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10-01-2016 | SGLT2 inhibitors | Review | Article

SGLT2 Inhibitors: Benefit/Risk Balance

Journal: Current Diabetes Reports

Author: André J. Scheen

Publisher: Springer US

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Abstract

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycemia by increasing urinary glucose excretion. They have been evaluated in patients with type 2 diabetes treated with diet/exercise, metformin, dual oral therapy or insulin. Three agents are available in Europe and the USA (canagliflozin, dapagliflozin, empagliflozin) and others are commercialized in Japan or in clinical development. SGLT2 inhibitors reduce glycated hemoglobin, with a minimal risk of hypoglycemia. They exert favorable effects beyond glucose control with consistent body weight, blood pressure, and serum uric acid reductions. Empagliflozin showed remarkable reductions in cardiovascular/all-cause mortality and in hospitalization for heart failure in patients with previous cardiovascular disease. Positive renal outcomes were also shown with empagliflozin. Mostly reported adverse events are genital mycotic infections, while urinary tract infections and events linked to volume depletion are rather rare. Concern about a risk of ketoacidosis and bone fractures has been recently raised, which deserves caution and further evaluation.
Literature
1.
Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol. 2013;1:140–51. CrossRefPubMed
2.
Hasan FM, Alsahli M, Gerich JE. SGLT2 inhibitors in the treatment of type 2 diabetes. Diabetes Res Clin Pract. 2014;104:297–322. CrossRefPubMed
3.
Scheen AJ, Paquot N. Metabolic effects of SGLT2 inhibitors beyond increased glucosuria: a review of clinical evidence. Diabetes Metab. 2014;40:S4–11. CrossRefPubMed
4.
Abdul-Ghani MA, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32:515–31. CrossRefPubMed
5.
Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med. 2015;66:255–70. CrossRefPubMed
6.
Scheen AJ. Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor. Clin Pharmacokinet. 2014;53:213–25. CrossRefPubMedPubMedCentral
7.
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. CrossRefPubMed
8.
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;159:262–74. CrossRefPubMed
9.
Berhan A, Barker A. Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus: a meta-analysis of randomized double-blind controlled trials. BMC Endocr Disord. 2013;13:58. CrossRefPubMedPubMedCentral
10.•
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. Extensive review on the pharmacokinetic, pharmacodynamic and clinical characteristics of SGLT2 inhibitors. CrossRefPubMed
11.
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 Complicat. 2015;29:1295–303. CrossRefPubMed
12.
Zhong X, Lai D, Ye Y, et al. Efficacy and safety of empagliflozin as add-on to metformin for type 2 diabetes: a systematic review and meta-analysis. Eur J Clin Pharmacol. 2016;72:655–63. CrossRefPubMed
13.
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140–9. CrossRefPubMed
14.
Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2016 executive summary. Endocr Pract. 2016;22:84–113. CrossRefPubMed
15.••
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28. Landmark study reporting a remarkable reduction in cardiovascular and all-cause mortality with the SGLT2 inhibitor empagliflozin in T2DM patients with CVD. CrossRefPubMed
16.••
Wanner C, Inzucchi SE, Lachin JM et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323–34. Recent report demonstrating an impressive reduction in renal outcomes with empagliflozin in the EMPA-REG population of T2DM patients with CVD.
17.•
Scheen AJ. SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment. Expert Opin Drug Saf. 2015;14:1879–904. Recent review paper describing the most recent data regarding the efficacy and safety profile of SGLT2 inhibitors. CrossRefPubMed
18.
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;38:1687–93. CrossRefPubMedPubMedCentral
19.
Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol. 2015;3:8–10. CrossRefPubMed
20.
Plosker GL. Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2014;74:807–24. CrossRefPubMed
22.
Plosker GL. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs. 2012;72:2289–312. CrossRefPubMed
23.
Plosker GL. Dapagliflozin: a review of its use in patients with type 2 diabetes. Drugs. 2014;74:2191–209. CrossRefPubMed
25.
Scott LJ. Empagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2014;74:1769–84. CrossRefPubMed
26.
European Medicines Agency. Assessment report : Jardiance. International non-proprietary name: empagliflozin. http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​EPAR_​-_​Public_​assessment_​report/​human/​002677/​WC500168594.​pdf 2014. (latest access June 7 2016).
27.
Nauck MA. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther. 2014;8:1335–80. CrossRefPubMedPubMedCentral
