Safety of Sodium-Glucose Co-Transporter 2 Inhibitors
2019; Elsevier BV; Volume: 124; Linguagem: Inglês
10.1016/j.amjcard.2019.10.029
ISSN1879-1913
AutoresJanet B. McGill, Savitha Subramanian,
Tópico(s)Metabolism, Diabetes, and Cancer
ResumoSodium-glucose co-transporter 2 (SGLT2) inhibitors have a well-defined safety profile based on data obtained from numerous clinical trials, including cardiovascular outcomes trials (CVOTs) and postmarketing pharmacovigilance reporting. Adverse events including risk of genital mycotic infection and volume depletion-related events are consistent with the mechanism of action of this drug class. However, several emergent (albeit infrequent) serious safety issues have also been reported. In their respective CVOTs, the proportion of patients with reported diabetic ketoacidosis was similar in empagliflozin or canagliflozin compared with their placebo groups, but it was higher for dapagliflozin. Canagliflozin may be associated with an increased risk of bone fracture and lower limb amputation; however, data are inconclusive. There is no evidence linking SGLT2 inhibitors with an increased risk of cancer, but these agents, particularly dapagliflozin, should be used with caution in patients with hematuria or a history of bladder cancer. Postmarketing reports of acute kidney injury have occurred in patients receiving SGLT2 inhibitors, and cases identified in recent CVOTs occurred with similar frequency in SGLT2 inhibitor and placebo groups. Common adverse events associated with SGLT2 inhibitors (such as genital infections or volume depletion) are generally mild and manageable by patients or by primary care physicians, and the risk of rare events (such as ketoacidosis) can be minimized by appropriate patient selection and early recognition of symptoms. When selecting treatment, it is important that clinicians weigh the known risks of SGLT2 inhibitors against their proven benefits, including the reduction of adverse cardiovascular and renal outcomes. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have a well-defined safety profile based on data obtained from numerous clinical trials, including cardiovascular outcomes trials (CVOTs) and postmarketing pharmacovigilance reporting. Adverse events including risk of genital mycotic infection and volume depletion-related events are consistent with the mechanism of action of this drug class. However, several emergent (albeit infrequent) serious safety issues have also been reported. In their respective CVOTs, the proportion of patients with reported diabetic ketoacidosis was similar in empagliflozin or canagliflozin compared with their placebo groups, but it was higher for dapagliflozin. Canagliflozin may be associated with an increased risk of bone fracture and lower limb amputation; however, data are inconclusive. There is no evidence linking SGLT2 inhibitors with an increased risk of cancer, but these agents, particularly dapagliflozin, should be used with caution in patients with hematuria or a history of bladder cancer. Postmarketing reports of acute kidney injury have occurred in patients receiving SGLT2 inhibitors, and cases identified in recent CVOTs occurred with similar frequency in SGLT2 inhibitor and placebo groups. Common adverse events associated with SGLT2 inhibitors (such as genital infections or volume depletion) are generally mild and manageable by patients or by primary care physicians, and the risk of rare events (such as ketoacidosis) can be minimized by appropriate patient selection and early recognition of symptoms. When selecting treatment, it is important that clinicians weigh the known risks of SGLT2 inhibitors against their proven benefits, including the reduction of adverse cardiovascular and renal outcomes. Data on sodium-glucose co-transporter 2 (SGLT2) inhibitors obtained from clinical trials, including cardiovascular outcomes trials (CVOTs) and postmarketing pharmacovigilance reporting have established a well-defined safety profile for these agents, and associated adverse events are mostly consistent with the mechanism of action of this drug class. However, a number of emergent, albeit less common, and potentially serious safety issues have been detected (Figure 1). Herein we discuss well-known and emergent adverse events associated with SGLT2 inhibitor therapy in patients with type 2 diabetes mellitus. Using PubMed, Boolean searches including terms related to safety or adverse events were performed to identify relevant English language articles relating to those SGLT2 inhibitors with regulatory approval in the United States for use in the management of type 2 diabetes mellitus—namely, dapagliflozin, canagliflozin, empagliflozin, and ertugliflozin. Fewer published reports and data were retrieved for ertugliflozin because it gained US regulatory approval in 2017. Safety data were derived from meta-analyses, systematic reviews, CVOTs, and observational cohort studies in which SGLT2 inhibitors were compared with placebo or other classes of glucose-lowering agents. Additional safety data were obtained from websites of the US Food and Drug Administration (FDA) and the prescribing information for the individual SGLT2 inhibitors marketed in the United States. The risk of hypoglycemia associated with SGLT2 inhibitors is low, unless co-administered with insulin or an insulin secretagogue (Supplemental Table 1, available online). 