Sodium-glucose co-transporter inhibitors, their role in type 1 diabetes treatment and a risk mitigation strategy for preventing diabetic ketoacidosis: The STOP DKA Protocol
Recent phase 3 clinical trials have evaluated the impact of adding sodium-glucose co-transporter (SGLT) inhibitors to the type 1 diabetes armamentarium. These trials studied SGLT2 inhibitors (dapagliflozin and empagliflozin) and a dual SGLT1 and SGLT2 inhibitor (sotagliflozin), and demonstrated that these oral non-insulin antihyperglycaemic medications are able not only to improve glycaemic control, but also to reduce body weight and extend time in range without increasing rates of hypoglycaemia in type 1 diabetes. Diabetic ketoacidosis (DKA) is a feature of type 1 diabetes and the risk is increased when SGLT inhibitors are used in type 1 diabetes. To minimize the risk of DKA and still gain the multiple benefits, we developed the “STOP DKA Protocol “, an easily accessible and practical tool, that provides a risk mitigation strategy for reducing DKA in patients with type 1 diabetes being treated with SGLT inhibitors.
CONFLICT OF INTEREST
R.M.G. reports research support from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Medtronic, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Takeda, serving on advisory panels for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Roche, Sanofi and Takeda, serving on speaker bureaus for Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi and Servier, and consulting for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk and Takeda. J.D.G. reports serving on advisory panels for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi, and serving on speaker bureaus for Amgen, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi. I.M.H. reports research support from AstraZeneca/Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, Medtronic, Merck & Co Inc, Novo Nordisk, Sanofi, and consulting fees and honoraria from AstraZeneca/Bristol Myers Squibb, Boehringer Ingelheim, Dexcom, Eli Lilly, GlaxoSmithKline, Roche Pharma, Insulet Corp, Janssen Pharmaceuticals, Merck & Co Inc, Novo Nordisk, Sanofi and Takeda. V.C.W. reports receiving clinical trial support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Pfizer and Sanofi, serving on advisory panels of and receiving speaker honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck and Sanofi. B.Z. reports serving on the scientific advisory board of clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi.
|dom13811-sup-0001-TableS1.docxWord 2007 document , 18.6 KB||Table S1. Baseline participant characteristics of phase 3 SGLT inhibitor trials with type 1 diabetes cohorts|
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
- 1, . Epidemiology of diabetes. Medicine (Abingdon). 2018; 47: 22-27.
- 2, , , et al. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989-2013: a multicentre prospective registration study. Diabetologia. 2019; 62: 408-417.
- 3 International Diabetes Federation. IDF Diabetes Atlas. 8th ed. Brussels: International Diabetes Federation; 2017.
- 4, , , et al; for the T1D Exchange Clinic NetworkState of type 1 diabetes management and outcomes from the T1D Exchange in 2016-2018. Diabetes Technol Ther. 2019; 21: 66-72.
- 5, , , et al. Marked increases in CGM use has not prevented increases in HbA1c levels in participants in the T1D Exchange (T1DX) Clinic Network. Diabetes. Orlando, FL: 78th Scientific Sessions of the American Diabetes Association; 2018: 1689.
- 6, , , , . Trends in diabetic ketoacidosis hospitalizations and in-hospital mortality - United States, 2000-2014. MMWR Morb Mortal Wkly Rep. 2018; 67: 362-365.
- 7, , , et al. Event rates and risk factors for the development of diabetic ketoacidosis in adult patients with type 1 diabetes: analysis from the DPV registry based on 46,966 patients. Diabetes Care. 2019; 42(3): e34-e36.
- 8, , . Trends in hospital admission for diabetic ketoacidosis in adults with type 1 and type 2 diabetes in England, 1998-2013: a retrospective cohort study. Diabetes Care. 2018; 41: 1870-1877.
- 9. The barrier of hypoglycemia in diabetes. Diabetes. 2008; 57: 3169-3176.
- 10. The incidence and impact of hypoglycemia in type 1 and type 2 diabetes. Int Diabetes Monitor. 2009; 21: 210-218.
- 11, , . Drugs for diabetes: part 8 SGLT2 inhibitors. Br J Cardiol. 2012; 19: 26-29.
- 12. Forxiga Approved in Japan for Type-1 Diabetes. Cambridge, UK: AstraZeneca PLC; 2019.
- 13. Forxiga Approved in Europe for Type-1 Diabetes. Cambridge, UK: AstraZeneca PLC; 2019.
- 14 Sanofi, Lexicon Pharmaceuticals. ZynquistaTM Now Approved in the European Union for Treatment of Adults with Type 1 Diabetes. Paris, France and The Woodlands, TX: Sanofi and Lexicon Pharmaceuticals; 2019.
