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Review

An update on the safety of SGLT2 inhibitors

Pages 295-311 | Received 10 Jan 2019, Accepted 28 Mar 2019, Published online: 16 Apr 2019

References

  • Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol. 2013;1:140–151.
  • Scheen AJ, Paquot N. Metabolic effects of SGLT2 inhibitors beyond increased glucosuria: a review of clinical evidence. Diabetes Metab. 2014;40:S4–S11.
  • DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13:11–26.
  • Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med. 2015;66:255–270.
  • Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75:33–59.
  • Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017;60:215–225.
  • Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.
  • Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657.
  • Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–357.
  • Scheen AJ. Cardiovascular effects of new oral glucose-lowering agents: DPP-4 and SGLT-2 inhibitors. Circ Res. 2018;122:1439–1459.
  • Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393:31–39.
  • Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41:2669–2701.
  • Fattah H, Vallon V. The potential role of SGLT2 inhibitors in the treatment of type 1 diabetes mellitus. Drugs. 2018;78:717–726.
  • Opingari E, Partridge ACR, Verma S, et al. SGLT2 inhibitors: practical considerations and recommendations for cardiologists. Curr Opin Cardiol. 2018;33:676–682.
  • Wanner C. EMPA-REG OUTCOME: the nephrologist‘s point of view. Am J Cardiol. 2017;120:S59–S67.
  • Singh M, Kumar A. Risks associated with SGLT2 inhibitors: an overview. Curr Drug Saf. 2018;13:84–91.
  • Carlson CJ, Santamarina ML. Update review of the safety of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with type 2 diabetes mellitus. Expert Opin Drug Saf. 2016;15:1401–1412.
  • Scheen AJ. The safety of gliptins: updated data in 2018. Expert Opin Drug Safety. 2018;17:387–405.
  • Scheen AJ. SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment. Expert Opin Drug Saf. 2015;14:1879–1904.
  • Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38:1687–1693.
  • Scheen AJ. Does lower-limb amputation concern all SGLT-2 inhibitors? Nat Rev Endocrinol. 2018;14:326–328.
  • Scheen AJ. Drug-drug interactions with SGLT-2 inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes. Clin Pharmacokinet. 2014;53:295–304.
  • Filippas-Ntekouan S, Filippatos TD, Elisaf MS. SGLT2 inhibitors: are they safe? Postgrad Med. 2018;130:72–82.
  • Scheen AJ. SGLT2 inhibitors: benefit/risk balance. Curr Diab Rep. 2016;16:92.
  • Lupsa BC, Inzucchi SE. Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits. Diabetologia. 2018;61:2118–2125.
  • Plosker GL. Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2014;74:807–824.
  • Deeks ED, Scheen AJ. Canagliflozin: a review in type 2 diabetes. Drugs. 2017;77:1577–1592.
  • Plosker GL. Dapagliflozin: a review of its use in patients with type 2 diabetes. Drugs. 2014;74:2191–2209.
  • Jabbour S, Seufert J, Scheen A, et al. Dapagliflozin in patients with type 2 diabetes mellitus: A pooled analysis of safety data from phase IIb/III clinical trials. Diabetes Obes Metab. 2018;20:620–628.
  • Scott LJ. Empagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2014;74:1769–1784.
  • Frampton JE. Empagliflozin: a review in type 2 diabetes. Drugs. 2018;78:1037–1048.
  • Cannon CP, McGuire DK, Pratley R, et al. Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV). Am Heart J. 2018;206:11–23.
  • Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation. 2017;136:249–259.
  • Kosiborod M, Lam CSP, Kohsaka S, et al. Lower cardiovascular risk associated with SGLT-2i in >400,000 patients: the CVD-REAL 2 study. J Am Coll Cardiol. 2018;71:2628–2639.
  • Udell JA, Yuan Z, Rush T, et al. Cardiovascular outcomes and risks after initiation of a sodium glucose co-transporter 2 inhibitor: results from the EASEL population-based cohort study. Circulation. 2018;137:1450–1459.
  • Scheen AJ. Effects of glucose-lowering agents on renal surrogate endpoints and hard clinical outcomes in patients with type 2 diabetes. Diabetes Metab. 2019;45:110–121.
  • Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–334.
  • Perkovic V, Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS program randomised clinical trials. Lancet Diabetes Endocrinol. 2018;6:691–704.
  • Wanner C, Lachin JM, Inzucchi SE, et al. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation. 2018;137:119–129.
  • Neuen BL, Ohkuma T, Neal B, et al. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function: data from the CANVAS program. Circulation. 2018;138:1537–1550.
  • Szalat A, Perlman A, Muszkat M, et al. Can SGLT2 inhibitors cause acute renal failure? Plausible role for altered glomerular hemodynamics and medullary hypoxia. Drug. 2018;41:239–252.
  • Briasoulis A, Al Dhaybi O, Bakris GL. SGLT2 inhibitors and mechanisms of hypertension. Curr Cardiol Rep. 2018;20:1.
  • Perlman A, Heyman SN, Matok I, et al. Acute renal failure with sodium-glucose-cotransporter-2 inhibitors: analysis of the FDA adverse event report system database. Nutr Metab Cardiovasc Dis. 2017;27:1108–1113.
  • Saly DL, Perazella MA. Harnessing basic and clinic tools to evaluate SGLT2 inhibitor nephrotoxicity. Am J Physiol Renal Physiol. 2017;313:F951–F954.
  • Tang H, Li D, Zhang J, et al. Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: A network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19:1106–1115.
  • Nadkarni GN, Ferrandino R, Chang A, et al. Acute kidney injury in patients on SGLT2 inhibitors: a propensity-matched analysis. Diabetes Care. 2017;40:1479–1485.
  • Cahn A, Melzer-Cohen C, Pollack R, et al. Acute renal outcomes with sodium-glucose co-transporter-2 inhibitors: real-world data analysis. Diabetes Obes Metab. 2019;21:340–348.
  • Ueda P, Svanstrom H, Melbye M, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ. 2018;363:k4365.
  • Shao Y, Lim GJ, Chua CL, et al. The effect of Ramadan fasting and continuing sodium-glucose co-transporter-2 (SGLT2) inhibitor use on ketonemia, blood pressure and renal function in Muslim patients with type 2 diabetes. Diabetes Res Clin Pract. 2018;142:85–91.
  • Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes. 2008;57:3169–3176.
  • Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262–274.
  • Yang XP, Lai D, Zhong XY, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes: systematic review and meta-analysis. Eur J Clin Pharmacol. 2014;70:1149–1158.
  • Zhang M, Zhang L, Wu B, et al. Dapagliflozin treatment for type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. 2014;30:204–221.
  • Liakos A, Karagiannis T, Athanasiadou E, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2014;16:984–993.
  • Wan Seman WJ, Kori N, Rajoo S, et al. Switching from sulphonylurea to a sodium-glucose cotransporter2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia. Diabetes Obes Metab. 2016;18:628–632.
  • Geerlings S, Fonseca V, Castro-Diaz D, et al. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract. 2014;103:373–381.
  • Liu XY, Zhang N, Chen R, et al. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2 years. J Diabetes Complications. 2015;29:1295–1303.
  • Puckrin R, Saltiel MP, Reynier P, et al. SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials. Acta Diabetol. 2018;55:503–514.
  • Li D, Wang T, Shen S, et al. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19:348–355.
  • Johnsson KM, Ptaszynska A, Schmitz B, et al. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27:473–478.
  • Donnan JR, Grandy CA, Chibrikov E, et al. Dose response of sodium glucose cotransporter-2 inhibitors in relation to urinary tract infections: a systematic review and network meta-analysis of randomized controlled trials. CMAJ Open. 2018;6:E594–E602.
  • Ptaszynska A, Johnsson KM, Parikh SJ, et al. Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Saf. 2014;37:815–829.
  • Gadzhanova S, Pratt N, Roughead E. Use of SGLT2 inhibitors for diabetes and risk of infection: analysis using general practice records from the NPS MedicineWise MedicineInsight program. Diabetes Res Clin Pract. 2017;130:180–185.
  • Kufel WD, Scrimenti A, Steele JM. A case of septic shock due to Serratia marcescens pyelonephritis and bacteremia in a patient receiving empagliflozin. J Pharm Pract. 2017;30:672–675.