1Janssen Pharmaceuticals, Inc. Prescribing information: INVOKANA®(canagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf. Accessed January 25, 2019.Google Scholar, 2AstraZeneca Pharmaceuticals LP. Prescribing information: FARXIGA® (dapagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202293s017lbl.pdf. Accessed January 25, 2019.Google Scholar, 3Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing information: JARDIANCE® (empagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204629s018lbl.pdf. Accessed January 25, 2019.Google Scholar, 4Merck Sharpe & Dohme Corp. Prescribing information: STEGLATRO™ (ertugliflozin) tablets, for oral use. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209803s001lbl.pdf. Accessed January 25, 2019.Google Scholar This was confirmed in several recent meta-analyses of data from SGLT2 inhibitor randomized controlled trials (RCTs).5Rådholm K. Wu J.H. Wong M.G. et al.Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes—a systematic review.Diabetes Res Clin Pract. 2018; 140: 118-128Google Scholar, 6Zhang Y.J. Han S.L. Sun X.F. et al.Efficacy and safety of empagliflozin for type 2 diabetes mellitus: meta-analysis of randomized controlled trials.Medicine (Baltimore). 2018; 97e12843Google Scholar, 7Zhang L. Zhang M. Lv Q. Tong N. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes and moderate renal function impairment: a systematic review and meta-analysis.Diabetes Res Clin Pract. 2018; 140: 295-303Google Scholar, 8Wang Z. Sun J. Han R. et al.Efficacy and safety of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as monotherapy or add-on to metformin in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.Diabetes Obes Metab. 2018; 20: 113-120Google Scholar, 9Li J. Shao Y.H. Wang X.G. Gong Y. Li C. Lu Y. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors as add-on to metformin and sulfonylurea treatment for the management of type 2 diabetes: a meta-analysis.Endocr J. 2018; 65: 335-344Google Scholar Mechanistically, SGLT2 inhibitors are not associated with increased hypoglycemic risk.10Filippas-Ntekouan S. Filippatos T.D. Elisaf M.S. SGLT2 inhibitors: are they safe?.Postgrad Med. 2018; 130: 72-82Google Scholar This is as a result of the continued renal glucose reabsorption capacity of SGLT1, as well as metabolic counter-regulatory mechanisms (ie, decreased insulin release and increased glucagon release leading to increased hepatic gluconeogenesis) that are unaffected by SGLT2 inhibition. A lower dose of insulin or insulin secretagogue may be required when used in combination therapy with an SGLT2 inhibitor.1Janssen Pharmaceuticals, Inc. Prescribing information: INVOKANA®(canagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf. Accessed January 25, 2019.Google Scholar, 2AstraZeneca Pharmaceuticals LP. Prescribing information: FARXIGA® (dapagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202293s017lbl.pdf. Accessed January 25, 2019.Google Scholar, 3Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing information: JARDIANCE® (empagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204629s018lbl.pdf. Accessed January 25, 2019.Google Scholar, 4Merck Sharpe & Dohme Corp. Prescribing information: STEGLATRO™ (ertugliflozin) tablets, for oral use. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209803s001lbl.pdf. Accessed January 25, 2019.Google Scholar SGLT2 inhibitors are associated with an increased risk of genital mycotic infection,5Rådholm K. Wu J.H. Wong M.G. et al.Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes—a systematic review.Diabetes Res Clin Pract. 2018; 140: 118-128Google Scholar, 6Zhang Y.J. Han S.L. Sun X.F. et al.Efficacy and safety of empagliflozin for type 2 diabetes mellitus: meta-analysis of randomized controlled trials.Medicine (Baltimore). 2018; 97e12843Google Scholar particularly in patients with a history of genital mycotic infection and in uncircumcised males.1Janssen Pharmaceuticals, Inc. Prescribing information: INVOKANA®(canagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf. Accessed January 25, 2019.Google Scholar, 2AstraZeneca Pharmaceuticals LP. Prescribing information: FARXIGA® (dapagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202293s017lbl.pdf. Accessed January 25, 2019.Google Scholar, 3Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing information: JARDIANCE® (empagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204629s018lbl.pdf. Accessed January 25, 2019.Google Scholar, 4Merck Sharpe & Dohme Corp. Prescribing information: STEGLATRO™ (ertugliflozin) tablets, for oral use. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209803s001lbl.pdf. Accessed January 25, 2019.Google Scholar Genital mycotic infections occur more frequently in females than males receiving treatment with SGLT2 inhibitors, are generally mild or moderate in severity, and respond to standard antifungal therapy. Rates of treatment discontinuations resulting from genital mycotic infection were low in SGLT2 inhibitor RCTs (Supplemental Table 1).1Janssen Pharmaceuticals, Inc. Prescribing information: INVOKANA®(canagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf. Accessed January 25, 2019.Google Scholar, 2AstraZeneca Pharmaceuticals LP. Prescribing information: FARXIGA® (dapagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202293s017lbl.pdf. Accessed January 25, 2019.Google Scholar, 3Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing information: JARDIANCE® (empagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204629s018lbl.pdf. Accessed January 25, 2019.Google Scholar, 4Merck Sharpe & Dohme Corp. Prescribing information: STEGLATRO™ (ertugliflozin) tablets, for oral use. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209803s001lbl.pdf. Accessed January 25, 2019.Google Scholar Data on the potential SGLT2 inhibitor-associated risk of urinary tract infection (UTI) are less consistent, and published reports have provided conflicting conclusions. Some SGLT2 inhibitor studies suggested an increased associated risk of UTI,11Devi R. Mali G. Chakraborty I. Unnikrishnan M.K. Abdulsalim S. Efficacy and safety of empagliflozin in type 2 diabetes mellitus: a meta-analysis of randomized controlled trials.Postgrad Med. 2017; 129: 382-392Google Scholar, 12Qiu R. Balis D. Xie J. Davies M.J. Desai M. Meininger G. Longer-term safety and tolerability of canagliflozin in patients with type 2 diabetes: a pooled analysis.Curr Med Res Opin. 2017; 33: 553-562Google Scholar, 13Storgaard H. Gluud L.L. Bennett C. et al.Benefits and harms of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis.PLoS One. 2016; 11e0166125Google Scholar, 14Zaccardi F. Webb D.R. Htike Z.Z. Youssef D. Khunti K. Davies M.J. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis.Diabetes Obes Metab. 2016; 18: 783-794Google Scholar whereas others did not.5Rådholm K. Wu J.H. Wong M.G. et al.Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes—a systematic review.Diabetes Res Clin Pract. 2018; 140: 118-128Google Scholar, 6Zhang Y.J. Han S.L. Sun X.F. et al.Efficacy and safety of empagliflozin for type 2 diabetes mellitus: meta-analysis of randomized controlled trials.Medicine (Baltimore). 2018; 97e12843Google Scholar, 7Zhang L. Zhang M. Lv Q. Tong N. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes and moderate renal function impairment: a systematic review and meta-analysis.Diabetes Res Clin Pract. 2018; 140: 295-303Google Scholar, 15Jabbour S. Seufert J. Scheen A. Bailey C.J. Karup C. Langkilde A.M. 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: 620-628Google Scholar, 16Li J. Gong Y. Li C. Lu Y. Liu Y. Shao Y. Long-term efficacy and safety of sodium-glucose cotransporter-2 inhibitors as add-on to metformin treatment in the management of type 2 diabetes mellitus: a meta-analysis.Medicine (Baltimore). 2017; 96e7201Google Scholar, 17Kohler S. Zeller C. Iliev H. Kaspers S. Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I-III clinical trials.Adv Ther. 2017; 34: 1707-1726Google Scholar, 18Liu J. Li L. Li S. et al.Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis.Sci Rep. 2017; 7: 2824Google Scholar, 19Neal B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Google Scholar, 20Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Google Scholar, 21Wiviott S.D. Raz I. Bonaca M.P. et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357Google Scholar A recent network meta-analysis of 105 RCTs involving SGLT2 inhibitors (N = 60,082) reported no significant difference in the risk of UTI between treatments with fully adjusted models.22Donnan J.R. Grandy C.A. 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-E602Google Scholar However, there are postmarketing reports of serious UTI occurring in patients receiving SGLT2 inhibitors, including cases of acute complicated UTI (urosepsis) and pyelonephritis requiring hospitalization.1Janssen Pharmaceuticals, Inc. Prescribing information: INVOKANA®(canagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf. Accessed January 25, 2019.Google Scholar, 2AstraZeneca Pharmaceuticals LP. Prescribing information: FARXIGA® (dapagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202293s017lbl.pdf. Accessed January 25, 2019.Google Scholar, 3Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing information: JARDIANCE® (empagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204629s018lbl.pdf. Accessed January 25, 2019.Google Scholar, 4Merck Sharpe & Dohme Corp. Prescribing information: STEGLATRO™ (ertugliflozin) tablets, for oral use. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209803s001lbl.pdf. Accessed January 25, 2019.Google Scholar Following initiation of SGLT2 inhibitor therapy, physicians should screen patients regularly for signs and symptoms of genital mycotic infection and UTI and treat as appropriate. SGLT2 inhibitors are associated with an increased risk of volume depletion-related adverse events (broadly including hypotension, syncope, and dehydration).5Rådholm K. Wu J.H. Wong M.G. et al.Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes—a systematic review.Diabetes Res Clin Pract. 2018; 140: 118-128Google Scholar Pooled data from SGLT2 inhibitor RCTs show increased rates of volume depletion-related adverse events (range 0.3%-4.4%) compared with placebo groups (range 0%-1.5%).1Janssen Pharmaceuticals, Inc. Prescribing information: INVOKANA®(canagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf. Accessed January 25, 2019.Google Scholar, 2AstraZeneca Pharmaceuticals LP. Prescribing information: FARXIGA® (dapagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202293s017lbl.pdf. Accessed January 25, 2019.Google Scholar, 3Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing information: JARDIANCE® (empagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204629s018lbl.pdf. Accessed January 25, 2019.Google Scholar, 4Merck Sharpe & Dohme Corp. Prescribing information: STEGLATRO™ (ertugliflozin) tablets, for oral use. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209803s001lbl.pdf. Accessed January 25, 2019.Google Scholar The US prescribing information for all 4 SGLT2 inhibitors states hypotension as a warning or precaution and describes the associated risk factors for symptomatic hypotension (Supplemental Table 1).1Janssen Pharmaceuticals, Inc. Prescribing information: INVOKANA®(canagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf. Accessed January 25, 2019.Google Scholar, 2AstraZeneca Pharmaceuticals LP. Prescribing information: FARXIGA® (dapagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202293s017lbl.pdf. Accessed January 25, 2019.Google Scholar, 3Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing information: JARDIANCE® (empagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204629s018lbl.pdf. Accessed January 25, 2019.Google Scholar, 4Merck Sharpe & Dohme Corp. Prescribing information: STEGLATRO™ (ertugliflozin) tablets, for oral use. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209803s001lbl.pdf. Accessed January 25, 2019.Google Scholar Before treatment initiation with SGLT2 inhibitors, volume status of patients should be assessed and corrected as appropriate. During therapy, patients should be monitored for signs and symptoms of hypotension and treated as appropriate. Reports of diabetic ketoacidosis associated with SGLT2 inhibitor use have been identified via postmarketing surveillance. A warning or precaution for ketoacidosis appears in the US prescribing information for the 4 FDA-approved SGLT2 inhibitors (Supplemental Table 1).1Janssen Pharmaceuticals, Inc. Prescribing information: INVOKANA®(canagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf. Accessed January 25, 2019.Google Scholar, 2AstraZeneca Pharmaceuticals LP. Prescribing information: FARXIGA® (dapagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202293s017lbl.pdf. Accessed January 25, 2019.Google Scholar, 3Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing information: JARDIANCE® (empagliflozin) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204629s018lbl.pdf. Accessed January 25, 2019.Google Scholar, 4Merck Sharpe & Dohme Corp. Prescribing information: STEGLATRO™ (ertugliflozin) tablets, for oral use. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209803s001lbl.pdf. Accessed January 25, 2019.Google Scholar Many of the SGLT2 inhibitor-associated cases of diabetic ketoacidosis presented without significant hyperglycemia (ie, euglycemic ketoacidosis; blood glucose <250 mg/dL [13.9 mmol/L]), which may delay recognition and treatment of the condition. Notably, a number of cases were reported in patients with type 1 diabetes mellitus; SGLT2 inhibitors are not approved by the FDA for use in type 1 diabetes mellitus. The FDA Adverse Event Reporting System (FAERS; period: Q1 2014 to Q3 2016) collected more than 2500 reports of diabetic ketoacidosis in which SGLT2 inhibitors were suspect or concomitant drugs.23Fadini G.P. Bonora B.M. Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA adverse event reporting system.Diabetologia. 