). Several observational studies have to the Hospital Episodes Statistics database, riod defined by the first prescription

18Department of Community Health Sciences, Uni- This article contains supplementary material © 2020 by the American Diabetes Association. versity of Manitoba, Winnipeg, Manitoba, Canada online at https://doi.org/10.2337/ﬁgshare.12652454. Readers may use this article as long as the work is Corresponding author: Lisa M. Lix, lisa.lix@ *A list of the CNODES investigators is provided in properly cited, the use is educational and not for ﬁ umanitoba.ca the supplementary material online. pro t, and the work is not altered. More information is available at https://www.diabetesjournals Received 6 February 2020 and accepted 6 July This article is featured in a podcast available at .org/content/license. 2020 https://www.diabetesjournals.org/content/diabetes- Clinical trial reg. no. NCT04017221, clinicaltrials core-update-podcasts. .gov 2446 SGLT2 Inhibitors and Risk of Amputation Diabetes Care Volume 43, October 2020

of SGLT2 inhibitors and 30 June 2018. inhibitors from their exposure set or vildagliptin) alone or in combination Individuals with a prior history of ampu- with the closest TCPS and in chrono- with non-SGLT2 inhibitor antidiabetic tation at any time before or on study logical order. However, in five sites, agents. Exposure was defined using an cohort entry were excluded. there was a loss of .10% of exposure as-treated approach whereby exposure sets after trimming the areas of non- was time-fixed and defined by the cohort Matching overlap of the TCPS distribution and entry drug. Patients were monitored We created exposure sets that were de- matching. In these sites, matching with until they discontinued treatment, defined by user type (incident vs. prevalent), replacement was performed using a cal- finedasagapof$30 days after the end level of antidiabetic treatment, prior use iper width of 60.2 SDs of log TCPS. of a prescription (grace period) or the of GLP-1 agonists, and calendar time (DPP- initiation of an SGLT2 inhibitor for users 4 inhibitor prescription within 120 days Covariates of DPP-4 inhibitors, or censored due to of the SGLT2 inhibitor initiation). Incident The following covariates, defined a priori, death, end of health care coverage, or users were defined as using SGLT2 in- were used to construct the TCPS in all end of study period, whichever occurred hibitororDPP-4inhibitorforthefirst time study cohorts: age, sex, calendar year at first. DPP-4 inhibitor use was the com- (i.e., new users). Incident SGLT2 inhibitor cohort entry, and diabetes duration (,1 parator because this class of antidiabetic users were matched to incident DPP-4 year, 1–4.9 years, 5–10 years, and .10 agent is also a second- or third-line treat- inhibitor users. Patients treated with DPP- years). We included comorbidities iden- ment and has not been shown to be 4 inhibitors who switched to or added an tified during the 3 years before study associated with increased amputation SGLT2 inhibitor to their treatment regi- cohort entry such as alcohol-related dis- risk (23). men (prevalent new users) were matched orders, cancer, cerebrovascular disease, to patients treated with DPP-4 inhibitors cirrhosis, coronary artery disease, dia- Study Outcomes for the same duration but who remained betic nephropathy, diabetic neuropathy, The primary study outcome was incident on DPP-4 inhibitor treatment (Supplemen- diabetic retinopathy, dialysis, hyperten- below-knee amputation, defined as hav- tary Fig. 1). We also matched, on the level sion, ischemic stroke, myocardial infarc- ing transtibial amputations or amputa- of antidiabetic treatment, a three-level tion,otherkidneydiseases,andperipheral tions involving the ankle and foot using categorical variable created as a proxy for arterial disease. We also included medica- procedure codes documented during severity of diabetes. Three levels of an- tion use in the year before study cohort hospitalization or physician claims data tidiabetic treatment were created to entry, such as acetylsalicylic acid, aldo- (24). Below-knee amputation was as- mirror the severity of type 2 diabetes sterone antagonists, a-glucosidase inhib- sessed, given that 71% of amputations based on the type and number of dif- itors, angiotensin II receptor blockers, that occurred in the CANVAS Program ferent antidiabetic agents in the prior ACE inhibitors, b-blockers, calcium chan- trial were at the toe and metatarsal level 365 days. The first level was defined as nel blockers, digitalis-like agents, direct (3,25). Furthermore, given that this study patients treated with only one antidia- renin inhibitors, GLP-1 receptor agonists, excluded individuals with a prior history betic agent or treated with lifestyle mod- insulin, loop diuretics, meglitinides, met- of amputation, it would be clinically ifications (i.e., they did not receive an formin, nonacetylsalicylic acid antiplate- unlikely for individuals to develop in- antidiabetic agent during the prior 365 days). let drugs, nonsteroidal anti-inflammatory cident above-knee amputation associ- The second level included patients who drugs, oral anticoagulants, other diuretics, ated with SGLT2 inhibitor use. The diagnostic required at least two noninsulin antidi- other lipid-lowering therapy, statins, and procedure codes used to define this abetic agents. Finally, the third level in- sulfonylureas, thiazide diuretics, and outcome are reported in Supplementary cluded patients who received insulin thiazolidinediones. Finally, we