Update review of the safety of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with type 2 diabetes mellitus

Expert Opinion on Drug Safety

Volumn 15, Issue 10, 2016, Pages 1401-1412

  Carlson, Curt J ^a   Santamarina, Marile L ^a  

^a PALM BEACH ATLANTIC UNIVERSITY   (United States)

Author keywords

Canagliflozin; dapagliflozin; empagliflozin; safety; sodium glucose cotransporter 2 inhibitors; tolerability; type 2 diabetes mellitus

Indexed keywords

ANGIOTENSIN RECEPTOR ANTAGONIST; ANTIDIABETIC AGENT; CALCITRIOL; CANAGLIFLOZIN; DAPAGLIFLOZIN; DIGOXIN; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DIURETIC AGENT; EMPAGLIFLOZIN; FIBROBLAST GROWTH FACTOR 23; INSULIN; INSULIN SECRETAGOGUE; LIPID; PARATHYROID HORMONE; PHOSPHATE; RIFAMPICIN; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; UNCLASSIFIED DRUG; 2-(3-(4-ETHOXYBENZYL)-4-CHLOROPHENYL)-6-HYDROXYMETHYLTETRAHYDRO-2H-PYRAN-3,4,5-TRIOL; BENZHYDRYL DERIVATIVE; GLUCOSE BLOOD LEVEL; GLUCOSIDE; SLC5A2 PROTEIN, HUMAN; SODIUM GLUCOSE COTRANSPORTER 2;

ALLERGIC REACTION; BLADDER CANCER; BONE DENSITY; CARDIOVASCULAR DISEASE; CARDIOVASCULAR EFFECT; CARDIOVASCULAR MORTALITY; CEREBROVASCULAR ACCIDENT; DRUG EFFECT; DRUG EFFICACY; DRUG INTERACTION; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; FRACTURE; GENITAL TRACT INFECTION; GLOMERULUS FILTRATION RATE; GLYCEMIC CONTROL; HEART INFARCTION; HUMAN; HYPERKALEMIA; HYPERSENSITIVITY; HYPOGLYCEMIA; HYPOTENSION; KETOACIDOSIS; KIDNEY DYSFUNCTION; LIPID BLOOD LEVEL; MONOTHERAPY; MYCOSIS; NOCTURIA; NON INSULIN DEPENDENT DIABETES MELLITUS; ORTHOSTATIC HYPOTENSION; OSMOTIC DIURESIS; PHASE 3 CLINICAL TRIAL (TOPIC); PHOSPHATE BLOOD LEVEL; POLLAKISURIA; POLYURIA; POSITIONAL DIZZINESS; PYELONEPHRITIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK FACTOR; TREATMENT OUTCOME; URINARY TRACT INFECTION; UROSEPSIS; ANTAGONISTS AND INHIBITORS; CHEMICALLY INDUCED; DIABETES MELLITUS, TYPE 2; DRUG EFFECTS; GLUCOSE BLOOD LEVEL;

BENZHYDRYL COMPOUNDS; BLOOD GLUCOSE; CANAGLIFLOZIN; DIABETES MELLITUS, TYPE 2; GLUCOSIDES; HUMANS; HYPOGLYCEMIA; HYPOGLYCEMIC AGENTS; SODIUM-GLUCOSE TRANSPORTER 2;

EID: 84988432095     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1080/14740338.2016.1216100     Document Type: Review

References (82)