- 15. FDA Turns Down Sotagliflozin for Type 1 Diabetes. New York: Medscape; 2019.
- 16 Diabetes Canada Clinical Practice Guidelines Expert Committee, , . Hyperglycemic emergencies in adults. Can J Diabetes. 2018; 42(Suppl 1): S109-S114.
- 17, , , et al. SGLT2 inhibitor-associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis. Clin Ther. 2016; 38: 2654-2664. e2651.
- 18, , . Sodium-glucose co-transporter-2 inhibitors in type 1 diabetes—a dangerous ally. US Endocrinology. 2017; 13: 75-78.
- 19 Australian Diabetes Educators Association. Clinical Guiding Principles for Sick Day Management of Adults with Type 1 and Type 2 Diabetes. Canberra, ACT, Australia: Australian Diabetes Educators Association; 2016.
- 20, , , , , . ISPAD Clinical Practice Consensus Guidelines 2018: sick day management in children and adolescents with diabetes. Pediatr Diabetes. 2018; 19(Suppl 27): 193-204.
- 21 Seattle Children's Hospital. In: K Ness, JB Hrachovec, K Klee, MG Leu, J Magin, eds. Insulin Sick Day Management for Diabetes (Non-DKA) Pathway. Seattle, WA: Seattle Children's Hospital; 2013.
- 22, , , et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017; 5: 864-876.
- 23, , , et al; DEPICT-1 InvestigatorsEfficacy and safety of Dapagliflozin in patients with inadequately controlled type 1 diabetes: the DEPICT-1 52-week study. Diabetes Care. 2018; 41: 2552-2559.
- 24, , , et al; DEPICT-2 InvestigatorsEfficacy and safety of Dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 24-week results from a randomized controlled trial. Diabetes Care. 2018; 41: 1938-1946.
- 25, , , et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care. 2018; 41: 2560-2569.
- 26, , , et al in vitro properties and in vivo effect on urinary glucose excretion of BI 10773, a novel selective SGLT2 inhibitor. Paper presented at: 69th Scientific Sessions of the American Diabetes Association; 2009; New Orleans, LA.
- 27, , , et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008; 57: 1723-1729.
- 28, , , et al JNJ-28431754/TA-7284, an SGLT inhibitor, lowers blood glucose and reduces body weight in obese and type 2 diabetic animal models. Paper presented at: 69th Scientific Sessions of the American Diabetes Association; 2009; New Orleans, LA.
- 29, , , et al. LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin Pharmacol Ther. 2012; 92: 158-169.
- 30, , , et al. Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release. Am J Physiol Gastrointest Liver Physiol. 2015; 308: G946-G954.
- 31, , , et al. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol. 2014; 306: F188-F193.
- 32, , , et al. Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: the North American inTandem1 Study. Diabetes Care. 2018; 41: 1970-1980.
- 33, , , et al. HbA1c and Hypoglycemia reductions at 24 and 52 weeks with Sotagliflozin in combination with insulin in adults with type 1 diabetes: the European inTandem2 study. Diabetes Care. 2018; 41: 1981-1990.
- 34, , , et al. Effects of Sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med. 2017; 377: 2337-2348.
- 35 Astellas Pharma Inc., Kotobuki Pharmaceutical Co. Ltd. Approval of Suglat® tablets, selective SGLT2 inhibitor, for additional Indication of type 1 diabetes mellitus and additional dosage and administration in Japan. https://www.astellas.com/en/news/14481. Accessed February 25, 2019.
- 36 European Medicines Agency. First Oral Add-on Treatment to Insulin for Treatment of Certain Patients with Type 1 Diabetes. Committee for Medicinal Products for Human Use (CHMP). London, England: European Medicines Agency; 2019.
- 37, , , . Strategy for mitigating DKA risk in patients with type 1 diabetes on adjunctive treatment with SGLT inhibitors: a STICH protocol. Diabetes Technol Ther. 2018; 20: 571-575.
- 38, , , et al. International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with Sodium-Glucose Cotransporter (SGLT) inhibitors. Diabetes Care. 2019; 42(6): 1147-1154.
- 39, , , . Diabetic ketoacidosis in pregnancy. Postgrad Med J. 2003; 79: 454-457.
- 40, , , et al. Fetal outcomes after diabetic ketoacidosis during pregnancy. Diabetes Care. 2017; 40: e77-e79.
- 41. Blood ketones: measurement, interpretation, limitations, and utility in the management of diabetic ketoacidosis. Rev Diabet Stud. 2016; 13: 217-225.