Journal List > J Korean Diabetes > v.15(3) > 1054924

Kim and Kim: The Side Effects of Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor

Abstract

Anti-diabetic drugs for effectively lowering glucose with limited side effects are necessary in providing patient-centered diabetic management. Sodium glucose cotransporter 2 (SGLT 2) inhibitors provide a novel therapeutic approach for managing type 2 diabetic patients by lowering glucose levels by increasing urinary excretion of glucose independently of insulin secretion or action. Several SGLT 2 inhibitors were recently approved and available in the US, European and Korean markets. SGLT 2 improved glycemic control with low propensity of hypoglycemia. Through the clinical trials, most SLGT2 inhibitors were generally well tolerated. Genital tract infections were more frequent in most clinical studies of SGLT2 inhibitors and urinary tract infections were slightly increased in some studies. This review will describe the main safety issues that have been uncovered in clinical trials of SGLT 2 inhibitors.

REFERENCES

1. Jeon JY, Kim DJ, Ko SH, Kwon HS, Lim S, Choi SH, Kim CS, An JH, Kim NH, Won JC, Kim JH, Cha BY, Song KH. Taskforce Team of Diabetes Fact Sheet of the Korean Diabetes Association. Current status of glycemic control of patients with diabetes in Korea: the fifth Korea national health and nutrition examination survey. Diabetes Metab J. 2014; 38:197–203.
crossref
2. Nair S, Wilding JP. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab. 2010; 95:34–42.
crossref
3. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012; 35:1364–79.
crossref
4. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010; 33:2217–24.
5. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010; 375:2223–33.
crossref
6. Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2011; 13:928–38.
crossref
7. Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012; 35:1473–8.
crossref
8. Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S. Dapagliflozin 006 Study Group. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med 2012 Mar 20;156. 405–15.
9. Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M, Parikh SJ. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011; 34:2015–22.
10. Stenlöf K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, Canovatchel W, Meininger G. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013; 15:372–82.
crossref
11. Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, Kawaguchi M, Canovatchel W, Meininger G. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013; 36:2508–15.
12. Wilding JP, Mathieu C, Vercruysse F, Usiskin K, Deng L, Canovatchel W. Canagliflozin (CANA), a sodiumglucose cotransporter 2 inhibitor, improves glycemic control and reduces bodyweight in subjects with type 2 diabetes (T2D) inadequately controlled with metformin (MET) and sulfonylurea (SU) [abstract]. Diabetes. 2012; 61:A262.
13. Matthew D, Fulcher GR, Perkovic V, de Zeeuw D, Mahaffey KW, Rosenstock J, Davies M, Capuano G, Desai M, Shaw W, Vercruysse F, Meininger G, Neal B. Efficacy and safety of canagliflozin, an inhibitor of sodium glucose cotransporter2, added on to insulin therapy with or without oral agents in type 2 diabetes [abstract]. Diabetologia. 2012; 55((Suppl 1)):S314.
14. Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab. 2013; 15:721–8.
crossref
15. Häring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, Woerle HJ. EMPA-REG MET Trial Investigators. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014; 37:1650–9.
crossref
16. Rosenstock J, Jelaska A, Wang F Kim G, Broedl U, Woerle HJ, Bajaj HS. Empagliflozin as add-on to basal insulin for 78 weeks improves glycemic control with weight loss in insulin-treated type 2 diabetes (T2DM). Can J Diabetes. 2013; 37:S32.
17. Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013; 27:473–8.
crossref
18. Plosker GL. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs. 2012; 72:2289–312.
19. Shah NK, Deeb WE, Choksi R, Epstein BJ. Dapagliflozin: a novel sodiumglucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus. Pharmacotherapy. 2012; 32:80–94.
crossref
20. Balis DA, Canovatchel W, Meininger G. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 noninferiority trial. Lancet. 2013; 382:941–50.
21. Jones D. Diabetes field cautiously upbeat despite possible setback for leading SGLT2 inhibitor. Nat Rev Drug Discov. 2011; 10:645–6.
crossref
22. Bailey CJ. Interpreting adverse signals in diabetes drug development programs. Diabetes Care. 2013; 36:2098–106.
crossref
23. Chen J, Williams S, Ho S, Loraine H, Hagan D, Whaley JM, Feder JN. Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members. Diabetes Ther. 2010; 1:57–92.
crossref
24. Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol. 2010; 5:133–41.
crossref
25. Kohan DE, Fioretto P, Tang W, List JF. 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.
crossref
26. Ljunggren Ö, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjöström CD, Sugg J, Parikh S. 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.
crossref
27. Leiter LA, Cefalu WT, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2014; 62:1252–62.
crossref
28. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, Figueroa K, Wajs E, Usiskin K, Meininger G. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013; 15:463–73.
crossref
29. Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, Broedl UC. on behalf of the EMPA-REG PIO™ trial investigators. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014; 16:147–58.
crossref

Table 1.
Adverse events of special interest associated with sodium glucose cotransporter 2 (SGLT2) inhibitors.
Study design Duration, wk Reference Hypoglycemiaa, % Genital infection %a, % Urinary tract infectiona, %
Dapagliflozin          
 Monotherapy (vs. placebo) 24 [4] 0–3 (3) 8–13 (1) 5–13 (4)
 Add-on to metformin (vs. placebo) 24 [5] 2–4 (3) 8–13 (5) 4–8 (8)
 Add-on to pioglitazone (vs. placebo) 24 [7] 0–2 (0) 7–8 (3) 4–8 (6)
 Add-on to glimepiride (vs. placebo) 24 [6] 7–8 (5) 4–7 (1) 4–7 (6)
 Add-on to insulin (vs. placebo) 48 [8] 54–60 (52) 6–11 (3) 8–11 (5)
 Add-on to metformin (vs. glipizide) 52 [9] 3.4 (39.7) 12.3 (2.7) 5.9 (7.6)
Canagliflozin          
 Monotherapy (vs. placebo) 26 [10] 3–4 (3) 6–7 (2) 5–7 (4)
 Add-on to metformin + sulfonylurea (vs. placebo) 26 [12] 27–30 (15) 10–11 (3) 6 (5)
 Add-on to insulin (vs. placebo) 18 [13] 49 (37) 7–9 (1) 2–3 (2)
 Monotherapy (vs. glimepiride) 52 [20] 5–6 (34) 9–11 (5) 6 (5)
 Monotherapy (vs. sitagliptin) 52 [11] 43 (41) 12 (2) 4(6)
Empagliflozin          
 Monotherapy (vs. placebo) 12 [14] 0 (1.2) 0–3.7 (0) 1.2–2.5 (1.2)
 Add-on to metformin (vs. placebo) 24 [15] 1.4–1.8 (0.5) 3.7–4.7 (0) 5.1–5.6 (4.9)
 Add-on to insulin (vs. placebo) 12 [16] 36.1 (35.3) 5.2-7.7 (1.8) 11.6-14.8 (8.8)
 Add-on to metformin + pioglitazone (vs. placebo) 24 [29] 1.2-2.4 (1.8) 3.6-8.5 (2.4) 11.9-17.0 (16.4)

a Ranges are given for each SGLT2 inhibitor if available.

TOOLS
Similar articles