included co- Table 2. treatment (alone or in combination with variates that are indicators of health care other antidiabetic agents). Time condi- use in the year before study cohort entry, tional propensity scores (TCPS) were including the number of inpatient hospi- Statistical Analyses then constructed separately for inci- talizations (0, 1–2, and $3) and number Patient characteristics were summarized dent and prevalent new users by using of physician visits (0–2, 3–5, and $6). in each study cohort using frequencies conditionallogisticregression stratified In the CPRD study cohort, additional a and percentages for categorical variables by exposure set to estimate the pro- priori defined covariates were included and means 6 SD for continuous varia- pensity of receiving a SGLT2 inhibitor in the TCPS models. These covariates in- bles. Multivariable Cox proportional haz- versus a DPP-4 inhibitor using the co- cluded BMI, smoking status (never, ever, ards models were used to estimate the variates shown in the COVARIATES section. and unknown), race, blood pressure, es- site-specific adjusted HR and the corre- Scores were computed for each indi- timated glomerular filtration rate, and sponding 95% CI for the risk of incident vidual in each exposure set; hence, an glycated hemoglobin A1c. below-knee amputation among SGLT2 individual may have different scores for inhibitor users versus DPP-4 inhibitor exposure sets they enter, depending Exposure Assessment users.Coxmodelswereadjustedforage, on the time of entry (i.e., time condi- Patients were classified as being current sex, diabetes duration, and deciles of tional). Additional covariates were in- users of SGLT2 inhibitors (canagliflozin, TCPS. In secondary analyses, we strat- cluded in the TCPS in the CPRD cohort dapagliflozin, or empagliflozin) alone or ified by age to determine whether the (please see COVARIATES section). SGLT2 combined with other antidiabetic agents, risk of amputation associated with SGLT2 inhibitor users were matched 1:1 with- or current users of DPP-4 inhibitors (alog- inhibitor use was higher among the el- out replacement to users of DPP-4 liptin, linagliptin, saxagliptin, sitagliptin, derly population ($70 and ,70 years), care.diabetesjournals.org Yu and Associates 2447

sex, prior insulin use (defined as insulin # 19_007A2) of the CPRD, and the ap- Statistics Deaths, V2, BC Ministry of use in the previous year), and SGLT2 proved protocol was made available to Health (publisher). Parts of this material inhibitor molecule. journal reviewers. The British Columbia are based on data and information com- Finally, we completed five sensitivity (BC) Ministry of Health approved access piled and provided by the Ontario Ministry analyses. First, we repeated the primary to and use of BC data for this study. of Health and Long-Term Care. This study analysis using grace periods of 0, 60, and Data sources were as follows (https:// was supported by Institute for Clinical 365 days to define continuous use of the www.popdata.bc.ca/data): BC Minis- Evaluative Sciences, which is funded by an study drug. Second, we stratified the try of Health (creator) (2018): Medical annual grant from the Ministry of Health primary analysis by incident and preva- Services Plan (MSP) Payment Informa- and Long-Term Care. Parts of this material lent new user status among SGLT2 in- tion File, BC Ministry ofHealth(publisher). are based on data and/or information hibitor users. Third, we defined exposure Ministry of Health (2018), BC Ministry of compiled and provided by the Canadian using an intention-to-treat approach in Health (creator) (2018): Consolidation Institute for Health information. which exposure was defined at cohort File (MSP Registration & Premium Bill- entry and patients were monitored until ing), BC Ministry of Health (publisher). RESULTS occurrence of the outcome or censored Ministry of Health (2018), BC Ministry of The study cohort included 207,817 SGLT2 due to death, end of health care cover- Health (creator) (2018): PharmaNet, BC inhibitor users matched to 207,817 DPP- age, end of study period, entry into the Ministry of Health (publisher). Data Stew- 4 inhibitor users (Fig. 1). Among the users SGLT2 inhibitor cohort for DPP-4 inhib- ardship Committee (2018) and Canadian of SGLT2 inhibitors, 102,263 were clas- itor users, or a maximum of 1 year of Institute for Health Information (creator) sified as incident new users and 105,554 follow-up, whichever occurred first. (2018): Discharge Abstract Database as prevalent new users. Baseline char- Fourth, given that SGLT2 inhibitor use is (Hospital Separations), BC Ministry of acteristics were well balanced after TCPS not indicated for patients on dialysis, we Health (publisher). Ministry of Health matching (Table 1 and Supplementary repeated the primary analysis after ex- (2018). BC Ministry of Health (publisher). Table 4). In the CPRD, the number of cluding individuals with a prior history of Ministry of Health (2018), BC Vital Sta- patients with renal insufficiency, defined dialysis using the study cohort from tistics Agency (creator) (2018): Vital as having an eGFR ,60 mL/min/1.73 m2 Ontario because this cohort contained the highest number of individuals with a prior history of dialysis. Kaplan-Meier curves for each site were visually eval- uated to assess potential departures from the assumption of proportional hazards. This assessment revealed no indication that the assumption was vi- olated at any of the sites. Finally, we repeated the primary analysis using a fixed-effects model.

