Automated Insulin Delivery with SGLT2i Combination Therapy in Type 1 Diabetes

Abstract

Background: Use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as adjunct therapy to insulin in type 1 diabetes (T1D) has been previously studied. In this study, we present data from the first free-living trial combining low-dose SGLT2i with commercial automated insulin delivery (AID) or predictive low glucose suspend (PLGS) systems. Methods: In an 8-week, randomized, controlled crossover trial, adults with T1D received 5 mg/day empagliflozin (EMPA) or no drug (NOEMPA) as adjunct to insulin therapy. Participants were also randomized to sequential orders of AID (Control-IQ) and PLGS (Basal-IQ) systems for 4 and 2 weeks, respectively. The primary endpoint was percent time-in-range (TIR) 70-180 mg/dL during daytime (7:00-23:00 h) while on AID (NCT04201496). Findings: A total of 39 subjects were enrolled, 35 were randomized, 34 (EMPA; n = 18 and NOEMPA n = 16) were analyzed according to the intention-to-treat principle, and 32 (EMPA; n = 16 and NOEMPA n = 16) completed the trial. On AID, EMPA versus NOEMPA had higher daytime TIR 81% versus 71% with a mean estimated difference of +9.9% (confidence interval [95% CI] 0.6-19.1); p = 0.04. On PLGS, the EMPA versus NOEMPA daytime TIR was 80% versus 63%, mean estimated difference of +16.5% (95% CI 7.3-25.7); p < 0.001. One subject on SGLT2i and AID had one episode of diabetic ketoacidosis with nonfunctioning insulin pump infusion site occlusion contributory. Interpretation: In an 8-week outpatient study, addition of 5 mg daily empagliflozin to commercially available AID or PLGS systems significantly improved daytime glucose control in individuals with T1D, without increased hypoglycemia risk. However, the risk of ketosis and ketoacidosis remains. Therefore, future studies with SGLT2i will need modifications to closed-loop control algorithms to enhance safety.

Keywords: Automated insulin infusion; Free-living conditions; Sodium-glucose cotransporter 2 inhibitor; Type 1 diabetes.

Conflict of interest statement

J.G. reports receiving industry research support and royalties from Dexcom through his institution. L.F. reports receiving industry research support from NovoNordisk and Dexcom through his institution. B.K. reports receiving a grant from the National Institutes of Health (NIH) and material support from Tandem Diabetes Care, related to the study; grants from Dexcom, Novo Nordisk, and Sanofi, outside the submitted work; and consulting fees from Sanofi and Tandem Diabetes Care, and reports having received speaking honoraria from Dexcom.

B.K. has patents (Nos. 8562587 and 9750438 B2) for continuous glucose monitor-based prevention of hypoglycemia by hypoglycemia risk assessment and smooth reduction of insulin delivery, with royalties paid to Dexcom, and a patent (No. 9430022 B2) for a method and apparatus for modular power management and protection of critical services in ambulatory medical devices, with royalties paid to Dexcom. A.B. reports receiving grant or material support from Tandem Diabetes Care and Dexcom as supplies for the study. No other potential conflicts of interest relevant to this article were reported.

Figures

FIG. 1.

Trial profile.

FIG. 2.

Detailed CIQ-EMPA versus CIQ-NOEMPA contrast with respect to TIR and CGM for each hour of the day. (A) An envelope plot of the percent time in the target range according to the time of day. (B) Postrandomization hourly median sensor glucose with interquartile envelope. Green lines represent the 70 and 180 mg/dL glycemic levels. Data points (thick lines) denote the hourly median values, and the lower and upper boundary of each shaded region the 25th and 75th percentiles, respectively. CGM, continuous glucose monitor; CIQ, Control-IQ™; EMPA, empagliflozin; NOEMPA, no drug; TIR, time-in-range.