  • Wu JH, Foote C, Blomster J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4:411–419.
  • Nyirjesy P, Sobel JD, Fung A, et al. Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr Med Res Opin. 2014;30:1109–1119.
  • Johnsson KM, Ptaszynska A, Schmitz B, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27:479–484.
  • Arakaki RF. Sodium-glucose cotransporter-2 inhibitors and genital and urinary tract infections in type 2 diabetes. Postgrad Med. 2016;128:409–417.
  • Fadini GP, Bonora BM, Mayur S, et al. Dipeptidyl peptidase-4 inhibitors moderate the risk of genitourinary tract infections associated with sodium-glucose co-transporter-2 inhibitors. Diabetes Obes Metab. 2018;20:740–744.
  • Adimadhyam S, Schumock GT, Calip GS, et al. Increased risk of mycotic infections associated with sodium-glucose co-transporter 2 inhibitors: a prescription sequence symmetry analysis. Br J Clin Pharmacol. 2019;85:160–168.
  • Thong KY, Yadagiri M, Barnes DJ, et al. Clinical risk factors predicting genital fungal infections with sodium-glucose cotransporter 2 inhibitor treatment: the ABCD nationwide dapagliflozin audit. Prim Care Diabetes. 2018;12:45–50.
  • Baker WL, Smyth LR, Riche DM, et al. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8:262–75 e9.
  • Sjostrom CD, Johansson P, Ptaszynska A, et al. Dapagliflozin lowers blood pressure in hypertensive and non-hypertensive patients with type 2 diabetes. Diab Vasc Dis Res. 2015;12:352–358.
  • Elmore LK, Baggett S, Kyle JA, et al. A review of the efficacy and safety of canagliflozin in elderly patients with type 2 diabetes. Consult Pharm. 2014;29:335–346.
  • Mikhail N. Safety of canagliflozin in patients with type 2 diabetes. Curr Drug Saf. 2014;9:127–132.
  • Mikhail N. Use of sodium-glucose cotransporter type 2 inhibitors in older adults with type 2 diabetes mellitus. South Med J. 2015;108:91–96.
  • John M, Cerdas S, Violante R, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus living in hot climates. Int J Clin Pract. 2016;70:775–785.
  • Lin HW, Tseng CH. A review on the relationship between SGLT2 inhibitors and cancer. Int J Endocrinol. 2014;2014:719578.
  • Ptaszynska A, Cohen SM, Messing EM, et al. Assessing bladder cancer risk in type 2 diabetes clinical trials: the dapagliflozin drug development program as a ‘case study‘. Diabetes Ther. 2015;6:357–375.
  • Tang H, Dai Q, Shi W, et al. SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Diabetologia. 2017;60:1862–1872.
  • Kohler S, Lee J, George JT, et al. Bladder cancer in the EMPA-REG OUTCOME trial. Diabetologia. 2017;60:2534–2535.
  • Shaikh AMY. SGLT2 inhibitors and cancer: why further evidence is required. Diabetologia. 2017;60:2536–2537.
  • Tang H, Han J, Song Y. Cancer risk in the EMPA-REG OUTCOME trial. Reply to Shaikh AMY [letter] and Kohler S, Lee J, George JT et al [letter]. Diabetologia. 2017;60:2538–2539.
  • Reilly TP, Graziano MJ, Janovitz EB, et al. Carcinogenicity risk assessment supports the chronic safety of dapagliflozin, an inhibitor of sodium-glucose co-transporter 2, in the treatment of type 2 diabetes mellitus. Diabetes Ther. 2014;5:73–96.
  • Scafoglio C, Hirayama BA, Kepe V, et al. Functional expression of sodium-glucose transporters in cancer. Proc Natl Acad Sci U S A. 2015;112:E4111–9.
  • Koepsell H. The Na(+)-D-glucose cotransporters SGLT1 and SGLT2 are targets for the treatment of diabetes and cancer. Pharmacol Ther. 2017;170:148–165.
  • Kuang H, Liao L, Chen H, et al. Therapeutic effect of sodium glucose co-transporter 2 inhibitor dapagliflozin on renal cell carcinoma. Med Sci Monit. 2017;23:3737–3745.