Meta-analysis We pooled the adjusted HRs from each site using DerSimonian and Laird random- effects meta-analysis with inverse variance weighting (26). Inclusion in the meta-analysis was restricted to sites with at least ﬁve events in each exposure group (Supplementary Table 3). Between- site heterogeneity was assessed using the I2 statistic. Analyses were conducted using RevMan version 5.3 software.

Data Source This study was made possible through data sharing agreements between the Canadian Network for Observational Drug Effect Studies member research centers and the respective provincial governments of Alberta, British Columbia, Manitoba Figure 1—Flowchart describing construction of the study cohort. Numbers may not add up (HIPC # 2018/2019-58), Nova Scotia, On- because small cells were suppressed due to privacy restrictions. Patients ,19 years in Alberta , ´ and 66 years in Ontario were included to ensure that patients had at least 1 year of data tario, Quebec, and Saskatchewan. This before cohort entry. Patients were eligible to enter the study cohort a maximum of two times, study was approved by the Independent a ﬁrst time with a DPP-4 inhibitor prescription and a second time with an SGLT2 inhibitor Scientiﬁc Advisory Committee (protocol prescription. 2448 SGLT2 Inhibitors and Risk of Amputation Diabetes Care Volume 43, October 2020

Table 1—Baseline characteristics of users of SGLT2 inhibitors and their matched was higher among DPP-4 inhibitor users DPP-4 users* compared with SGLT2 inhibitor users SGLT2 inhibitors DPP-4 inhibitors (Supplementary Table 4). (n 5 207,817) (n 5 207,817) The mean exposed follow-up time for 6 Age (years) 63.8 6 9.5 64.0 6 9.6 the matched cohort was 11 9 months, 18–35 3,479 (1.7) 3,612 (1.7) generating 369,458 person-years of ob- 36–45 12,288 (5.9) 11,915 (5.7) servation.Therateofincidentbelow-knee 46–55 30,845 (14.8) 30,105 (14.5) amputation was similar among SGLT2 in- 56–65 47,711 (23.0) 48,079 (23.1) hibitor users (1.3 per 1,000 person-years) 66–75 89,410 (43.0) 87,993 (42.3) versus DPP-4 inhibitor users (1.5 per 1,000 – 76 85 22,074 (10.6) 23,920 (11.5) person-years) in the matched cohort. .85 2,010 (1.0) 2,193 (1.1) There was no significant increased risk Female sex 86,360 (41.6) 87,030 (41.9) of incident below-knee amputation asso- Calendar year at cohort entry ciated with SGLT2 inhibitor use compared 2013 320 (0.2) 343 (0.2) 2014 6,954 (3.3) 7,322 (3.5) with DPP-4 inhibitor use (HR 0.88; 95% CI 2 2015 51,464 (24.8) 50,921 (24.5) 0.71–1.09; I 5 18%) (Table 2 and Fig. 2). 2016 66,242 (31.9) 66,422 (32.0) In secondary analyses, the risk of in- 2017 61,291 (29.5) 61,013 (29.4) cident below-knee amputation associated 2018 21,546 (10.4) 21,796 (10.5) with SGLT2 inhibitor use versus DPP-4 New user status inhibitor use did not differ according to Incident users 102,263 (49.2) 102,263 (49.2) age ($70 vs. ,70 years), sex, or history of Prevalent users 105,554 (50.8) 105,554 (50.8) prior insulin use or SGLT2 inhibitor mol- SGLT2 inhibitor molecule ecule(Table3).Theresultsremained Canagliflozin 87,922 (42.3) – Dapagliflozin 63,792 (30.7) – consistent across most sensitivity anal- Empagliflozin 56,103 (27.0) – yses, including among patients with no Diabetes duration (years) 12.6 6 6.6 12.5 6 6.6 prior history of dialysis (Supplementary ,1 7,166 (3.4) 7,341 (3.5) Table5).However,therewasatrend 1–4.9 25,204 (12.1) 25,766 (12.4) toward an increased risk of incident 5–10 52,543 (25.3) 52,758 (25.4) below-knee amputation among preva- .10 122,904 (59.1) 121,952 (58.7) lent new users of SGLT2 inhibitors ver- Comorbidities† sus DPP-4 inhibitor users (HR 1.29; 95% Alcohol-related disorders 3,626 (1.7) 3,658 (1.8) CI 0.97–1.70) (Table 3). Cancer 21,692 (10.4) 21,937 (10.6) Cerebrovascular disease 9,892 (4.8) 10,156 (4.9) Cirrhosis 3,621 (1.7) 3,606 (1.7) CONCLUSIONS Coronary artery disease 44,710 (21.5) 43,939 (21.1) In this large, multicenter observational Diabetic nephropathy 7,476 (3.6) 7,478 (3.6) study, using administrative data from