Association of British Clinical Diabetologists (ABCD) position statement on the risk of diabetic ketoacidosis associated with the use of sodium-glucose cotransporter-2 inhibitors


  • Umesh Dashora Conquest Hospital, Hastings, UK
  • Alison Gallagher University Hospitals of Leicester NHS Trust, UK
  • Ketan Dhatariya Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
  • Peter Winocour East and North Herts NHS Trust, Hertfordshire, UK
  • Rob Gregory University Hospitals of Leicester NHS Trust, UK
  • On Behalf of the ABCD Committee



SGLT-2 inhibitors, diabetic ketoacidosis, ABCD


Diabetic Ketoacidosis (DKA) has been reported in patients with diabetes taking SGLT-2 inhibitor drugs both in clinical trials and in real life situations, particularly amongst patients taking insulin. The US Food and Drug Administration (FDA) has issued a safety communication following 20 cases of DKA in patients receiving these drugs.1 This concern has also prompted an American Association of Clinical Endocrinologists and American College of Endocrinology position statement covering the use of SGLT-2 inhibitors in people with type 2 diabetes.2 The following is the ABCD position statement on this issue.


U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Bethesda, MD: U.S. Food and Drug Administration; 2015. Available at: ucm446845.htm (accessed June, 2016).

Handelsman Y, Henry RR, Bloomgarden ZT, 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 Jun 1. [Epub ahead of print]. Available at: (accessed June, 2016).

Dhatariya K. Comment on Erondu et al. Diabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program. Diabetes Care 2015;38:1680-1686. Diabetes Care 2016;39:e18.

Centers for Disease Control and Prevention. NCHS National Hospital Discharge Survey. Atlanta, GA: Centers for Disease Control and Prevention; 2010. Available at: (accessed June , 2016).

Centers for Disease Control and Prevention. Diabetes Public Health Resource: crude and age-adjusted hospital discharge rates for diabetic ketoacidosis (DKA) as first-listed diagnosis per 1,000 diabetic population, United States, 1988-2009. Atlanta, GA: Centers for Disease Control and Prevention; 2016. Available at: (accessed June, 2016).

Wang ZH, Kihl-Selstam E, Eriksson JW. Ketoacidosis occurs in both type 1 and type 2 diabetes—a population-based study from Northern Sweden. Diabet Med 2008;25:867-870.

Erondu N, Desai M, Ways K, et al. Diabetic ketoacidosis and related events in the Canagliflozin Type 2 Diabetes Clinical Program. Diabetes Care 2015;38:1680-1686.

Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-2128.

Henry RR, Thakkar P, Tong C, 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;38:2258-65.

Peters AL, Henry RR, Thakkar P, et al. Diabetic Ketoacidosis With Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, in Patients With Type 1 Diabetes. Diabetes Care 2016;39:532-8.

Henry RR, Rosenstock J, Edelman S, et al. Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study. Diabetes Care 2015;38:412-19.

Tamez HE, Tamez AL, Garza LA, 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.

Perkins BA, Cherney DZ, Partridge H, et al. Sodium glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of an 8-week open-label proof-of concept trial. Diabetes Care 2014;37:1480-83.

Pieber TR, Famulla S, Eilbracht J, 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;17:928-35.

Sands AT, Zambrowicz BP, Rosenstock J, et al. Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes. Diabetes Care 2015;38:1181-88.

Julicher S. Notification to the PRAC/EMA Secretariat of a referral under article 20 of regulation (EC) 726/2004. London, UK: European Medicines Agency; 2015. Available at: library/Referralsdocument/SGLT2_inhibitors__20/ Procedure started/ WC500187925.pdf (accessed June,

Tang H, Li D, Wang T, et al. 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 Jun 14:dc160885.

West K, Webb LA, Fenech M, et al. Possible risk factors for the development of sodium-glucose co-transporter 2 inhibitor-associated diabetic ketoacidosis in type 2 diabetes. British Journal of Diabetes 2016;16:78-81.

Ferrannini E, Baldi S, Frascerra S, et al. Shift to Fatty Substrate Utilization in Response to Sodium–Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes. Diabetes 2016;65:1190-5.

Sha S, Devineni D, Ghosh A, 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;13:669-72.

Ferrannini E, Veltkamp SA, Smulders RA, et al. Renal glucose handling: impact of chronic kidney disease and sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care 2013;36:1260-5.

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.

Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015;38:1638-42.

Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis. Diabetes Care 2016 Jun 10:dc160330.

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 Jun 10:dc160542.

Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. The Journal of Clinical Endocrinology & Metabolism 2015;100:2849-52.

Maruyama H, Hisatomi A, Orci L, et al. Insulin within islets is a physiologic glucagon release inhibitor. J Clin Invest 1984;74:2296-9.

Bonner C, Kerr-Conte J, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med 2015;21:512-17.

Kaku K, Watada H, Iwamoto Y, et al. Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study. Cardiovasc Diabetol 2014;13:65.

Devenny JJ, Godonis HE, Harvey SJ, et al. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity (Silver Spring). 2012;20:1645-52.

Yokono M, Takasu T, Hayashizaki Y, et al. SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. Eur J Pharmacol 2014;727:66-74.

Cohen JJ, Berglund F, Lotspeich WD. Renal tubular reabsorption of acetoacetate, inorganic sulfate and inorganic phosphate in the dog as affected by glucose and phlorizin. Am J Physiol 1956;184:91-96.

Cahill GF, Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006;26:1-22.

Burge MR, Garcia N, Qualls CR, et al. Differential effects of fasting and dehydration in the pathogenesis of diabetic ketoacidosis. Metabolism 2001;50:171-7.

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.

Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009;32:1335-43.

Savage MW, Dhatariya KK, Kilvert A et al. Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis. Diabetic Medicine 2011;28:508-15.

Dhatariya K. The use of point-of-care blood ketone monitors in the management of diabetic ketoacidosis in adults. Ann Clin Biochem 2014;51:525-7.

Medicines and healthcare products regulatory agency. SGLT2 inhibitors: updated advice on the risk of diabetic ketoacidosis, 2016. Available at (accessed July 2016)






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