  • Kaji K, Nishimura N, Seki K, et al. Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake. Int J Cancer. 2018;142:1712–1722.
  • US Food and Drug Administration. Drug safety communications: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. [cited 2019 Mar 20]. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM446954.pdf
  • European Medicines Agency. EMA confirms recommendations to minimise ketoacidosis risk with SGLT2 inhibitors for diabetes. [cited 2019 Mar 20]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/SGLT2_inhibitors/human_referral_prac_000052.jsp&mid=WC0b01ac05805c516f
  • Erondu N, Desai M, Ways K, et al. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015;38:1680–1686.
  • Monami M, Nreu B, Zannoni S, et al. Effects of SGLT-2 inhibitors on diabetic ketoacidosis: A meta-analysis of randomised controlled trials. Diabetes Res Clin Pract. 2017;130:53–60.
  • Wang Y, Desai M, Ryan PB, et al. Incidence of diabetic ketoacidosis among patients with type 2 diabetes mellitus treated with SGLT2 inhibitors and other antihyperglycemic agents. Diabetes Res Clin Pract. 2017;128:83–90.
  • Fralick M, Schneeweiss S, Patorno E. Risk of diabetic ketoacidosis after initiation of an SGLT2 inhibitor. N Engl J Med. 2017;376:2300–2302.
  • Kim YG, Jeon JY, Han SJ, et al. Sodium-glucose co-transporter-2 inhibitors and the risk of ketoacidosis in patients with type 2 diabetes mellitus: A nationwide population-based cohort study. Diabetes Obes Metab. 2018;20:1852–1858.
  • Jensen ML, Persson F, Andersen GS, et al. Incidence of ketoacidosis in the Danish type 2 diabetes population before and after introduction of sodium-glucose cotransporter 2 inhibitors-A nationwide, retrospective cohort study, 1995-2014. Diabetes Care. 2017;40:e57–e58.
  • Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System. Diabetologia. 2017;60:1385–1389.
  • Blau JE, Tella SH, Taylor SI, et al. Ketoacidosis associated with SGLT2 inhibitor treatment: analysis of FAERS data. Diabetes Metab Res Rev. 2017;33(8).
  • D‘Elia JA, Segal AR, Bayliss GP, et al. Sodium-glucose cotransporter-2 inhibition and acidosis in patients with type 2 diabetes: a review of US FDA data and possible conclusions. Int J Nephrol Renovasc Dis. 2017;10:153–158.
  • Meyer EJ, Gabb G, Jesudason D. SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis: a South Australian clinical case series and Australian spontaneous adverse event notifications. Diabetes Care. 2018;41:e47–e49.
  • Ado Moumouni AN, Robin P, Hillaire-Buys D, et al. SGLT-2 inhibitors and ketoacidosis: a disproportionality analysis in the World Health Organization‘s adverse drug reactions database. Fundam Clin Pharmacol. 2018;32:216–226.
  • Ogawa W, Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. J Diabetes Investig. 2016;7:135–138.
  • Palmer BF, Clegg DJ, Taylor SI, et al. Diabetic ketoacidosis, sodium glucose transporter-2 inhibitors and the kidney. J Diabetes Complications. 2016;30:1162–1166.
  • Taylor SI, Blau JE, Rother KI. Perspective: SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100:2849–2852.
  • Milder DA, Milder TY, Kam PCA. Sodium-glucose co-transporter type-2 inhibitors: pharmacology and peri-operative considerations. Anaesthesia. 2018;73:1008–1018.
  • Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol. 2015;3:8–10.
  • Meier C, Schwartz AV, Egger A, et al. Effects of diabetes drugs on the skeleton. Bone. 2016;82:83–100.
  • de Jong MA, Petrykiv SI, Laverman GD, et al. Effects of dapagliflozin on circulating markers of phosphate homeostasis. Clin J Am Soc Nephrol. 2019;14:66–73.
  • Kalaitzoglou E, Fowlkes JL, Popescu I, et al. Diabetes pharmacotherapy and effects on the musculoskeletal system. Diabetes Metab Res Rev. 2019;35:e3100.
