Skip to main content
Top

08-06-2017 | SGLT2 inhibitors | Review | Article

SGLT2-I in the Hospital Setting: Diabetic Ketoacidosis and Other Benefits and Concerns

Journal: Current Diabetes Reports

Authors: Joshua A. Levine, Susan L. Karam, Grazia Aleppo

Publisher: Springer US

Abstract

Purpose of Review

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of antihyperglycemic agents. They are increasingly being prescribed in the outpatient diabetic population. In this review, we examine the risks and benefits of continuation and initiation of SGLT2 inhibitors in the inpatient setting.

Recent Findings

There are currently no published data regarding safety and efficacy of SGLT2 inhibitor use in the hospital. Outpatient data suggests that SGLT2 inhibitors have low hypoglycemic risk. They also decrease systolic blood pressure and can prevent cardiovascular death. The EMPA-REG study also showed a decrease in admissions for acute decompensated heart failure. There have been increasing cases of diabetic ketoacidosis, and specifically the euglycemic manifestation, associated with SGLT2 inhibitors use. We present two cases of inpatient SGLT2 inhibitor use, one of continuation of outpatient therapy and one of new initiation of therapy. We then discuss potential risks and methods to mitigate these as well as benefits of these medications in the inpatient setting.

Summary

We cautiously suggest the use of SGLT2 inhibitors in the hospital. However, these must be used judiciously and the practitioner must be aware of euglycemic diabetic ketoacidosis and its risk factors in this population.
Literature
1.
Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733–94. doi:10.​1152/​physrev.​00055.​2009.CrossRefPubMed
2.
Nauck MA. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther. 2014;8:1335–80. doi:10.​2147/​DDDT.​S50773.CrossRefPubMedPubMedCentral
3.
Chasis H, Jolliffe N, Smith HW. The action of phlorizin on the excretion of glucose, xylose, sucrose, creatinine and urea by man. J Clin Invest. 1933;12(6):1083–90. doi:10.​1172/​JCI100559.CrossRefPubMedPubMedCentral
4.
Rossetti L, Shulman GI, Zawalich W, DeFronzo RA. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Invest. 1987;80(4):1037–44. doi:10.​1172/​JCI113157.CrossRefPubMedPubMedCentral
5.
Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest. 1987;79(5):1510–5. doi:10.​1172/​JCI112981.CrossRefPubMedPubMedCentral
6.
Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, 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(1):83–90. doi:10.​1111/​j.​1463-1326.​2011.​01517.​x.CrossRefPubMed
7.
•• Stenlof K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372–82. doi:10.​1111/​dom.​12054. Phase III clinical trial of canagliflozin versus placebo. CrossRefPubMedPubMedCentral
8.
•• 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(10):2217–24. doi:10.​2337/​dc10-0612. Phase III clinical trial of dapagliflozin versus placebo. CrossRefPubMedPubMedCentral
9.
•• Roden MWJ, Eilbracht J, Delafont B, Kim G, Woerle HJ, Broedl UC. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013;1(3):208–19. Phase III clinical trial of empagliflozin versus placebo. CrossRefPubMed
10.
Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, et al. 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 non-inferiority trial. Lancet. 2013;382(9896):941–50. doi:10.​1016/​S0140-6736(13)60683-2.CrossRefPubMed
11.
Nauck MA, Del Prato S, Meier JJ, Duran-Garcia S, Rohwedder K, Elze M, et al. 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(9):2015–22. doi:10.​2337/​dc11-0606.CrossRefPubMedPubMedCentral
12.
Haring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, et al. 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(6):1650–9. doi:10.​2337/​dc13-2105.CrossRefPubMed
13.
Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463–73. doi:10.​1111/​dom.​12090.CrossRefPubMedPubMedCentral
14.
Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012;156(6):405–15. doi:10.​7326/​0003-4819-156-6-201203200-00003.CrossRefPubMed
15.
Rosenstock J, Jelaska A, Frappin G, Salsali A, Kim G, Woerle HJ, et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014;37(7):1815–23. doi:10.​2337/​dc13-3055.CrossRefPubMed
16.
•• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. doi:10.​1056/​NEJMoa1504720. This study showed a risk reduction in cardiovascular outcomes in patients being treated with empagliflozin versus placebo. CrossRefPubMed
17.
FDA. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. 2016. http://​www.​fda.​gov/​NewsEvents/​Newsroom/​PressAnnouncemen​ts/​ucm531517.​htm. Accessed December 4 2016.
18.
Association AD. Standards of medical care in diabetes. Diabetes Care. 2016;39(S1):1–112.
19.
Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Endocr Pract. 2009;15(4):353–69. doi:10.​4158/​EP09102.​RA.CrossRefPubMed