1. H.Bays Sodium glucose co-transporter type 2 (SGLT2) inhibitors:targeting the kidney to improve glycemic control in diabetes mellitus. Diabetes Ther. 2013;4:195–220.
2. M.A.Abdul-Ghani, R.A.DeFronzo. Inhibition of renal glucose reabsorption:a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14:782–790.• Early review describing how the inhibition of renal glucose reabsorption provides a new therapeutic target in T2DM.
3. R.A.DeFronzo, J.A.Davidson, S.Del Prato. The role of the kidneys in glucose homeostasis:a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012;14:5–14.
4. M.A.Abdul-Ghani, R.A.DeFronzo. Lowering plasma glucose concentration by inhibiting renal sodium-glucose cotransport. J Intern Med. 2014;276:352–363.
5. M.A.Abdul-Ghani, R.A.DeFronzo, L.Norton. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30–50% of filtered glucose load in humans. Diabetes. 2013;62:3324–3328.
6. Prescribing information (03/2016):INVOKANA (canagliflozin) tablets, for oral use. [cited 2016 Apr 8]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204042s011lbl.pdf
7. Prescribing information (12/2015):FARXIGA® (dapagliflozin) tablets, for oral use. [cited 2016 Apr 8]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202293s008lbl.pdf
8. Prescribing information (03/2016):JARDIANCE® (empagliflozin) tablets, for oral use. [cited 2016 Apr 8]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204629s005lbl.pdf
9. Forxiga (dapagliflozin) authorisation details. [cited 2016 Mar 18]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002322/human_med_001546.jsp&mid=WC0b01ac058001d124
10. Invokana (canagliflozin) authorisation details. [cited 2016 Mar 18]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002649/human_med_001707.jsp&mid=WC0b01ac058001d124
11. Jardiance (empagliflozin) authorisation details. [cited 2016 Mar 18]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002677/human_med_001764.jsp&mid=WC0b01ac058001d124
12. Drug Safety Communication. FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. 2015 Dec 4 [cited 2016 Jan 18]. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM475487.pdf
13. R.Grempler, L.Thomas, M.Eckhardt, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor:characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14:83–90.
14. A.J.Scheen. SGLT2 inhibition:efficacy and safety in type 2 diabetes treatment. Expert Opin Drug Saf. 2015;14:1879–1904.
15. X.-P.Yang, D.Lai, X.-Y.Zhong, 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.
16. M.Zhang, L.Zhang, B.Wu, 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.
17. A.Liakos, T.Karagiannis, E.Athanasiadou, et al. Efficacy and safety of empagliflozin for type 2 diabetes:a systematic review and meta-analysis. Diabetes Obes Metab. 2014;16:984–993.
18. A.J.Garber, M.J.Abrahamson, J.I.Barzilay, 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.•• SGLT2 inhibitors included in AACE algorithm.
19. American Diabetes Association. 7. Approaches to glycemic treatment. Diabetes Care. 2016;39:S52–S59.•• SGLT2 inhibitors included in ADA guidance.
20. R.R.Henry, P.Thakkar, C.Tong, et al. Efficacy and Safety of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes. Diabetes Care. 2015;38:2258–2265.
21. H.E.Tamez, A.L.Tamez, L.A.Garza, et al. Dapagliflozin as an adjunct therapy to insulin in the treatment of patients with type 1 diabetes mellitus. J Diabetes Metab Disord. 2015;14:78.
22. T.R.Pieber, S.Famulla, J.Eilbracht, et al. Empagliflozin as adjunct to insulin in patients with type 1 diabetes:a 4-week, randomized, placebo-controlled trial (EASE-1). Diabetes Obes Metab. 2015;17:928–935.
23. B.Zinman, C.Wanner, J.M.Lachin, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.•• Landmark trial:this is the first cardiovascular outcomes trial of a glucose lowering medication to demonstrate efficacy in reducing cardiovascular disease risk in T2DM patients.
24. S.Kohler, A.Salsali, S.Hantel, et al. Safety and tolerability of empagliflozin in patients with type 2 diabetes. Clin Ther. 2016;38:1299–1313.
25. S.Geerlings, V.Fonseca, D.Castro-Diaz, et al. Genital and urinary tract infections in diabetes:impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract. 2014;103:373–381.
26. P.Nyirjesy, Y.Zhao, K.Ways, et al. Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. Curr Med Res Opin. 2012;28:1173–1178.
27. K.M.Johnsson, A.Ptaszynska, B.Schmitz, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27:479–484.
28. K.Whalen, S.Miller, E.S.Onge. The role of sodium-glucose co-transporter 2 inhibitors in the treatment of type 2 diabetes. Clin Ther. 2015;37:1150–1166.
29. P.Nyirjesy, J.D.Sobel, A.Fung, 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.
30. R.Parveen, N.B.Agarwal, N.Kaushal, et al. Efficacy and safety of canagliflozin in type 2 diabetes mellitus:systematic review of randomized controlled trials. Expert Opin Pharmacother. 2016;17:105–115.
31. A.Ptaszynska, K.M.Johnsson, S.J.Parikh, 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.
32. B.Bode, K.Stenlöf, S.Harris, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55–80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17:294–303.
33. A.J.Scheen. Pharmacokinetics, pharmacodynamics and clinical use of SGLT2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease. Clin Pharmacokinet. 2015;54:691–708.
34. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease:evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1–S266.
35. A.H.Barnett, A.Mithal, J.Manassie, et al. 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. Lancet Diabetes Endocrinol. 2014;2:369–384.
36. D.E.Kohan, P.Fioretto, K.Johnsson, et al. The effect of dapagliflozin on renal function in patients with type 2 diabetes. J Nephrol. 2016;29:391–400.
37. V.Perkovic, M.Jardine, U.Vijapurkar, et al. Renal effects of canagliflozin in type 2 diabetes mellitus. Curr Med Res Opin. 2015;31:2219–2231.
38. N.Mikhail. Safety of canagliflozin in patients with type 2 diabetes. Curr Drug Saf. 2014;9:127–132.
39. A.Ptaszynska, E.Hardy, E.Johnsson, et al. Effects of dapagliflozin on cardiovascular risk factors. Postgrad Med. 2013;125:181–189.
40. B.Haas, N.Eckstein, V.Pfeifer, et al. Efficacy, safety and regulatory status of SGLT2 inhibitors:focus on canagliflozin. Nutr Diabetes. 2014;4:e143.
41. A.Liakos, T.Karagiannis, E.Bekiari, et al. Update on long-term efficacy and safety of dapagliflozin in patients with type 2 diabetes mellitus. Ther Adv Endocrinol Metab. 2015;6:61–67.
42. Drug safety communication:FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. 2015 May 5 [cited 2015 Jul13]. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM446954.pdf.• First safety announcement from US FDA warning of increased risk of ketoacidosis with SGLT2 inhibitors.
43. Review of diabetic medicines called SGLT2 inhibitors started. 2015 [cited 2015 Jun24]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/SGLT2_inhibitors/human_referral_prac_000052.jsp&mid=WC0b01ac05805c516f
44. 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. 2015 Sep 9 [cited2016 Jan18]. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM461790.pdf
45. N.B.Watts, J.P.Bilezikian, K.Usiskin, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101:157–166.
46. J.P.Bilezikian, N.B.Watts, K.Usiskin, 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.
47. Ö.Ljunggren, J.Bolinder, L.Johansson, 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.
48. CANVAS - CANagliflozin cardioVascular Assessment Study. [cited 2016 Jan 21]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01032629
49. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). [cited 2016 Jan 21]. Available from: https://clinicaltrials.gov/ct2/show/NCT01730534
50. J.Bolinder, Ö.Ljunggren, L.Johansson, 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.
51. S.I.Taylor, J.E.Blau, K.I.Rother. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol. 2015;3:8–10.
52. E.Liao. FGF23 associated bone diseases. Front Med. 2013;7:65–80.
53. M.Janghorbani, R.M.Van Dam, W.C.Willett, et al. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol. 2007;166:495–505.
54. T.Yamaguchi, T.Sugimoto. Bone metabolism and fracture risk in type 2 diabetes mellitus. Bonekey Rep. 2012;1:36.
