{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T08:00:53Z","timestamp":1793779253823,"version":"4.6.1"},"reference-count":10,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T00:00:00Z","timestamp":1620864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T00:00:00Z","timestamp":1620864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cardiovasc Diabetol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In a recent meta-analysis of randomized controlled trials of sodium glucose co-transporter 2 inhibitors (SGLT2i) in patients with diabetes, Lin and colleagues showed a positive association between SGLT2i-induced blood pressure and weight reduction and the risk of lower limb events. These results support the potential mechanism of a volume depletion effect of SGLT2i to explain the increase risk of amputation observed with this pharmacological class. Since the first result of the CANVAS trial raised a concern regarding the risk of amputation with SGLT2i, this hypothesis emerged from studies showing a higher incidence of amputations in patients with diabetes using diuretics. Furthermore, recent data found that copeptin, a surrogate marker of hydration status was also associated with lower limb outcomes. In conclusion, this assumption of diuretic-induced hypovolemia explanation highlights the fact that medications that induce a contraction of plasma volume, both traditional and novel agents with a diuretic mode of action should be introduced cautiously in patients with diabetes at high risk of diabetic foot events.<\/jats:p>","DOI":"10.1186\/s12933-021-01301-x","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T17:03:58Z","timestamp":1620925438000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["SGLT2 inhibitors and lower limb complications: the diuretic-induced hypovolemia hypothesis"],"prefix":"10.1186","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6268-7360","authenticated-orcid":false,"given":"Louis","family":"Potier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamel","family":"Mohammedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilberto","family":"Velho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronan","family":"Roussel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,13]]},"reference":[{"key":"1301_CR1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s12933-021-01276-9","volume":"20","author":"C Lin","year":"2021","unstructured":"Lin C, Zhu X, Cai X, Yang W, Lv F, Nie L, et al. SGLT2 inhibitors and lower limb complications: an updated meta-analysis. Cardiovasc Diabetol. 2021;20:91.","journal-title":"Cardiovasc Diabetol"},{"key":"1301_CR2","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1056\/NEJMoa1611925","volume":"377","author":"B Neal","year":"2017","unstructured":"Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644\u201357.","journal-title":"N Engl J Med"},{"issue":"18","key":"1301_CR3","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1093\/eurheartj\/ehaa1022","volume":"42","author":"C Vlachopoulos","year":"2020","unstructured":"Vlachopoulos C, Terentes-Printzios D, Tsioufis K. Do SGLT2 inhibitors increase the risk of amputation? Make haste slowly. Eur Heart J. 2020;42(18):1739\u201341.","journal-title":"Eur Heart J."},{"key":"1301_CR4","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1002\/pds.932","volume":"13","author":"JA Erkens","year":"2004","unstructured":"Erkens JA, Klungel OH, Stolk RP, Spoelstra JA, Grobbee DE, Leufkens HGM. Antihypertensive drug therapy and the risk of lower extremity amputations in pharmacologically treated type 2 diabetes patients. Pharmacoepidemiol Drug Saf. 2004;13:139\u201346.","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"1301_CR5","doi-asserted-by":"publisher","first-page":"2981","DOI":"10.1001\/jama.288.23.2981","volume":"288","author":"ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group","year":"2002","unstructured":"ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981\u201397.","journal-title":"JAMA"},{"key":"1301_CR6","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/S0140-6736(00)02527-7","volume":"356","author":"MJ Brown","year":"2000","unstructured":"Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet Lond Engl. 2000;356:366\u201372.","journal-title":"Lancet Lond Engl"},{"key":"1301_CR7","doi-asserted-by":"publisher","first-page":"e1054","DOI":"10.1097\/MD.0000000000001054","volume":"94","author":"T Gary","year":"2015","unstructured":"Gary T, Belaj K, Hafner F, Eller P, Rief P, Hackl G, et al. Graz critical limb ischemia score: a risk score for critical limb ischemia in peripheral arterial occlusive disease. Medicine. 2015;94:e1054.","journal-title":"Medicine"},{"key":"1301_CR8","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1007\/s00125-019-4835-z","volume":"62","author":"L Potier","year":"2019","unstructured":"Potier L, Roussel R, Velho G, Saulnier P-J, Bumbu A, Matar O, et al. Lower limb events in individuals with type 2 diabetes: evidence for an increased risk associated with diuretic use. Diabetologia. 2019;62:939\u201347.","journal-title":"Diabetologia"},{"key":"1301_CR9","doi-asserted-by":"publisher","first-page":"2290","DOI":"10.2337\/dc19-1062","volume":"42","author":"L Potier","year":"2019","unstructured":"Potier L, Roussel R, Marre M, Bjornstad P, Cherney DZ, El Boustany R, et al. Plasma copeptin and risk of lower-extremity amputation in type 1 and type 2 diabetes. Diabetes Care. 2019;42:2290\u20137.","journal-title":"Diabetes Care"},{"key":"1301_CR10","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1080\/03007995.2020.1840340","volume":"36","author":"A Alshnbari","year":"2020","unstructured":"Alshnbari A, Alkharaiji M, Anyanwagu U, Idris I. Diuretics and risk of lower extremity amputation amongst patients with insulin-treated type 2 diabetes - exploring the mechanism of possible sodium glucose co-transporter 2 inhibitor induced risk of lower extremity amputations. Curr Med Res Opin. 2020;36:1985\u20139.","journal-title":"Curr Med Res Opin"}],"container-title":["Cardiovascular Diabetology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12933-021-01301-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12933-021-01301-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12933-021-01301-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T17:04:10Z","timestamp":1620925450000},"score":1,"resource":{"primary":{"URL":"https:\/\/cardiab.biomedcentral.com\/articles\/10.1186\/s12933-021-01301-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,13]]},"references-count":10,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1301"],"URL":"https:\/\/doi.org\/10.1186\/s12933-021-01301-x","relation":{},"ISSN":["1475-2840"],"issn-type":[{"value":"1475-2840","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,13]]},"assertion":[{"value":"5 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"LP reports grants, personal fees and non-financial support from NOVO NORDISK, grants, personal fees and non-financial support from SANOFI, personal fees and non-financial support from ELI LILLY, non-financial support from SERVIER, outside the submitted work and all modest. RR reports grants, personal fees and non-financial support from sanofi, personal fees and non-financial support from MSD, grants from Amgen, personal fees from Physiogenex, personal fees from Astra-Zeneca, grants and personal fees from Novo Nordisk, personal fees from Janssen, personal fees from Eli Lilly, personal fees from Abbott, personal fees from Medtronic, personal fees from Servier, outside the submitted work and all modest. KM reports personal fees and non-financial support from Novo Nordisk and Sanofi and non-financial support from VitalAir. GV have nothing to disclose.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"107"}}