2017; 60: 1385-1389Google Scholar The proportion of patients with reported diabetic ketoacidosis was similar in the SGLT2 inhibitor and placebo groups during the CVOTs for empagliflozin (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removal of Excess Glucose [EMPA-REG OUTCOME]) and canagliflozin (CANVAS Program; Integrated analysis of Canagliflozin Cardiovascular Assessment Study [CANVAS], and CANVAS-Renal trials), but it was higher for dapagliflozin than placebo in the dapagliflozin CVOT (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 [DECLARE-TIMI 58]) (Table 1).19Neal B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Google Scholar, 20Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Google Scholar, 21Wiviott S.D. Raz I. Bonaca M.P. et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357Google ScholarTable 1Safety Data From SGLT2 Inhibitor CVOTsEMPA-REG OUTCOME20Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Google ScholarCANVAS Program19Neal B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Google ScholarDECLARE-TIMI 5821Wiviott S.D. Raz I. Bonaca M.P. et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357Google ScholarDiabetic ketoacidosis4/4687 (0.1%) empa pooled vs 1/2333( 6 months’ cumulative exposure up to trial termination.36Events per 1000 patient-years: 1.0 cana vs 1.1 placebo (P = 0.74)26/8574 (0.3%) dapa vs 45/8569 (0.5%) placebo (HR 0.57; 95% CI 0.35, 0.93; P = 0.02)Urosepsis17/4687 (0.4%) empa pooled vs 3/2333 (0.1%) placebo*P value not reported.No reports of this eventNo reports of this eventAcute kidney injury45/4687 (1.0%) empa pooled vs 37/2333 (1.6%) placebo (P <0.05)Events per 1000 patient-years: 3.0 cana vs 4.1 placebo (P = 0.33)125/8574 (1.5%) dapa vs 175/8569 (2.0%) placebo (HR 0.69; 95% CI 0.55, 0.87; P = 0.002)Lower limb amputation88/4687 (1.9%) empa pooled vs 43/2333 (1.8%) placebo (HR 1.00; 95% CI 0.70, 1.44; P = 0.9924)‡Post hoc analysis.45Events per 1000 patient-years: 6.3 cana vs 3.4 placebo (HR 1.97; 95% CI 1.41, 2.75; P 6 months’ cumulative exposure up to trial termination.36Kohler S. Lee J. George J.T. Inzucchi S.E. Zinman B. Bladder cancer in the EMPA-REG OUTCOME trial.Diabetologia. 2017; 60: 2534-2535Google Scholar‡ Post hoc analysis.45Inzucchi S.E. Iliev H. Pfarr E. Zinman B. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME trial.Diabetes Care. 2018; 41: e4-e5Google Scholar Open table in a new tab Ertugliflozin CVOT (VERTIS-CV; Evaluation of Ertugliflozin Efficacy and Safety–Cardiovascular Outcomes trial) is in progress, with primary completion expected in Q3 2019. cana = canagliflozin; CANVAS Program = Integrated analysis of CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-Renal trials; CI = confidence interval; CVOT = cardiovascular outcomes trial; dapa = dapagliflozin; DECLARE-TIMI 58 = Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; empa = empagliflozin; EMPA-REG OUTCOME = Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removal of Excess Glucose; HR = hazard ratio; SGLT2 = sodium-glucose co-transporter 2. The potential mechanism by which SGLT2 inhibitors may lead to diabetic ketoacidosis has been described.24Rosenstock J. Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors.Diabetes Care. 2015; 38: 1638-1642Google Scholar, 25Qiu H. Novikov A. Vallon V. Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: basic mechanisms and therapeutic perspectives [epub].Diabetes Metab Res Rev. 2017; 33https://doi.org/10.1002/dmrr.2886Google Scholar Diabetic ketoacidosis should be considered in a patient with type 2 diabetes mellitus receiving SGLT2 inhibitor treatment who presents with malaise, nausea, and/or vomiting. The drug should be discontinued and appropriate treatment initiated (eg, diabetic ketoacidosis may require insulin and replacement of fluid and carbohydrate). SGLT2 inhibitors should be stopped temporarily during acute illness or surgery or for clinical procedures that require patients to limit or cease fluid intake26Meyer E.J. 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-e49Google Scholar; diagnosis of autoimmune diabetes (type 1 diabetes mellitus or latent autoimmune diabetes of adulthood) should be excluded.26Meyer E.J. 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-e49Google Scholar, 27Burke K.R. Schumacher C.A. Harpe S.E. SGLT2 inhibitors: a systematic review of diabetic ketoacidosis and related risk factors in the primary literature.Pharmacotherapy. 2017; 37: 187-194Google Scholar All patients should be educated on maintaining sufficient hydration and carbohydrate intake while receiving SGLT2 inhibitors.24Rosenstock J. Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors.Diabetes Care. 2015; 38: 1638-1642Google Scholar Certain SGLT2 inhibitors may be associated with an increased bone fracture risk among at-risk groups of patients with type 2 diabetes mellitus.28Kalaitzoglou E. Fowlkes J.L. Popescu I. Thrailkill K.M. Diabetes pharmacotherapy and effects on the musculoskeletal system.Diabetes Metab Res Rev. 2018; 35e3100Google Scholar Increased fracture risk was observed with canagliflozin, occurring as early as 12 weeks post-treatment initiation in CANVAS (Table 1),19Neal B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Google Scholar and bone fracture is listed as a warning or precaution in th
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