Diabetic neuropathy 3,807 (1.8) 3,844 (1.8) seven Canadian provinces and the U.K. Diabetic retinopathy 5,266 (2.5) 5,296 (2.5) CPRD, we found no increased risk of Dialysis 277 (0.1) 315 (0.2) incident below-knee amputation asso- Hypertension 111,130 (53.5) 111,332 (53.6) Ischemic stroke 2,448 (1.2) 2,535 (1.2) ciated with SGLT2 inhibitor versus DPP- Myocardial infarction 5,326 (2.6) 5,113 (2.5) 4 inhibitor use among patients with type Other kidney diseases 10,222 (4.9) 10,850 (5.2) 2 diabetes (HR 0.88; 95% CI 0.71–1.09). Peripheral arterial disease 4,472 (2.2) 4,471 (2.2) Results were consistent across subgroups Use of medications† defined by age, sex, and prior insulin use. Acetylsalicylic acid 36,875 (17.7) 36,792 (17.7) Similarly, there was no increased risk of Aldosterone antagonists 6,146 (3.0) 6,182 (3.0) below-knee amputation associated with a -Glucosidase inhibitors 3,057 (1.5) 2,949 (1.4) individual SGLT2 inhibitor use, including Angiotensin II receptor blockers 66,747 (32.1) 66,301 (31.9) fl ACE inhibitors 94,489 (45.5) 94,092 (45.3) canagli ozin, compared with DPP-4 in- b-Blockers 58,854 (28.3) 58,371 (28.1) hibitor use. Calcium channel blockers 63,281 (30.5) 63,671 (30.6) Concerns regarding an increased risk Digitalis-like agents 2,586 (1.2) 2,624 (1.3) of amputation associated with the use of Direct renin inhibitors 104 (0.1) 92 (0.0) SGLT2 inhibitors arose when the CANVAS GLP-1 receptor agonists 8,464 (4.1) 8,464 (4.1) Program trial found a nearly twofold Insulin 57,143 (27.5) 57,143 (27.5) increased risk associated with canagli- Loop diuretics 21,314 (10.3) 21,559 (10.4) fl Meglitinides 4,680 (2.3) 4,707 (2.3) ozin use versus placebo (HR 1.97; 95% CI Metformin 180,662 (86.9) 180,828 (87.0) 1.41–2.75) (3). In light of this finding, Nonacetylsalicylic acid antiplatelet drugs 14,034 (6.8) 13,655 (6.6) further analyses were conducted in the Nonsteroidal anti-inflammatory drugs 40,470 (19.5) 40,263 (19.4) BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Continued on p. 2449 Mellitus Patients (EMPA-REG OUTCOME) care.diabetesjournals.org Yu and Associates 2449

Table 1—Continued pharmacovigilance analyses conducted us- SGLT2 inhibitors DPP-4 inhibitors ing the U.S. Food and Drug Administra- (n 5 207,817) (n 5 207,817) tion Adverse Event Reporting System, which found an increased reporting of Oral anticoagulants 13,393 (6.4) 13,359 (6.4) amputation specifically among canagli- Other diuretics 18,497 (8.9) 18,406 (8.9) flozin users (proportional reporting ratio Other lipid-lowering therapy 23,524 (11.3) 22,937 (11.0) – Statins 159,742 (76.9) 159,061 (76.5) [PRR] 5.33; 95% CI 4.04 7.04) compared Sulfonylureas 108,451 (52.2) 108,327 (52.1) with users of non-SGLT2 inhibitor antidi- Thiazide diuretics 45,019 (21.7) 44,788 (21.6) abetic agents (10). Subsequently, another Thiazolidinediones 5,175 (2.5) 4,863 (2.3) pharmacovigilance analysis conducted Different classes of non-antidiabetic drugs, n‡ using the World Health Organization 0–1 8,465 (4.1) 8,666 (4.2) global database of individual case safety – 2 5 65,919 (31.7) 66,729 (32.1) reports (Vigibase) found that the PRRwas $6 133,433 (64.2) 132,422 (63.7) increased for all available SGLT2 inhib- † Health care use itors compared with other antidiabetic Inpatient hospitalizations, n fl 0 176,833 (85.1) 176,723 (85.0) medications (canagli ozin: PRR 7.09; 1–2 28,687 (13.8) 28,697 (13.8) 95% CI 5.25–9.57; empagliflozin: PRR $3 2,296 (1.1) 2,398 (1.2) 4.96; 95% CI 2.89–8.50; and dapagliflo- Physician visits, n zin: PRR for toe-amputations 2.62; 95% 0–2 14,963 (7.2) 15,117 (7.3) CI 1.33–5.14) (11). Nevertheless, there – 3 5 31,883 (15.3) 32,206 (15.5) are well-recognized limitations to $6 160,971 (77.5) 160,494 (77.2) using adverse event reporting data, Data are presented as n (%) or mean 6 SD. *Patients on SGLT2 inhibitors were matched to patients which include difficulties with adverse on DPP-4 inhibitors from their exposure set (defined on level of antidiabetic therapy, prior use of GLP-1 receptor agonists, time