{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T08:00:55Z","timestamp":1793779255122,"version":"4.6.1"},"reference-count":30,"publisher":"American Diabetes Association","issue":"10","license":[{"start":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T00:00:00Z","timestamp":1600646400000},"content-version":"vor","delay-in-days":47,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["DSE-146021"],"award-info":[{"award-number":["DSE-146021"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,10,1]]},"abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>Reports of amputations associated with sodium\u2013glucose cotransporter 2 (SGLT2) inhibitors have been inconsistent. We aimed to compare the risk of below-knee amputation with SGLT2 inhibitors versus dipeptidyl peptidase 4 (DPP-4) inhibitors among patients with type 2 diabetes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>This multicenter observational study used administrative health care databases from seven Canadian provinces and the U.K. Incident SGLT2 inhibitor users were matched to DPP-4 inhibitor users using a prevalent new-user design and time-conditional propensity scores. Cox proportional hazards models were used to estimate site-specific adjusted hazard ratios (HR) and corresponding 95% CIs of incident below-knee amputation for SGLT2 inhibitor versus DPP-4 inhibitor users. Random effects meta-analyses were used to pool the site-specific results.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>The study cohort included 207,817 incident SGLT2 inhibitor users matched to 207,817 DPP-4 inhibitor users. During a mean exposed follow-up time of 11 months, the amputation rate was 1.3 per 1,000 person-years among SGLT2 inhibitor users and 1.5 per 1,000 person-years among DPP-4 inhibitor users. The adjusted HR of below-knee amputations associated with SGLT2 inhibitor use compared with DPP-4 inhibitor use was 0.88 (95% CI 0.71\u20131.09). Similar results were obtained in stratified analyses by specific SGLT2 inhibitor molecule.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>In this large multicenter observational study, there was no association between SGLT2 inhibitor use and incident below-knee amputations among patients with type 2 diabetes compared with DPP-4 inhibitor use. While these findings provide some reassurance, studies with a longer duration of follow-up are needed to assess potential long-term effects.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/dc20-0267","type":"journal-article","created":{"date-parts":[[2020,8,6]],"date-time":"2020-08-06T02:15:25Z","timestamp":1596680125000},"page":"2444-2452","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":35,"title":["Sodium\u2013Glucose Cotransporter 2 Inhibitors and the Risk of Below-Knee Amputation: A Multicenter Observational Study"],"prefix":"10.2337","volume":"43","clinical-trial-number":[{"clinical-trial-number":"nct04017221","registry":"10.18810\/clinical-trials-gov","type":"results"},{"clinical-trial-number":"nct04017221","registry":"10.18810\/clinical-trials-gov","type":"results"}],"author":[{"given":"Oriana Hoi Yun","family":"Yu","sequence":"first","affiliation":[{"name":"Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Division of Endocrinology, Department of Medicine, Jewish General Hospital, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Dell\u2019Aniello","sequence":"additional","affiliation":[{"name":"Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3598-3628","authenticated-orcid":false,"given":"Baiju R.","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Toronto, Toronto, Ontario, Canada"},{"name":"Institute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada"},{"name":"Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa C.","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Daigle","sequence":"additional","affiliation":[{"name":"Institut national d'excellence en sant\u00e9 et en services sociaux (INESSS), Qu\u00e9bec City, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Fralick","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Toronto, Toronto, Ontario, Canada"},{"name":"Sinai Health System, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6005-4006","authenticated-orcid":false,"given":"Antonios","family":"Douros","sequence":"additional","affiliation":[{"name":"Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Departments of Medicine and of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Institute of Clinical Pharmacology and Toxicology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany"},{"name":"Berlin Institute of Health, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nianping","family":"Hu","sequence":"additional","affiliation":[{"name":"The Health Quality Council, Saskatoon, Saskatchewan, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Alessi-Severini","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada"},{"name":"Manitoba Centre for Health Policy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anat","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn C.","family":"Bugden","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada"},{"name":"School of Pharmacy, Memorial University of Newfoundland, St. John\u2019s, Newfoundland and Labrador, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul E.","family":"Ronksley","sequence":"additional","affiliation":[{"name":"Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6055-0088","authenticated-orcid":false,"given":"Kristian