2876-LB: Triple Therapy for Type 1 Diabetes with Insulin, Semaglutide, and Dapagliflozin (TTT1): A Phase 3 Clinical Trial

Introduction and Objective: Adjunct therapy with non-insulin glucose-lowering agents is an attractive therapeutic strategy in type 1 diabetes (T1D) but carries risks of hypoglycemia and ketosis. We assessed the efficacy and safety of adding semaglutide weekly injection and oral dapagliflozin in with insulin therapy in overweight (BMI > 25 kg/m2) adults with T1D and HbA1c 7.5 - 11.0 % inclusive. Methods: In Period 1 (weeks 1 to 26) participants were randomized 2:1 (open label) to standard of care (SOC) insulin treatment with or without semaglutide (uptitrated to 1.0 mg weekly); in Period 2 (weeks 26 to 52), those randomized to semaglutide were further randomized (double-blind) to dapagliflozin (10 mg daily) or placebo. The primary outcome was change in HbA1c in Period 2. Hypoglycaemia and ketoacidosis were key safety outcomes. Analysis was by intention-to-treat. Results: 78 adults with T1D (aged 45±13.7 years, 51% female, HbA1c 8.3±0.7%, BMI 33±6.1 kg/m2) were randomized in Period 1 and 36 in Period 2. In Period 1, HbA1c was reduced by 0.45% (95% CI -0.78, -0.127; p=0.0072) and body weight was reduced by 10.2 kg (95% CI -12.8, - 7.7; p<0.0001) by semaglutide vs SOC. In Period 2, HbA1c was further reduced by 0.46% (95% CI -0.78, -0.14; p=0.003) by dapagliflozin vs placebo (primary outcome) but body weight was not further reduced (-1.0 kg; 95% CI -2.72, 0.66; p=0.2219). Over Periods 1&2 (52 weeks), HbA1c was reduced by 0.36% (95% CI -0.67, -0.05; p=0.0235) in those randomized to semaglutide and dapagliflozin vs SOC. Time below Range was not affected by either treatment but more Level 2 hypoglycemia events occurred on semaglutide than on SOC in Period 1 [17 vs 9 events per patient year, incidence rate ratio 2.6, 95% CI 1.4, 5.0, p=0.0047). One episode of ketoacidosis occurred in a participant randomized to placebo in Period 2. Conclusion: Semaglutide adjunct therapy reduced HbA1c and body weight in overweight adults with T1D; HbA1c was further reduced by addition of dapagliflozin. Semaglutide was associated with an initial excess of Level 2 hypoglycemia. Disclosure H.A. Ghanim: None. J.G. Timmons: None. N. Greenlaw: Other - Grant to my institution for the TTT1 study; Current; JDRF. A. McConnachie: None. A. Chaudhuri: Consultant; Current; Lilly. Research Support; Current; Lilly. Consultant; Current; Novo Nordisk. Research Support; Current; Novo Nordisk, AbbVie Inc., Inventiva Pharma, Akero Therapeutics, Inc. M.A. Batra: None. J.G. Boyle: None. P.A. Dandona: None. J.R. Petrie: Other - Endpoint Committee Member; Current; Boehringer Ingelheim International GmbH, IQVIA Inc. Research Support; Ended; Merck KGaA, Novo Nordisk A/S. Other - Travel support; Ended; Sanofi. Advisory Panel; Ended; Sanofi. Other - Donation and discounting of sensors for use in clinical trial; Ended; Dexcom, Inc. Funding Breakthrough-T1D (3-SRA-2019-669-M-B)