20.
Umpierrez GE, Gianchandani R, Smiley D, Jacobs S, Wesorick DH, Newton C, et al. Safety and efficacy of sitagliptin therapy for the inpatient management of general medicine and surgery patients with type 2 diabetes: a pilot, randomized, controlled study. Diabetes Care. 2013;36(11):3430–5. doi:10.​2337/​dc13-0277.CrossRefPubMedPubMedCentral
21.
Yang XP, Lai D, Zhong XY, Shen HP, Huang YL. Efficacy and safety of canagliflozin in subjects with type 2 diabetes: systematic review and meta-analysis. Eur J Clin Pharmacol. 2014;70(10):1149–58. doi:10.​1007/​s00228-014-1730-x.CrossRefPubMed
22.
Zhang M, Zhang L, Wu B, Song H, An Z, Li S. Dapagliflozin treatment for type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. 2014;30(3):204–21. doi:10.​1002/​dmrr.​2479.CrossRefPubMed
23.
Liakos A, Karagiannis T, Athanasiadou E, Sarigianni M, Mainou M, Papatheodorou K, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2014;16(10):984–93. doi:10.​1111/​dom.​12307.CrossRefPubMed
24.
• Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1687–93. doi:10.​2337/​dc15-0843. Case series showing euglycemic DKA in patients treated with canagliflozin. CrossRefPubMedPubMedCentral
25.
• Erondu N, Desai M, Ways K, Meininger G. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015;38(9):1680–6. doi:10.​2337/​dc15-1251. Analysis of adverse events and DKA in patients enrolled in canagliflozin trials. CrossRefPubMedPubMedCentral
26.
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. http://​www.​fda.​gov/​downloads/​drugs/​drugsafety/​ucm475487.​pdf. Accessed November 20 2016.
27.
Tang H, Li D, Wang T, Zhai S, Song Y. Effect of sodium-glucose cotransporter 2 inhibitors on diabetic ketoacidosis among patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Diabetes Care. 2016;39(8):e123–4. doi:10.​2337/​dc16-0885.CrossRefPubMed
28.
Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38(9):1638–42. doi:10.​2337/​dc15-1380.CrossRefPubMed
29.
Sha S, Devineni D, Ghosh A, Polidori D, Chien S, Wexler D, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab. 2011;13(7):669–72. doi:10.​1111/​j.​1463-1326.​2011.​01406.​x.CrossRefPubMed
30.
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335–43. doi:10.​2337/​dc09-9032.CrossRefPubMedPubMedCentral
31.
Rewers A. Current controversies in treatment and prevention of diabetic ketoacidosis. Adv Pediatr Infect Dis. 2010;57(1):247–67. doi:10.​1016/​j.​yapd.​2010.​09.​001.
32.
Wolfsdorf J, Glaser N, Sperling MA, American Diabetes A. Diabetic ketoacidosis in infants, children, and adolescents: a consensus statement from the American Diabetes Association. Diabetes Care. 2006;29(5):1150–9. doi:10.​2337/​diacare.​2951150.CrossRefPubMed
33.
Rewers A, McFann K, Chase HP. Bedside monitoring of blood beta-hydroxybutyrate levels in the management of diabetic ketoacidosis in children. Diabetes Technol Ther 2006;8(6):671–6.
34.
Byrne HA, Tieszen KL, Hollis S, Dornan TL, New JP. Evaluation of an electrochemical sensor for measuring blood ketones. Diabetes Care 2000;23(4):500–3.
35.
Wallace TM, Meston NM, Gardner SG, Matthews DR. The hospital and home use of a 30-second hand-held blood ketone meter: guidelines for clinical practice. Diabet Med 2001;18(8):640–5.
36.
Sha S, Polidori D, Heise T, Natarajan J, Farrell K, Wang SS, 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(11):1087–95. doi:10.​1111/​dom.​12322.CrossRefPubMed
37.
Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, 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(19):1526–34. doi:10.​1093/​eurheartj/​ehv728.CrossRefPubMedPubMedCentral
38.
Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8(4):262–275 e9. doi:10.​1016/​j.​jash.​2014.​01.​007.CrossRefPubMed
39.
Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S, Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4(3):211–20. doi:10.​1016/​S2213-8587(15)00417-9.CrossRefPubMed
40.
Weber MA, Mansfield TA, Alessi F, Iqbal N, Parikh S, Ptaszynska A. Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade. Blood Press. 2016;25(2):93–103. doi:10.​3109/​08037051.​2015.​1116258.CrossRefPubMed
41.
Devineni D, Vaccaro N, Polidori D, Rusch S, Wajs E. Effects of hydrochlorothiazide on the pharmacokinetics, pharmacodynamics, and tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants. Clin Ther. 2014;36(5):698–710. doi:10.​1016/​j.​clinthera.​2014.​02.​022.CrossRefPubMed
42.
• Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–34. doi:10.​1056/​NEJMoa1515920. This study demonstrated a reduction in progression to diabetic nephropathy in patients on empagliflozin in the EMPA-REG trial. CrossRefPubMed

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform. 

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »