Use of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 1 Diabetes and Rates of Diabetic Ketoacidosis

Abstract

To estimate real-world off-label use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 1 diabetes, estimate rates of diabetic ketoacidosis (DKA), and compare them with DKA rates observed in sotagliflozin clinical trials. RESEARCH DESIGN AND METHODSWe identified initiators of SGLT2 inhibitors in the Sentinel System from March 2013 to June 2018, determined the prevalence of type 1 diabetes using a narrow and a broad definition, and measured rates of DKA using administrative claims data. Standardized incidence ratios (SIRs) were calculated using age-and sexspecific follow-up time in Sentinel and age-and sex-specific DKA rates from sotagliflozin trials 309, 310, and 312. RESULTSAmong 475,527 initiators of SGLT2 inhibitors, 0.50% and 0.92% met narrow and broad criteria for type 1 diabetes, respectively. Rates of DKA in the narrow and broad groups were 7.1/100 person-years and 4.3/100 person-years, respectively. Among patients who met narrow criteria for type 1 diabetes, rates of DKA were highest for patients aged 25-44 years, especially females aged 25-44 years (19.7/100 person-years). More DKA events were observed during off-label use of SGLT2 inhibitors in Sentinel than would be expected based on sotagliflozin clinical trials (SIR 5 1.83; 95% CI 1.45-2.28). CONCLUSIONSReal-world off-label use of SGLT2 inhibitors among patients with type 1 diabetes accounted for a small proportion of overall SGLT2 inhibitor use. However, the risk for DKA during off-label use was notable, especially among young, female patients. Although real-word rates of DKA exceeded the expectation based on clinical trials, results should be interpreted with caution due to differences in study methods, patient samples, and study drugs.Inhibition of sodium-glucose cotransporter 2 (SGLT2) in the proximal tubules suppresses renal glucose reabsorption, resulting in urinary glucose excretion and lowering of blood glucose in patients with diabetes. Canagliflozin (1), dapagliflozin (2), empagliflozin (3), and ertugliflozin (4) are SGLT2 inhibitors indicated as adjuncts to diet and exercise to improve glycemic control in adults with type 2 diabetes. Because of proven cardiovascular benefits (5,6

Risk of amputation with canagliflozin across categories of age and cardiovascular risk in three US nationwide databases: cohort study

“…These characteristics were selected because they could be associated with directing drugs to a specific patient group. For example, some patients with type 1 diabetes in the US are prescribed SGLT2 inhibitors off label 19. Similar to the CANVAS Program, patients with a prior amputation were not excluded.…”

Multicenter, open-label, two-arm pilot trial for safety reduction of basal insulin dose combined with SGLT2 inhibitor in type 1 diabetes mellitus: A study protocol for RISING-STAR

“…The U.S. Food and Drug Administration estimates that one additional case of ketoacidosis occurs every 26 years when patients with type 1 diabetes are treated with sotagli ozin. Assuming a case fatality rate of 0-4%, this estimate corresponds to 16 additional deaths per year per 100,000 patients with type 1 diabetes treated (31,32). Thus, although a reduction in basal insulin dose in SGLT2 inhibitor therapy in type 1 diabetes is bene cial in the prevention of hypoglycemia, there is a risk of increasing the risk of diabetic ketoacidosis [17].…”

Using real‐world safety data in regulatory approval decisions: Sotagliflozin and the risk of diabetic ketoacidosis

“…Sotagliflozin, a dual inhibitor of sodium-glucose cotransporter 1 (SGLT1) and sodiumglucose cotransporter 2 (SGLT2), provides a contemporary example of how real-world data can be effectively considered during the drug approval process. 3,4 The first-discovered SGLT1/SGLT2 inhibitor was phlorizin. It is a naturally occurring glucoside found in the root bark of fruit trees and was first isolated in the late 1800s.…”

“…1 The FDA did that exactly. 3,4 Using a distributed data network with data from over 100 million patients through the Sentinel Initiative, the FDA identified that up to 1% of prescriptions for SGLT2 inhibitors were for patients with type 1 diabetes. 3,4 In this population, the rate of DKA was about 7 per 100 person-years, and as high as 20 per 100 personyears among women aged of 25 to 44 years.…”

“…3,4 Using a distributed data network with data from over 100 million patients through the Sentinel Initiative, the FDA identified that up to 1% of prescriptions for SGLT2 inhibitors were for patients with type 1 diabetes. 3,4 In this population, the rate of DKA was about 7 per 100 person-years, and as high as 20 per 100 personyears among women aged of 25 to 44 years. 3 These data help provide rough estimates for the rate of DKA in routine care if sotagliflozin were to be used and suggest the rate of DKA might be higher than the estimates from the randomized trials (5 per 100 person-years).…”