  • Mannucci E, Monami M. Bone fractures with sodium-glucose co-transporter-2 inhibitors: how real is the risk? Drug Saf. 2017;40:115–119.
  • Tang HL, Li DD, Zhang JJ, et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2016;18:1199–1206.
  • Ruanpeng D, Ungprasert P, Sangtian J, et al. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes Metab Res Rev. 2017;33(6).
  • Azharuddin M, Adil M, Ghosh P, et al. Sodium-glucose cotransporter 2 inhibitors and fracture risk in patients with type 2 diabetes mellitus: A systematic literature review and Bayesian network meta-analysis of randomized controlled trials. Diabetes Res Clin Pract. 2018;146:180–190.
  • Ljunggren O, Bolinder J, Johansson L, et al. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab. 2012;14:990–999.
  • Bolinder J, Ljunggren O, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16:159–169.
  • Kohan DE, Fioretto P, Tang W, et al. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85:962–971.
  • Kohler S, Kaspers S, Salsali A, et al. Analysis of fractures in patients with type 2 diabetes treated with empagliflozin in pooled data from placebo-controlled trials and a head-to-head study versus glimepiride. Diabetes Care. 2018;41:1809–1816.
  • U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. [cited 2019 Mar 20]. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm461449.htm
  • Alba M, Xie J, Fung A, et al. The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus. Curr Med Res Opin. 2016;32:75–85.
  • Kaneko M, Narukawa M. Effects of sodium-glucose cotransporter 2 inhibitors on amputation, bone fracture, and cardiovascular outcomes in patients with type 2 diabetes mellitus using an alternative measure to the hazard ratio. Clin Drug Investig. 2019;39:179–186.
  • Blevins TC, Farooki A. Bone effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus. Postgrad Med. 2017;129:159–168.
  • Bilezikian JP, Watts NB, Usiskin K, et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab. 2016;101:44–51.
  • Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101:157–166.
  • Toulis KA, Bilezikian JP, Thomas GN, et al. Initiation of dapagliflozin and treatment-emergent fractures. Diabetes Obes Metab. 2018;20:1070–1074.
  • Fralick M, Kim SC, Schneeweiss S, et al. Fracture risk after initiation of use of canagliflozin: a cohort study. Ann Intern Med. 2019; published on line. DOI:10.7326/M18-0567
  • European Medicines Agency. SGLT2 inhibitors (previously canagliflozin): information on potential risk of toe amputation to be included in prescribing information. [cited 2019 Mar 20]. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/sglt2-inhibitors-previously-canagliflozin
  • U.S. Food and Drug Administration. FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). [cited 2019 Mar 20]. Available from: https://www.fda.gov/downloads/Drugs/DrugSafety/UCM558427.pdf
  • Inzucchi SE, Iliev H, Pfarr E, et al. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41:e4–e5.
  • Verma S, Mazer CD, Al-Omran M, et al. Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease: a subanalysis of EMPA-REG OUTCOME. Circulation. 2018;137:405–407.
  • Kohler S, Zeller C, Iliev H, et al. Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I-III clinical trials. Adv Ther. 2017;34:1707–1726.
  • Li D, Yang JY, Wang T, et al. Risks of diabetic foot syndrome and amputation associated with sodium glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Metab. 2018;44:410–414.
  • Monami M, Zannoni S, Nreu B, et al. Toe amputations with SGLT-2 inhibitors: data from randomized clinical trials. Acta Diabetol. 2017;54:411–413.
  • Dawwas GK, Smith SM, Park H. Cardiovascular outcomes of sodium glucose cotransporter-2 inhibitors in patients with type 2 diabetes. Diabetes Obes Metab. 2019;21:28–36.
  • Yuan Z, DeFalco FJ, Ryan PB, et al. Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: A retrospective cohort study. Diabetes Obes Metab. 2018;20:582–589.
  • Adimadhyam S, Lee TA, Calip GS, et al. Risk of amputations associated with SGLT2 inhibitors compared to DPP-4 inhibitors: A propensity-matched cohort study. Diabetes Obes Metab. 2018;20:2792–2799.
  • Chang HY, Singh S, Mansour O, et al. Association between sodium-glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes. JAMA Intern Med. 2018;178:1190–1198.
