{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:50:36Z","timestamp":1787028636344,"version":"build-2736575974"},"reference-count":71,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T00:00:00Z","timestamp":1686268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Our aim was to evaluate osteomyelitis and other major lower limb safety outcomes (i.e., peripheral artery disease or PAD, ulcers, atraumatic fractures, amputations, symmetric polyneuropathy, and infections) in patients affected by type 2 diabetes mellitus (T2DM) and treated with sodium-glucose cotransporter 2 inhibitors (SGLT2-is). We thus performed a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing SGLT2-is at approved doses for T2DM with a placebo or standard of care. MEDLINE, Embase, and Cochrane CENTRAL were searched through August 2022. Separate intention-to-treat analyses were implemented for each molecule to calculate Mantel-Haenszel risk ratios (RRMH) with 95% confidence intervals (CIs) through a random-effects model. We processed data from 42 RCTs for a total of 29,491 and 23,052 patients, respectively assigned to SGLT2-i and comparator groups. SGLT2-is showed a pooled neutral effect on osteomyelitis, PAD, fractures, and symmetric polyneuropathy, whereas slightly deleterious sway on ulcers (RRMH 1.39 [1.01\u20131.91]), amputations (RRMH 1.27 [1.04\u20131.55]), and infections (RRMH 1.20 [1.02\u20131.40]). In conclusion, SGLT2-is appear to not significantly interfere with the onset of osteomyelitis, PAD, lower limb fractures, or symmetric polyneuropathy, even though the number of these events proved consistently higher in the investigational groups; otherwise, local ulcers, amputations, and overall infections may be favoured by their employment. This study is registered with the Open Science Framework (OSF).<\/jats:p>","DOI":"10.3390\/jcm12123958","type":"journal-article","created":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T09:54:32Z","timestamp":1686304472000},"page":"3958","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Association of Sodium-Glucose Cotransporter 2 Inhibitors with Osteomyelitis and Other Lower Limb Safety Outcomes in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials"],"prefix":"10.3390","volume":"12","author":[{"given":"Alessandro","family":"Nani","sequence":"first","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8895-3425","authenticated-orcid":false,"given":"Federica","family":"Carrara","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"},{"name":"Hospital Pharmacy, Humanitas Gavazzeni, 24125 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara Maria Eleonora","family":"Paulesu","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Dalle Fratte","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Padroni","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Enisci","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Concetta","family":"Bilancio","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9771-1719","authenticated-orcid":false,"given":"Maria Silvia","family":"Romio","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Bertuzzi","sequence":"additional","affiliation":[{"name":"Department of Diabetology, Niguarda Hospital, 20162 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basilio","family":"Pintaudi","sequence":"additional","affiliation":[{"name":"Department of Diabetology, Niguarda Hospital, 20162 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12933-022-01455-2","article-title":"Efficacy and safety of sodium-glucose cotransporter 2 inhibitors initiation in patients with acute heart failure, with and without type 2 diabetes: A systematic review and meta-analysis","volume":"21","author":"Salah","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1080\/14740338.2020.1733967","article-title":"Efficacy and safety profile of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease","volume":"19","author":"Scheen","year":"2020","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e022577","DOI":"10.1136\/bmjopen-2018-022577","article-title":"Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: A systematic review and meta-analysis","volume":"9","author":"Donnan","year":"2019","journal-title":"BMJ Open"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1056\/NEJMoa2004967","article-title":"Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes","volume":"383","author":"Cannon","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12933-019-0903-4","article-title":"Class effects of SGLT2 inhibitors on cardiorenal outcomes","volume":"18","author":"Kluger","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1056\/NEJMoa1812389","article-title":"Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes","volume":"380","author":"Wiviott","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_7","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":"ref_8","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":"ref_9","doi-asserted-by":"crossref","unstructured":"Hou, Y.-C., Zheng, C.-M., Yen, T.-H., and Lu, K.