B.","family":"Filion","sequence":"additional","affiliation":[{"name":"Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Departments of Medicine and of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Ernst","sequence":"additional","affiliation":[{"name":"Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Departments of Medicine and of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8685-3212","authenticated-orcid":false,"given":"Lisa M.","family":"Lix","sequence":"additional","affiliation":[{"name":"Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Canadian Network for Observational Drug Effect Studies (CNODES) Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samy","family":"Suissa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin R.","family":"Dormuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda R.","family":"Hemmelgarn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Quail","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Chateau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Michael","family":"Paterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"LeLorier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian R.","family":"Levy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Ernst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian B.","family":"Filion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M.","family":"Lix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Platt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid S.","family":"Sketris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2020,8,5]]},"reference":[{"key":"2022031223552072500_B1","doi-asserted-by":"crossref","first-page":"S98","DOI":"10.2337\/dc20-S009","article-title":"9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes\u20142020","volume":"43","author":"American Diabetes Association","year":"2020","journal-title":"Diabetes Care"},{"key":"2022031223552072500_B2","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1111\/obr.12755","article-title":"Weight loss associated with sodium-glucose cotransporter-2 inhibition: a review of evidence and underlying mechanisms","volume":"19","author":"Lee","year":"2018","journal-title":"Obes Rev"},{"key":"2022031223552072500_B3","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1056\/NEJMoa1611925","article-title":"Canagliflozin and cardiovascular and renal events in type 2 diabetes","volume":"377","author":"Neal","year":"2017","journal-title":"N Engl J Med"},{"key":"2022031223552072500_B4","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N Engl J Med"},{"key":"2022031223552072500_B5","first-page":"347","article-title":"Dapagliflozin and cardiovascular outcomes in type 2 diabetes","volume-title":"N Engl J Med","author":"Wiviott","year":"2019"},{"key":"2022031223552072500_B6","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1111\/dom.13687","article-title":"Time trends in prescribing of type 2 diabetes drugs, glycaemic response and risk factors: a retrospective analysis of primary care data, 2010-2017","volume":"21","author":"Dennis","year":"2019","journal-title":"Diabetes Obes Metab"},{"key":"2022031223552072500_B7","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1111\/dom.13647","article-title":"Sodium-glucose co-transporter-2 inhibitor use and risk of lower-extremity amputation: evolving questions, evolving answers","volume":"21","author":"Yang","year":"2019","journal-title":"Diabetes Obes Metab"},{"key":"2022031223552072500_B8","unstructured":"U.S. Food and Drug Administration\n          . FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR), 2017. Accessed 6 January 2020. Available from\u2008https:\/\/www.fda.gov\/Drugs\/DrugSafety\/ucm557507.htm"},{"key":"2022031223552072500_B9","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1056\/NEJMoa1811744","article-title":"Canagliflozin and renal outcomes in type 2 diabetes and nephropathy","volume":"380","author":"Perkovic","year":"2019","journal-title":"N Engl J Med"},{"key":"2022031223552072500_B10","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/S2213-8587(17)30257-7","article-title":"SGLT2 inhibitors and amputations in the US FDA Adverse Event Reporting System","volume":"5","author":"Fadini","year":"2017","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2022031223552072500_B11","first-page":"1531","article-title":"SGLT-2 inhibitors and the risk of lower-limb amputation: is this a class effect","volume-title":"Diabetes Obes Metab","author":"Khouri","year":"2018"},{"key":"2022031223552072500_B12","first-page":"582","article-title":"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","volume-title":"Diabetes Obes Metab","author":"Yuan","year":"2018"},{"key":"2022031223552072500_B13","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1111\/dom.13424","article-title":"Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: a real-world meta-analysis of 4 observational databases (OBSERVE-4D)","volume":"20","author":"Ryan","year":"2018","journal-title":"Diabetes Obes Metab"},{"key":"2022031223552072500_B14","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1001\/jamainternmed.2018.3034","article-title":"Association between sodium-glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes","volume":"178","author":"Chang","year":"2018","journal-title":"JAMA Intern Med"},{"key":"2022031223552072500_B15","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/dom.13477","article-title":"Cardiovascular outcomes of sodium glucose cotransporter-2 inhibitors in patients with type 