28.••
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;4:411–9. Well documented review on the efficacy and safety on SGLT2 inhibitors focusing on cardiovascular outcomes in patients with T2DM. CrossRefPubMed
29.•
Zaccardi F, Webb DR, Htike ZZ, et al. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18:783–94. Recent systematic review comparing the efficacy and safety of three SGLT2 inhibitors canagliflozin, dapagliflozin and empagliflozin in patients with T2DM. CrossRefPubMed
30.
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;70:1149–58. CrossRefPubMed
31.
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;30:204–21. CrossRefPubMed
32.
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;37:815–29. CrossRefPubMed
33.
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;16:984–93. CrossRefPubMed
34.
Scheen AJ, Van Gaal LF. Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes. Lancet Diabetes Endocrinol. 2014;2:911–22. CrossRefPubMed
35.
Van Gaal L, Scheen A. Weight management in type 2 diabetes: current and emerging approaches to treatment. Diabetes Care. 2015;38:1161–72. CrossRefPubMed
36.
Barnett AH. Impact of sodium glucose cotransporter 2 inhibitors on weight in patients with type 2 diabetes mellitus. Postgrad Med. 2013;125:92–100. CrossRefPubMed
37.
Lambers Heerspink HJ, de Zeeuw D, Wie L, et al. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15:853–62. CrossRefPubMed
38.
Sha S, Polidori D, Heise T, et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16:1087–95. CrossRefPubMed
39.
Blonde L, Stenlof K, Fung A, et al. Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks. Postgrad Med. 2016;128:371–80. CrossRefPubMed
40.
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;16:159–69. CrossRefPubMed
41.
Ferrannini G, Hach T, Crowe S, et al. Energy balance after sodium glucose cotransporter 2 (SGLT2) inhibition. Diabetes Care. 2015;38:1730–5. CrossRefPubMedPubMedCentral
42.
Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014;8:330–9. CrossRefPubMed
43.
Cefalu WT, Stenlof K, Leiter LA, et al. Effects of canagliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes. Diabetologia. 2015;58:1183–7. CrossRefPubMedPubMedCentral
44.
Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in EMPA-REG OUTCOME: comparison with classic diuretics. Diabetes Metab. 2016. doi: 10.​1016/​j.​diabet.​2016.​05.​006.
45.
Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens. 2015;9:48–53. CrossRefPubMed
46.
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. CrossRefPubMed
47.
Borghi C, Rosei EA, Bardin T, et al. Serum uric acid and the risk of cardiovascular and renal disease. J Hypertens. 2015;33:1729–41. discussion 41. CrossRefPubMed
48.
Chino Y, Samukawa Y, Sakai S, et al. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos. 2014;35:391–404. CrossRefPubMedPubMedCentral
49.
Lytvyn Y, Skrtic M, Yang GK, et al. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Ren Physiol. 2015;308:F77–83. CrossRef
50.
Ptaszynska A, Hardy E, Johnsson E, et al. Effects of dapagliflozin on cardiovascular risk factors. Postgrad Med. 2013;125:181–9. CrossRefPubMed
51.
Davies MJ, Trujillo A, Vijapurkar U, et al. Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2015;17:426–9. CrossRefPubMed
52.
Mikhail N. Safety of canagliflozin in patients with type 2 diabetes. Curr Drug Saf. 2014;9:127–32. CrossRefPubMed
53.
Briand F, Mayoux E, Brousseau E, et al. Empagliflozin, via switching metabolism towards lipid utilization, moderately increases LDL-cholesterol levels through reduced LDL catabolism. Diabetes. 2016;65:2032–8. CrossRefPubMed
54.
Scheen AJ. Reduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial: a critical analysis. Diabetes Metab. 2016;42:71–6. CrossRefPubMed
55.
DeFronzo RA. The EMPA-REG study: what has it told us? A diabetologist’s perspective. J Diabetes Complicat. 2016;30:1–2. CrossRefPubMed
56.
Sattar N, McLaren J, Kristensen SL, et al. SGLT2 inhibition and cardiovascular events: why did EMPA-REG OUTCOMES surprise and what were the likely mechanisms? Diabetologia. 2016;59:1333–9. CrossRefPubMedPubMedCentral
57.
Abdul-Ghani M, Del Prato S, Chilton R, et al. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME study. Diabetes Care. 2016;39:717–25. CrossRefPubMed
58.
Marx N, McGuire DK. Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus. Eur Heart J. 2016. doi: 10.​1093/​eurheartj/​ehw110. PubMed
59.
Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39:1108–14. CrossRefPubMed
60.
Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39:1115–22. CrossRefPubMed
61.
Standl E, Schnell O, McGuire DK. Heart failure considerations of antihyperglycemic medications for type 2 diabetes. Circ Res. 2016;118:1830–43. CrossRefPubMed
62.
Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37:1526–34. CrossRefPubMedPubMedCentral
63.