  • Ryan PB, Buse JB, Schuemie MJ, et al. 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). Diabetes Obes Metab. 2018;20:2585–2597.
  • Yang JY, Wang T, Pate V, et al. Sodium-glucose co-transporter-2 inhibitor use and risk of lower-extremity amputation: evolving questions, evolving answers. Diabetes Obes Metab. 2019; published on line. DOI:10.1111/dom.13647
  • Fadini G, Avogaro A. SGTL2 inhibitors and amputations in the US FDA adverse event reporting system. Lancet Diabetes Endocrinol. 2017;5:680–681.
  • Khouri C, Cracowski JL, Roustit M. SGLT-2 inhibitors and the risk of lower-limb amputation: is this a class effect? Diabetes Obes Metab. 2018;20:1531–1534.
  • Kumar S, Costello AJ, Colman PG. Fournier‘s gangrene in a man on empagliflozin for treatment of Type 2 diabetes. Diabet Med. 2017;34:1646–1648.
  • Food and Drug Administration. FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. [cited 2019 Mar 20]. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm
  • Mellander A, Billger M, Johnsson E, et al. Hypersensitivity events, including potentially hypersensitivity-related skin events, with dapagliflozin in patients with type 2 diabetes mellitus: a pooled analysis. Clin Drug Investig. 2016;36:925–933.
  • Raschi E, Parisotto M, Forcesi E, et al. Adverse events with sodium-glucose co-transporter-2 inhibitors: A global analysis of international spontaneous reporting systems. Nutr Metab Cardiovasc Dis. 2017;27:1098–1107.
  • Sakaeda T, Kobuchi S, Yoshioka R, et al. Susceptibility to serious skin and subcutaneous tissue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2) inhibitors. Int J Med Sci. 2018;15:937–943.
  • Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150–156.
  • Pinto LC, Rados DV, Barkan SS, et al. Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: A meta-analysis with trial sequential analysis. Sci Rep. 2018;8:782.
  • Monami M, Nreu B, Scatena A, et al. Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): data from randomized controlled trials. Diabetes Obes Metab. 2017;19:1233–1241.
  • Modi A, Agrawal A, Morgan F. Euglycemic diabetic ketoacidosis. Curr Diabetes Rev. 2017;13:315–321.
  • Burke KR, Schumacher CA, Harpe SE. SGLT2 inhibitors: a systematic review of diabetic ketoacidosis and related risk factors in the primary literature. Pharmacotherapy. 2017;37:187–194.
  • Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638–1642.
  • Pfutzner A, Klonoff D, Heinemann L, et al. Euglycemic ketosis in patients with type 2 diabetes on SGLT2-inhibitor therapy-an emerging problem and solutions offered by diabetes technology. Endocrine. 2017;56:212–216.
  • Tanaka A, Node K. Increased amputation risk with canagliflozin treatment: behind the large cardiovascular benefit? Cardiovasc Diabetol. 2017;16:129.
  • Leon Jimenez D, Manuel Lopez Chozas J, Espino Montoro A, et al. Could renin-angiotensin-aldosterone system activation explain the amputations associated with canagliflozin? the nitric oxide hypothesis. Diabetes Res Clin Pract. 2019;148:10–13.
  • Bonaca MP, Beckman JA. Sodium glucose cotransporter 2 inhibitors and amputation risk: achilles‘ heel or opportunity for discovery? Circulation. 2018;137:1460–1462.
  • Fralick M, Patorno E, Fischer MA. Sodium-glucose cotransporter 2 inhibitors and the risk of amputation: results and challenges from the real world. JAMA Intern Med. 2018;178:1199–1200.
  • Matthews DR, Li Q, Perkovic V, et al. Effects of Canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia 2019 Mar 12. doi:10.1007/s00125-019-4839-8. [ Epub ahead of print].
  • Dietrich I, Braga GA, de Melo FG, et al. The diabetic foot as a proxy for cardiovascular events and mortality review. Curr Atheroscler Rep. 2017;19:44.
  • Lim GB. Dapagliflozin DECLAREd safe. Nat Rev Cardiol. 2019;16:4.

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