2 diabetes","volume":"21","author":"Dawwas","year":"2019","journal-title":"Diabetes Obes Metab"},{"key":"2022031223552072500_B16","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1161\/CIRCULATIONAHA.117.031227","article-title":"Cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter 2 inhibitor: results from the EASEL population-based cohort study (evidence for cardiovascular outcomes with sodium glucose cotransporter 2 inhibitors in the real world)","volume":"137","author":"Udell","year":"2018","journal-title":"Circulation"},{"key":"2022031223552072500_B17","doi-asserted-by":"crossref","first-page":"k4365","DOI":"10.1136\/bmj.k4365","article-title":"Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study","volume":"363","author":"Ueda","year":"2018","journal-title":"BMJ"},{"key":"2022031223552072500_B18","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.1111\/dom.13459","article-title":"Risk of amputations associated with SGLT2 inhibitors compared to DPP-4 inhibitors: a propensity-matched cohort study","volume":"20","author":"Adimadhyam","year":"2018","journal-title":"Diabetes Obes Metab"},{"key":"2022031223552072500_B19","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1046\/j.1365-2125.1998.00701.x","article-title":"Use of the UK General Practice Research Database for pharmacoepidemiology","volume":"45","author":"Garc\u00eda Rodr\u00edguez","year":"1998","journal-title":"Br J Clin Pharmacol"},{"key":"2022031223552072500_B20","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1093\/ije\/dyv098","article-title":"Data resource profile: Clinical Practice Research Datalink (CPRD)","volume":"44","author":"Herrett","year":"2015","journal-title":"Int J Epidemiol"},{"key":"2022031223552072500_B21","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1592\/phco.23.5.686.32205","article-title":"Validity of the general practice research database","volume":"23","author":"Jick","year":"2003","journal-title":"Pharmacotherapy"},{"key":"2022031223552072500_B22","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/pds.4107","article-title":"Prevalent new-user cohort designs for comparative drug effect studies by time-conditional propensity scores","volume":"26","author":"Suissa","year":"2017","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"2022031223552072500_B23","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.amjmed.2016.10.016","article-title":"Dipeptidyl peptidase-4 inhibitors, peripheral arterial disease, and lower extremity amputation risk in diabetic patients","volume":"130","author":"Chang","year":"2017","journal-title":"Am J Med"},{"key":"2022031223552072500_B24","doi-asserted-by":"crossref","first-page":"e00836","DOI":"10.1016\/j.heliyon.2018.e00836","article-title":"Risk of contralateral lower limb amputation and death after initial lower limb amputation - a population-based study","volume":"4","author":"Huseynova","year":"2018","journal-title":"Heliyon"},{"key":"2022031223552072500_B25","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12933-019-0869-2","article-title":"The CANVAS Program: implications of canagliflozin on reducing cardiovascular risk in patients with type 2 diabetes mellitus","volume":"18","author":"Carbone","year":"2019","journal-title":"Cardiovasc Diabetol"},{"key":"2022031223552072500_B26","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/0197-2456(86)90046-2","article-title":"Meta-analysis in clinical trials","volume":"7","author":"DerSimonian","year":"1986","journal-title":"Control Clin Trials"},{"key":"2022031223552072500_B27","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.2337\/dc17-1551","article-title":"Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME trial","volume":"41","author":"Inzucchi","year":"2018","journal-title":"Diabetes Care"},{"key":"2022031223552072500_B28","doi-asserted-by":"crossref","first-page":"C40","DOI":"10.1016\/S0149-2918(98)80007-6","article-title":"Limitations and strengths of spontaneous reports data","volume":"20","author":"Goldman","year":"1998","journal-title":"Clin Ther"},{"key":"2022031223552072500_B29","first-page":"S1","article-title":"Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada","volume":"42","author":"Diabetes Canada Clinical Practice Guidelines Expert Committee","year":"2018","journal-title":"Can J Diabetes"},{"key":"2022031223552072500_B30","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.2337\/diacare.24.9.1689","article-title":"Increased risk of lower-extremity amputation among Caucasian diabetic patients on dialysis","volume":"24","author":"Morbach","year":"2001","journal-title":"Diabetes Care"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/care.diabetesjournals.org\/syndication\/doi\/10.2337\/dc20-0267","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/43\/10\/2444\/630036\/dc200267.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/43\/10\/2444\/630036\/dc200267.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T03:53:21Z","timestamp":1647143601000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/43\/10\/2444\/35902\/Sodium-Glucose-Cotransporter-2-Inhibitors-and-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,5]]},"references-count":30,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,8,5]]},"published-print":{"date-parts":[[2020,10,1]]}},"URL":"https:\/\/doi.org\/10.2337\/dc20-0267","relation":{},"ISSN":["0149-5992","1935-5548"],"issn-type":[{"value":"0149-5992","type":"print"},{"value":"1935-5548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,5]]}}}