55. V.V.Shanbhogue, D.M.Mitchell, C.J.Rosen, et al. Type 2 diabetes and the skeleton:new insights into sweet bones. Lancet Diabetes Endocrinol. 2016;4:159–173.
56. A.E.Kitabchi, G.E.Umpierrez, J.M.Miles, et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32:1335–1343.
57. American Diabetes Association. 13. Diabetes Care in the Hospital. Diabetes Care. 2016;39(Suppl 1):S99–S104.
58. A.L.Peters, E.O.Buschur, J.B.Buse, et al. Euglycemic diabetic ketoacidosis:a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38:1687–1693.
59. H.Harati, V.Sharma, A.Motazedi. Sodium-glucose cotransporter 2 inhibitor-associated diabetic ketoacidosis:report of two cases with hyperglycemic ketoacidosis in type 1 diabetes. J Diabetes. 2016;8:165.
60. A.Gelaye, A.Haidar, C.Kassab, et al. Severe Ketoacidosis Associated with Canagliflozin (Invokana):A Safety Concern. Case Rep Crit Care. 2016;2016:1656182.
61. P.Roach, P.Skierczynski. Euglycemic diabetic ketoacidosis in a patient with type 2 diabetes after treatment with empagliflozin. Diabetes Care. 2016;39:e3.
62. H.Storgaard, J.I.Bagger, F.K.Knop, et al. Diabetic ketoacidosis in a patient with type 2 diabetes after initiation of sodium-glucose cotransporter 2 inhibitor treatment. Basic Clin Pharmacol Toxicol. 2016;118:168–170.
63. J.Hine, H.Paterson, E.Abrol, et al. SGLT inhibition and euglycaemic diabetic ketoacidosis. Lancet Diabetes Endocrinol. 2015;3:503–504.
64. A.Kaur, S.J.Winters. Severe hypercalcemia and hypernatremia in a patient treated with canagliflozin. Endocrinol Diabetes Metab Case Rep. 2015;2015:150042.
65. J.Rosenstock, E.Ferrannini. Euglycemic diabetic ketoacidosis:a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638–1642.
66. N.Erondu, M.Desai, K.Ways, et al. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015;38:1680–1686.
67. C.Bonner, J.Kerr-Conte, V.Gmyr, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21:512–517.
68. E.Ferrannini, E.Muscelli, S.Frascerra, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.
69. Y.Handelsman, R.R.Henry, Z.T.Bloomgarden, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic Ketoacidosis. Endocr Pract. 2016;22:753–762.
70. R.A.DeFronzo. The EMPA-REG study:What has it told us? A diabetologist’s perspective. J Diabetes Complications. 2016;30:1–2.
71. A.J.Scheen. Reduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial:A critical analysis. Diabetes Metab. 2016;42:71–76.
72. R.Chilton, I.Tikkanen, C.P.Cannon, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17:1180–1193.
73. A.J.Scheen, N.Esser, N.Paquot. Antidiabetic agents:potential anti-inflammatory activity beyond glucose control. Diabetes Metab. 2015;41:183–194.
74. A.Ceriello, S.Genovese, E.Mannucci, et al. Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol. 2015;3:929–930.
75. B.J.Jones, T.Tan, S.R.Bloom. Minireview:glucagon in stress and energy homeostasis. Endocrinology. 2012;153:1049–1054.
76. B.Neal, V.Perkovic, D.De Zeeuw, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)–a randomized placebo-controlled trial. Am Heart J. 2013;166:217–223 e11.
77. Cardiovascular outcomes following treatment with ertugliflozin in participants with type 2 diabetes mellitus and established vascular disease (MK-8835-004). [cited 2016 Jan 21]. Available from: https://www.clinicaltrials.gov/ct2/show/record/NCT01986881
78. J.A.Kanis, F.Borgstrom, C.De Laet, et al. Assessment of fracture risk. Osteoporos Int. 2005;16:581–589.
79. G.E.Umpierrez. Ketosis-prone type 2 diabetes:time to revise the classification of diabetes. Diabetes Care. 2006;29:2755–2757.
80. G.Goodstein, A.Milanesi, J.E.Weinreb. Ketosis-prone type 2 diabetes in a veteran population. Diabetes Care. 2014;37:e74–e75.
81. E.Laugesen, J.A.Østergaard, R.D.Leslie. Latent autoimmune diabetes of the adult:current knowledge and uncertainty. Diabet Med. 2015;32:843–852.
82. S.Arora, S.O.Henderson, T.Long, et al. Diagnostic accuracy of point-of-care testing for diabetic ketoacidosis at emergency-department triage:{beta}-hydroxybutyrate versus the urine dipstick. Diabetes Care. 2011;34:852–854.