on DPP-4 inhibitors for prevalent new users, and calendar time) event recognition, underreporting of ad- on TCPS. Because of privacy restrictions, values of ,6 were replaced by 3 before pooling. verse events, absence of a denominator, †Comorbiditieswereassessedinthe 3yearsbeforestudycohortentry,andmedicationsandhealth biases that affect event reporting, and care use were assessed in the year before study cohort entry. ‡In Saskatchewan, the number of variations in report quality (28). non-antidiabetic drug classes was defined using the list of medication covariates rather than Anatomical Therapeutic Chemical–defined classes due to unavailability of Anatomical Therapeutic To date, there have been eight obser- Chemical codes. In Quebec´ and the CPRD, drug classification was performed using the American vational studies, to our knowledge, that Hospital Formulary Service and the British National Formulary, respectively. have assessed the risk of amputation associated with SGLT2 inhibitor use; these studies have produced heteroge- trial to assess amputation risk (27). These randomization to dapagliflozin versus neous results (7,12–17). Six of these analyses revealed no increased risk of placebo (HR 1.09; 95% CI 0.84–1.40) studies used the MarketScan Commer- amputation with empagliflozin (HR 1.00; (5). Recently, the CREDENCE trial, which cial Claims and Encounters Database, 95% CI 0.70–1.44) (27). However, as ac- enrolled patients with type 2 diabetes with five studies showing no association knowledged by the authors, the ascer- and chronic renal disease to study renal between SGLT2 inhibitor use and am- tainment of amputations may have been outcomes associated with canagliflozin putation (12–15) and one study showing inaccurate, and the results of such post use, did not find an increased risk of an increased risk of amputation with hoc analyses must be interpreted with amputation among patients treated with SGLT2 inhibitor use compared with DPP- caution. In the Dapagliflozin Effect on canagliflozin (HR 1.11; 95% CI 0.79–1.56) 4 inhibitor use (HR 1.69; 95% CI 1.20– Cardiovascular Events–Thrombolysis in (9). 2.38) (7). Interestingly, in that study, Myocardial Infarction 58 trial (DECLARE- The safety signal regarding an increased SGLT2 inhibitor use was not associated TIMI 58) trial, there was no increased risk of amputation identified in the with an increased risk of lower-extremity risk of amputation associated with CANVAS Program trial was supported by amputation compared with sulfonylurea

Table 2—Crude and adjusted HR for the association between the use of SGLT2 inhibitors and the risk of below-knee amputation among patients with type 2 diabetes Crude incidence Adjusted models‡ Treatment Patients Events Mean follow-up Person- rate (per 1,000 Crude HR group (n) (n) time (years) years person-years)* (95% CI)† HR (95% CI) I2 (%) SGLT2 207,817 253 0.90 187,641 1.3 0.87 0.88 18 inhibitors (0.69–1.10) (0.71–1.09) DPP-4 inhibitors 207,817 281 0.88 181,817 1.5 Reference Reference *Incidence rate was calculated using all study cohorts. †Patients on SGLT2 inhibitors were matched to patients on DPP-4 inhibitors from their exposure set (deﬁned on the level of antidiabetic therapy, time on DPP-4 inhibitors [for prevalent new users only], prior use of GLP-1 receptor agonists, and within 120 days of the SGLT2 inhibitor prescription) on TCPS. HR estimation was restricted to sites with at least ﬁve events in each exposure group. ‡Outcome models were adjusted for age (continuous), sex, diabetes duration (continuous), and deciles of TCPS. 2450 SGLT2 Inhibitors and Risk of Amputation Diabetes Care Volume 43, October 2020

Figure 2—HR (95% CI) of below-knee amputation associated with SGLT2 inhibitor use compared with DPP-4 inhibitor use among patients with type 2 diabetes. Nova Scotia was not included in this analysis because where were fewer than ﬁve events in one of the two exposure groups. IV, inverse variance.