-C. (2020). Molecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217833"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s12933-020-01071-y","article-title":"SGLT2i: Beyond the glucose-lowering effect","volume":"19","author":"Ni","year":"2020","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.jacc.2019.11.031","article-title":"Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review","volume":"75","author":"Zelniker","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nakamura, A. (2022). Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Pancreatic \u03b2-Cell Mass and Function. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095104"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Li, C.-X., Liang, S., Gao, L., and Liu, H. (2021). Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: A real-world systematic review and meta-analysis. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0244689"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41598-020-80603-8","article-title":"Cardiovascular safety and efficacy of metformin-SGLT2i versus metformin-sulfonylureas in type 2 diabetes: Systematic review and meta-analysis of randomized controlled trials","volume":"11","author":"Gebrie","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/S2213-8587(13)70050-0","article-title":"SGLT inhibitors in management of diabetes","volume":"1","author":"Tahrani","year":"2013","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1002\/clc.23508","article-title":"The cardiovascular outcomes, heart failure and kidney disease trials tell that the time to use Sodium Glucose Cotransporter 2 inhibitors is now","volume":"43","author":"Johansen","year":"2020","journal-title":"Clin. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/s40266-020-00757-y","article-title":"Use of SGLT2 Inhibitors in Older Adults: Scientific Evidence and Practical Aspects","volume":"37","author":"Cavalcanti","year":"2020","journal-title":"Drugs Aging"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.diabres.2019.05.028","article-title":"Peripheral artery disease and amputations with Sodium-Glucose co-Transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials","volume":"153","author":"Dicembrini","year":"2019","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2106\/JBJS.N.01350","article-title":"Trends in the epidemiology of osteomyelitis: A population-based study, 1969 to 2009","volume":"97","author":"Kremers","year":"2015","journal-title":"J. Bone Joint Surg. Am."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan\u2014A web and mobile app for systematic reviews","volume":"5","author":"Ouzzani","year":"2016","journal-title":"Syst. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/ggi.14363","article-title":"Effects of ipragliflozin on left ventricular diastolic function in patients with type 2 diabetes and heart failure with preserved ejection fraction: The EXCEED randomized controlled multicenter study","volume":"22","author":"Akasaka","year":"2022","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1111\/dom.12460","article-title":"Dose-ranging efficacy and safety study of ertugliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin","volume":"17","author":"Amin","year":"2015","journal-title":"Diabetes Obes. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1111\/jdi.13533","article-title":"Simplification of complex insulin regimens using canagliflozin or liraglutide in patients with well-controlled type 2 diabetes: A 24-week randomized controlled trial","volume":"12","author":"Ando","year":"2021","journal-title":"J. Diabetes Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1111\/dom.14259","article-title":"Glycaemic control with add-on thiazolidinedione or a sodium-glucose co-transporter-2 inhibitor in patients with type 2 diabetes after the failure of an oral triple antidiabetic regimen: A 24-week, randomized controlled trial","volume":"23","author":"Bae","year":"2021","journal-title":"Diabetes Obes.Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S2213-8587(13)70208-0","article-title":"Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: A randomised, double-blind, placebo-controlled trial","volume":"2","author":"Barnett","year":"2014","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e3335","DOI":"10.1002\/dmrr.3335","article-title":"The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA-HF study","volume":"36","author":"Carbone","year":"2020","journal-title":"Diabetes\/Metabolism Res. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1007\/s13300-021-01011-3","article-title":"Empagliflozin Improves Liver Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial","volume":"12","author":"Chehrehgosha","year":"2021","journal-title":"Diabetes Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1111\/dom.13116","article-title":"Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study","volume":"20","author":"Liu","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1111\/dom.13413","article-title":"On Behalf of the DERIVE Study Investigators Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): The DERIVE Study","volume":"20","author":"Fioretto","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1111\/dom.13631","article-title":"Long-term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104-week VERTIS MET trial","volume":"21","author":"Gallo","year":"2019","journal-title":"Diabetes Obes. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s13300-017-0354-4","article-title":"Ertugliflozin Compared with Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: The VERTIS SU Randomized Study","volume":"9","author":"Hollander","year":"2018","journal-title":"Diabetes Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12933-016-0407-4","article-title":"Efficacy and safety of canagliflozin in combination with insulin: A double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus","volume":"15","author":"Inagaki","year":"2016","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1507\/endocrj.EJ20-0222","article-title":"Effects of dapagliflozin on renin-angiotensin-aldosterone system under renin-angiotensin system inhibitor administration","volume":"67","author":"Isshiki","year":"2020","journal-title":"Endocr. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ahj.2020.07.011","article-title":"Twelve weeks of treatment with empagliflozin in patients with heart failure and reduced ejection fraction: A double-blinded, randomized, and placebo-controlled trial","volume":"228","author":"Jensen","year":"2020","journal-title":"Am. Heart J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1475-2840-13-65","article-title":"Efficacy and safety of monotherapy with the novel sodium\/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: A combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study","volume":"13","author":"Kaku","year":"2014","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s13340-014-0164-0","article-title":"Ipragliflozin improves glycemic control in Japanese patients with type 2 diabetes mellitus: The BRIGHTEN study","volume":"6","author":"Kashiwagi","year":"2015","journal-title":"Diabetol. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s13340-014-0184-9","article-title":"Efficacy and safety of ipragliflozin as an add-on to a sulfonylurea in Japanese patients with inadequately controlled type 2 diabetes: Results of the randomized, placebo-controlled, double-blind, phase III EMIT study","volume":"6","author":"Kashiwagi","year":"2014","journal-title":"Diabetol. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12933-020-01079-4","article-title":"Tofogliflozin does not delay progression of carotid atherosclerosis in patients with type 2 diabetes: A prospective, randomized, open-label, parallel-group comparative study","volume":"19","author":"Katakami","year":"2020","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1111\/dom.13352","article-title":"Empagliflozin as add-on to linagliptin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52-week, randomized, placebo-controlled trial","volume":"20","author":"Kawamori","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1111\/dom.14059","article-title":"Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes: A randomized, 24-week, open-label, controlled trial (STOP-OB)","volume":"22","author":"Kitazawa","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1111\/dom.12127","article-title":"Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes","volume":"15","author":"Wie","year":"2013","journal-title":"Diabetes Obes. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/S2213-8587(19)30311-0","article-title":"Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): A double-blind, phase 3b, randomised controlled trial","volume":"7","author":"Lingvay","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s13300-017-0358-0","article-title":"Ertugliflozin and Sitagliptin Co-initiation in Patients with Type 2 Diabetes: The VERTIS SITA Randomized Study","volume":"9","author":"Miller","year":"2018","journal-title":"Diabetes Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1161\/CIRCULATIONAHA.119.042929","article-title":"Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial","volume":"140","author":"Nassif","year":"2019","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1002\/ejhf.2560","article-title":"Short-term effects of dapagliflozin on maximal functional capacity in heart failure with reduced ejection fraction (DAPA-VO 2): A randomized clinical trial","volume":"24","author":"Palau","year":"2022","journal-title":"Eur. J. Heart Fail."},{"key":"ref_46","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":"ref_47","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S2213-8587(19)30086-5","article-title":"Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): A randomised, double-blind, placebo-controlled trial","volume":"7","author":"Pollock","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1111\/dom.13194","article-title":"Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial","volume":"20","author":"Pratley","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12933-020-01175-5","article-title":"Empagliflozin does not change cardiac index nor systemic vascular resistance but rapidly improves left ventricular filling pressure in patients with type 2 diabetes: A randomized controlled study","volume":"20","author":"Rau","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.2337\/dc11-1693","article-title":"Effects of Dapagliflozin, an SGLT2 Inhibitor, on HbA1c, Body Weight, and Hypoglycemia Risk in Patients With Type 2 Diabetes Inadequately Controlled on Pioglitazone Monotherapy","volume":"35","author":"Rosenstock","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1111\/dom.14721","article-title":"The effects of empagliflozin, dietary energy restriction, or both on appetite-regulatory gut peptides in individuals with type 2 diabetes and overweight or obesity: The SEESAW randomized, double-blind, placebo-controlled trial","volume":"24","author":"Sargeant","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/dom.12387","article-title":"Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: A 16-week randomized, placebo-controlled clinical trial","volume":"17","author":"Burgess","year":"2015","journal-title":"Diabetes Obes. Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1111\/dom.13909","article-title":"Efficacy and safety of empagliflozin as add-on to insulin in Japanese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial","volume":"22","author":"Sone","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/s41591-022-01703-8","article-title":"The SGLT2 inhibitor canagliflozin in heart failure: The CHIEF-HF remote, patient-centered randomized trial","volume":"28","author":"Spertus","year":"2022","journal-title":"Nat. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1177\/1479164118782872","article-title":"Renoprotective effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, in type 2 diabetes patients with chronic kidney disease: A randomized open-label prospective trial","volume":"15","author":"Takashima","year":"2018","journal-title":"Diabetes Vasc. Dis. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.1111\/dom.13770","article-title":"Addition of canagliflozin to insulin improves glycaemic control and reduces insulin dose in patients with type 2 diabetes mellitus: A randomized controlled trial","volume":"21","author":"Torimoto","year":"2019","journal-title":"Diabetes Obes. Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/S2213-8587(20)30369-7","article-title":"Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: A prespecified analysis from the DAPA-CKD trial","volume":"9","author":"Wheeler","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1111\/1753-0407.12634","article-title":"Dapagliflozin as add-on therapy in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs: A randomized controlled trial","volume":"10","author":"Yang","year":"2018","journal-title":"J. Diabetes"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1111\/1753-0407.12357","article-title":"Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: A randomized controlled trial","volume":"8","author":"Yang","year":"2016","journal-title":"J. Diabetes"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.2337\/dci22-0027","article-title":"Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO)","volume":"45","author":"Khunti","year":"2022","journal-title":"Diabetes Care"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1007\/s00125-022-05787-2","article-title":"Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)","volume":"65","author":"Davies","year":"2022","journal-title":"Diabetologia"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/eurheartj\/ehz486","article-title":"2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD","volume":"41","author":"Cosentino","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"m4573","DOI":"10.1136\/bmj.m4573","article-title":"Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: Systematic review and network meta-analysis of randomised controlled trials","volume":"372","author":"Palmer","year":"2021","journal-title":"BMJ"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1001\/jamacardio.2020.4511","article-title":"Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis","volume":"6","author":"McGuire","year":"2021","journal-title":"JAMA Cardiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12933-022-01476-x","article-title":"Association of SGLT2 inhibitors with cardiovascular, kidney, and safety outcomes among patients with diabetic kidney disease: A meta-analysis","volume":"21","author":"Kaze","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Heyward, J., Mansour, O., Olson, L., Singh, S., and Alexander, G.C. (2020). Association between sodium-glucose cotransporter 2 (SGLT2) inhib-itors and lower extremity amputation: A systematic review and meta-analysis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0234065"},{"key":"ref_67","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":"ref_68","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1093\/eurheartj\/ehaa956","article-title":"The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium-glucose cotransporter type-2 inhibitors: Real-world study","volume":"42","author":"Paul","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1111\/dom.14159","article-title":"Sodium-glucose co-transporter-2 inhibitors and major adverse limb events: A trial-level meta-analysis including 51 713 individuals","volume":"22","author":"Huang","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/dom.14840","article-title":"Global mortality of diabetic foot ulcer: A systematic review and meta-analysis of observational studies","volume":"25","author":"Chen","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1002\/PHAR.1010","article-title":"Dapagliflozin: A Novel Sodium-Glucose Cotransporter Type 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus","volume":"32","author":"Shah","year":"2012","journal-title":"Pharmacother. J. Hum. Pharmacol. 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