Raz I, Cahn A. Heart failure: SGLT2 inhibitors and heart failure—clinical implications. Nat Rev Cardiol. 2016;13:185–6. CrossRefPubMed
64.
Tanaka A, Inoue T, Kitakaze M, et al. Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial. Cardiovasc Diabetol. 2016;15:57. CrossRefPubMedPubMedCentral
65.
Scheen AJ. Pharmacokinetics, pharmacodynamics and clinical use of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease. Clin Pharmacokinet. 2015;54:691–708. CrossRefPubMed
66.
Novikov A, Vallon V. Sodium glucose cotransporter 2 inhibition in the diabetic kidney: an update. Curr Opin Nephrol Hypertens. 2016;25:50–8. CrossRefPubMed
67.
Vallon V, Thomson SC. Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu Rev Physiol. 2012;74:351–75. CrossRefPubMed
68.
De Nicola L, Gabbai FB, Liberti ME, et al. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. Am J Kidney Dis. 2014;64:16–24. CrossRefPubMed
69.
Leiter LA, Yoon KH, Arias P, et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care. 2015;38:355–64. CrossRefPubMed
70.
Foote C, Perkovic V, Neal B. Effects of SGLT2 inhibitors on cardiovascular outcomes. Diab Vasc Dis Res. 2012;9:117–23. CrossRefPubMed
71.
Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166:217–23. e11. CrossRefPubMed
72.
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;103:373–81. CrossRefPubMed
73.
Johnsson KM, Ptaszynska A, Schmitz B, et al. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complicat. 2013;27:473–8. CrossRefPubMed
74.
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;30:1109–19. CrossRefPubMed
75.
Johnsson KM, Ptaszynska A, Schmitz B, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complicat. 2013;27:479–84. CrossRefPubMed
76.
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;12:352–8. CrossRefPubMed
77.
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;29:335–46. CrossRefPubMed
78.
Mikhail N. Use of sodium-glucose cotransporter type 2 inhibitors in older adults with type 2 diabetes mellitus. South Med J. 2015;108:91–6. CrossRefPubMed
79.
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. http://​www.​fda.​gov/​downloads/​Drugs/​DrugSafety/​UCM446954.​pdf 2015 (latest access June 7 2016).
80.
European Medicines Agency. EMA confirms recommendations to minimise ketoacidosis risk with SGLT2 inhibitors for diabetes. http://​www.​ema.​europa.​eu/​ema/​index.​jsp?​curl=​pages/​medicines/​human/​referrals/​SGLT2_​inhibitors/​human_​referral_​prac_​000052jsp&​mid=​WC0b01ac05805c51​6f 2016 (latest access June 7 2016).
81.
Modi A, Agrawal A, Morgan F. Euglycemic diabetic ketoacidosis. Curr Diabetes Rev. 2016 (in press).
82.
Ogawa W, Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. J Diabetes Investig. 2016;7:135–8. CrossRefPubMed
83.
Palmer BF, Clegg DJ, Taylor SI, et al. Diabetic ketoacidosis, sodium glucose transporter-2 inhibitors and the kidney. J Diabetes Complicat. 2016;30:1162–6.
84.
Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124:509–14. CrossRefPubMedPubMedCentral
85.
Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508. CrossRefPubMedPubMedCentral
86.
Taylor SI, Blau JE, Rother KI. Perspective: SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100:2849–52. CrossRefPubMedPubMedCentral
87.
Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21:512–7. CrossRefPubMed
88.
Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638–42. CrossRefPubMed
89.
Erondu N, Desai M, Ways K, et al. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015;38:1680–6. CrossRefPubMedPubMedCentral
90.
Meier C, Schwartz AV, Egger A, et al. Effects of diabetes drugs on the skeleton. Bone. 2016;82:93–100. CrossRefPubMed
91.
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;14:990–9. CrossRefPubMed
92.
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;85:962–71. CrossRefPubMed
93.
Food and Drug Administration. Invokana and Invokamet (canagliflozin): drug safety communication—new information on bone fracture risk and decreased bone mineral density. http://​www.​fda.​gov/​Safety/​MedWatch/​SafetyInformatio​n/​SafetyAlertsforH​umanMedicalProdu​cts/​ucm461876.​htm 2015. (latest access June 7 2016).
94.
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;32:1375–85.
95.
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;101:157–66. CrossRefPubMed
96.
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. CrossRefPubMed
97.
European Medicines Agency. EMA reviews diabetes medicine canagliflozin. Review follows data on toe amputations in ongoing study. http://​www.​ema.​europa.​eu/​ema/​index.​jsp?​curl=​pages/​medicines/​human/​referrals/​Canagliflozin/​human_​referral_​prac_​000059.​jsp&​mid=​WC0b01ac05805c51​6f 2016. (latest access June 7 2016).
98.
Lin HW, Tseng CH. A review on the relationship between SGLT2 inhibitors and cancer. Int J Endocrinol. 2014;2014:719578. PubMedPubMedCentral
99.
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;6:357–75. CrossRefPubMedPubMedCentral