use (7). Udell et al. (16) performed an of the amputations in the SGLT2 inhibitor 2.48; 95% CI 1.14–5.40). The heteroge- observational study using the U.S. De- group were among patients treated with neity of the findings of these previous partment of Defense Health System and canagliflozin. This finding was also ob- studies may be due to a number of found that patients initiating an SGLT2 served in the study performed by Ueda factors, including differences in the inhibitor had a nearly twofold increased et al. (17), using the Swedish/Danish populations assessed, methodologies risk of lower-extremity amputation com- National Register, which found that used, comparator drug used, differen- pared with patients treated with non- SGLT2 inhibitor users had an increased ces in the extent of amputation (i.e., SGLT2 inhibitor antidiabetic agents (HR risk of incident amputation compared some studies included above-knee am- 1.99;95%CI1.12–3.51). However,most with GLP-1 receptor agonist users (HR putations) (14,18), duration of follow-up time, and the inclusion of patients with prior history of amputation (7,13,17,18). Some of these inconsistencies were ob- Table 3—Summary of results of stratified and sensitivity analyses of pooled adjusted served within the same study when the HR (95% CI) for below-knee amputation for SGLT2 inhibitor use versus DPP-4 researchers varied the exclusion criteria inhibitor use among patients with type 2 diabetes 2 for their study population (i.e., excluding Number of sites included Adjusted HR (95% CI)* I (%) patients with prior history of amputation, Main analysis 7 0.88 (0.71–1.09) 18 insulin use, renal insufficiency, and base- Age line cardiovascular disease) and when $70 years 3 1.13 (0.81–1.56) 0 different comparators were used in the , – 70 years 6 0.80 (0.58 1.12) 46 analyses (7). Sex Our study has several strengths, in- Females 3 1.04 (0.64–1.70) 17 Males 6 0.87 (0.65–1.15) 38 cluding the use of DPP-4 inhibitors as comparators because they are prescribed Prior insulin use† Yes 6 0.69 (0.46–1.03) 51 at a similar stage of type 2 diabetes as No 4 1.14 (0.87–1.50) 0 SGLT2 inhibitors (i.e., as second- or third- SGLT2 inhibitor molecule line treatment). The use of the prevalent Canagliflozin 5 0.98 (0.77–1.25) 0 new-user design allowed inclusion of Dapagliflozin 4 0.69 (0.45–1.06) 0 patients who switched to or added an Empagliflozin 3 1.08 (0.70–1.68) 0 SGLT2 inhibitor, which is reflective of Varying grace period clinical practice and allows our findings 0 day 4 1.12 (0.74–1.69) 0 to be more generalizable to the realities – 60 days 7 0.90 (0.73 1.12) 28 of clinical practice. Indeed, we noted 365 days 7 0.90 (0.72–1.11) 46 ;50% of SGLT2 inhibitor users had pre- New user status Incident users 6 0.68 (0.53–0.88) 0 viously used DPP-4 inhibitors. Finally, Prevalent users 3 1.29 (0.97–1.70) 0 with data from eight databases across Intention-to-treat approach‡ 6 0.81 (0.63–1.05) 35 two countries, our study is the largest No prior history of dialysis 1 1.13 (0.81–1.57) NA observational study conducted examining Fixed-effects model analysis 7 0.90 (0.75–1.08) 18 this safety issue to date, increasing the precision and generalizability of our results. fi Inclusion in each meta-analysis was restricted to sites with at least ve events in each exposure Ourstudyalsohas potentiallimitations. group. NA, not applicable. *Outcome models were adjusted for age (continuous), sex, diabetes duration (continuous), and deciles of TCPS. †Prior insulin use was defined as a prescription for First, residual confounding is possible insulin in the year prior. ‡In the intention-to-treat approach, maximum follow-up was 1 year. given that this is an observational study. care.diabetesjournals.org Yu and Associates 2451

However, we used various approaches to with canagliflozin treatment in the CAN- The opinions, results, and conclusions reported minimize confounding by using an active VASProgramtrialwasobservedneartheend in this article are those of the authors. No endorse- comparator and extensive matching. ofthestudyperiod(mean follow-upof ;3.6 ment by the provinces, data stewards, the Institute for Clinical Evaluative Sciences, the Canadian In- Second, there is potential confounding years) (3). Furthermore, our study focused stitute for Health Information, or the Institut na- by contraindication as physicians may on patients with no prior history of am- tional d’excellence en sante´ et en services sociaux have been less likely to prescribe SGLT2 putation, whereas the CANVAS Program is intended or should be inferred. inhibitors to patients who were at higher trial and the CREDENCE trial involved Duality of Interest. S.A.-S. has research funding from Pfizer and Merck for studies not involving risk for amputation. Furthermore, there is patientswithapriorhistoryofamputation. SGLT2 inhibitors or DPP-4 inhibitors. No other an imbalance in the proportion of SGLT2 Thus, the patients in these trials have an potential conflicts of interest relevant to this inhibitor versus DPP-4 inhibitor users with underlying higher risk of amputation com- article were reported. renal insufficiency (eGFR ,60 mL/min/ pared with the population cohort of our Author Contributions. O.H.Y.Y. drafted the 1.73 m2) noted in the CPRD cohort, be- study (the rate of amputation in our study manuscript. O.H.Y.Y., S.D., B.R.S., V.C.B., J.-M.D., M.F., A.D., N.H., S.A.-S., A.F., S.C.B., P.E.R., K.B.F., cause use of SGLT2 inhibitors is not rec- was 1.3 per 1,000 person-years vs. 6.3 P.E., and L.M.L. were involved in the study design, ommended for patients with significant per 1,000 person-years in the CANVAS interpretation of results, and critically reviewed renal insufficiency (i.e., eGFR ,45 mL/ Program trial and 12.3 per 1,000 per- the manuscript for important intellectual con- min/1.73 m2) (1,29). Although the eGFR son-years in the CREDENCE trial) (3,9). tent. L.M.L. conducted the meta-analyses. All fi findings from the CPRD comprised a small In conclusion, in this multicenter ob- authors approved the nal version of the manuscript. L.M.L. is the guarantor of this work and, percentage of the total cohort (3.3% of the servational study, we found no evidence as such, had full access to all the data in the study weight of the meta-analysis), there may of an association between SGLT2 inhib- and takes responsibility for the integrity of the be residual confounding because patients itor use and incident below-knee ampu- data and the accuracy of the data analysis. with renal insufficiency have a higher risk tation compared with DPP-4 inhibitor use of amputation compared with patients among patients with type 2 diabetes. References with normal renal function (30). As such, Similarly, there was no increased risk of 1. American Diabetes Association. 9. Pharma- cologic approaches to glycemic treatment: Stand- DPP-4 inhibitor users may have an un- below-knee amputation associated with d fi ards of Medical Care in Diabetes 2020.Diabetes derlying higher risk of amputation com- speci c SGLT2 inhibitor molecule use Care 2020;43(Suppl. 1):S98–S110 pared with SGLT2 inhibitor users, and this compared with DPP-4 inhibitor use. Fu- 2. Lee PC, Ganguly S, Goh SY. Weight loss as- could mask the higher risk of amputation ture studies will be needed to further sociated with sodium-glucose cotransporter-2 associated with SGLT2 inhibitor use. How- address whether SGLT2 inhibitor use inhibition: a review of evidence and underlying – ever, in our sensitivity analysis, our results increases the risk of incident below-knee mechanisms. Obes Rev 2018;19:1630 1641 3. Neal B, Perkovic V, Mahaffey KW, et al.; CAN- remained consistent among patients with amputation over the longer term. VAS Program Collaborative Group. Canagliflozin no prior history of dialysis (i.e., during the and cardiovascular and renal events in type 2 3 years before study cohort entry). diabetes. N Engl J Med 2017;377:644–657 Third, the databases used in this study 4. Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG Acknowledgments. The authors thank Audray OUTCOME Investigators. Empagliflozin, cardiovas- capture dispensing of medications (i.e., Ca- St-Jean and Corine Mizrahi (Jewish General cular outcomes, and mortality in type 2 di- nadian databases) or prescriptions (i.e., Hospital) at the CNODES Coordinating Center abetes. N Engl J Med 2015;373:2117–2128 CPRD) without any guarantee that these for their important contributions to this work. 5. Wiviott SD, Raz I, Bonaca MP, et al.; DECLARE– medications were taken by the patient. The authors also acknowledge the programming TIMI 58 Investigators. Dapagliflozin and cardio- Fourth, we did not study the specificsite andanalyticalsupportof theanalystsat eachsite: vascular outcomes in type 2 diabetes. N Engl J Greg Carney and Jason Kim (University of British Med 2019;380:347–357 of below-knee amputation because we Columbia; British Columbia), Zhihai Ma (Univer- 6. Dennis JM, Henley WE, McGovern AP, et al.; anticipated insufficient events per site. sity of Calgary; Alberta), Matthew Dahl (Univer- MASTERMIND Consortium. Time trends in pre- Fifth, we included users of SGLT2 in- sity of Manitoba; Manitoba), Yan Wang and Steve scribing of type 2 diabetes drugs, glycaemic re- hibitors who had (prevalent new users) Doucette (Dalhousie University; Nova Scotia), C. sponse and risk factors: a retrospective analysis of and had not (incident new users) used Fangyun Wu (Institute for Clinical Evaluative Sci- primary care data, 2010-2017. Diabetes Obes ences; Ontario), Jean-Marc Daigle (Institut na- Metab 2019;21:1576–1584 DPP4 inhibitors previously, which may tional d’excellence en sante´ et en services 7. Yang JY, Wang T, Pate V, et al. Sodium-glucose consist of individuals that differ in the sociaux; Quebec),´ and Hui Yin and Christopher co-transporter-2 inhibitor use and risk of lower- severity of diabetes and risk for compli- Filliter (Jewish General Hospital; CPRD). The extremityamputation:evolvingquestions,evolv- cations associated with diabetes. In strat- authors thank also thank Hala Tamim (York ing answers. Diabetes Obes Metab 2019;21: – ified analyses, the risk of below-knee University) for her contributions to this study. 1223 1236 Funding. The Canadian Network for Observa- 8. U.S. Food and Drug Administration. FDA Drug amputation associated with SGLT2 in- tional Drug Effect Studies, a collaborating center Safety Communication: FDA confirms increased hibitor use compared with DPP-4 inhib- of the Drug Safety and Effectiveness Network risk of leg and foot amputations with the diabe- itor use was higher among prevalent new (DSEN), is funded by the Canadian Institutes of tes medicine canagliflozin (Invokana, Invokamet, users of SGLT2 inhibitors, but this did not Health Research (grant # DSE-146021). This study Invokamet XR), 2017. Accessed 6 January 2020. fi was supported by the Institute for Clinical Eval- Available from https://www.fda.gov/Drugs/ reach statistical signi cance. uative Sciences, which is funded by an annual DrugSafety/ucm557507.htm Finally, the duration of follow-up was grant from the Ministry of Health and Long-Term 9. Perkovic V, Jardine MJ, Neal B, et al.; CRE- modest, and future studies with a longer Care. O.H.Y.Y. receives salary support from the DENCE Trial Investigators. Canagliflozin and renal duration of follow-up are needed to Fonds de recherche du Quebec´ –sante´ (FRQS). outcomes in type 2 diabetes and nephropathy. – determine whether long-term use of V.C.B. holds a doctoral award from the FRQS. N Engl J Med 2019;380:2295 2306 K.B.F. receives salary support from the FRQS 10. Fadini GP, Avogaro A. SGLT2 inhibitors and SGLT2 inhibitors is associated with below- and William Dawson Scholar award from McGill amputations in the US FDA Adverse Event Re- knee amputation risk, because the in- University. L.M.L. is supported by a Tier I Canada porting System. Lancet Diabetes Endocrinol 2017; creased risk of amputation associated Research Chair. 5:680–681 2452 SGLT2 Inhibitors and Risk of Amputation Diabetes Care Volume 43, October 2020

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