Efficacy and Safety of Dapagliflozin in Patients with Inadequately Controlled Type 1 Diabetes—DEPICT-2 Study

Abstract

The DEPICT-2 trial (NCT02460978) evaluated the efficacy and safety of dapagliflozin (DAPA) as add-on to adjustable insulin (INS) in patients (pts) with inadequately controlled T1D (A1c 7.5-10.5%) over 24 weeks. This phase 3 study randomized pts 1:1:1 to DAPA 5 mg (n=271), 10 mg (n=270) or placebo (PBO; n=272) plus INS. INS dose could be adjusted by the investigator according to self-monitored blood glucose readings, local guidance and individual circumstances. At Week 24, DAPA 5 and 10 mg significantly decreased A1c (0.37% and 0.42% reductions in the DAPA 5 mg and 10 mg groups respectively), total daily insulin dose (TDD), and body weight (Table). As measured by masked continuous glucose monitoring (CGM), mean interstitial glucose, mean amplitude of glucose excursion (MAGE) and mean percent of readings within target glycemic range (>70-≤180 mg/dL) vs. PBO were improved. There was an increase in pts who reduced their A1c by ≥0.5% without severe hypoglycemia (odds ratios [95% CI]: 2.71 [1.81, 4.06] and 3.07 [2.05, 4.60] for DAPA 5 and 10 mg respectively). Hypoglycemic events, including severe hypoglycemia were balanced between treatment groups. There were more adjudicated definite diabetic ketoacidosis (DKA) events on DAPA. In conclusion, DAPA vs. PBO as add-on to INS in pts with T1D was well tolerated, improved glycemic control and decreased variability without increasing hypoglycemia but with more DKA events. Week 24 outcomesDAPA 5 mg + INS (n=271)DAPA 10 mg + INS (n=270)Placebo + INS (n=272)HbA1c, % Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 8.45 (0.69) −0.34 (0.05) −0.37 (−0.49, −0.26) <0.0001. 8.39 (0.67) −0.39 (0.05) −0.42 (−0.53, −0.30) <0.0001. 8.40 (0.63) 0.03 (0.05) . .TDD, IU Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 59.09 (28.05) −8.73 (1.22) −10.78 (−13.73, −7.72) <0.0001. 59.28 (28.21) −9.(1.23) −11.(−14.04, −8.02) <0.0001. 56.45 (25.23) 2.29 (1.39) . .Body weight, kg Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 79.22 (17.21) −3.22 (0.27) −3.21 (−3.96, −2.45) <0.0001. 80.39 (18.51) −3.76 (0.27) −3.74 (−4.49, −2.99) <0.0001. 79.03 (19.05) −0.02 (0.28) . .24-h CGM glucose reading, mg/dL Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 192.67 (28.68) −6.46 (1.83) −15.66 (−20.26, −11.05) <0.0001. 191.53 (28.09) −10.54 (1.83) −19.74 (−24.34, −15.14) <0.0001. 190.89 (28.95) 9.20 (1.85) . .MAGE during 24-h CGM, mg/dL Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 169.35 (29.60) −10.17 (1.90) −9.85 (−14.66, −5.03) <0.0001. 171.02 (29.85) −9.68 (1.91) −9.36 (−14.16, −4.55) 0.0001. 168.38 (29.29) −0.33 (1.93) . .24-h interstitial glucose values within >70-≤180 mg/dL, % Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 43.50 (12.43) 5.92 (0.82) 9.02 (6.97, 11.06) <0.0001. 43.68 (11.83) 7.60 (0.82) 10.70 (8.66, 12.74) <0.0001. 43.53 (12.55) −3.10 (0.83) . .Safety data (patients with an event) ≥1 AE, n (%) ≥1 SAE, n (%) ≥1 related SAE, n (%) ≥1 event of hypoglycemia, n (%) ≥1 event of severe hypoglycemia, n (%) Definite DKA, n (%). 197 (72.7) 18 (6.6) 13 (4.8) 223 (82.3) 17 (6.3) 7 (2.6). 181 (67.0) 7 (2.6) 3 (1.1) 231 (85.6) 23 (8.5) 6 (2.2). 172 (63.2) 5 (1.8) 2 (0.7) 234 (86.0) 21 (7.7) 0 Disclosure C. Mathieu: Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novartis AG. Advisory Panel; Self; Novartis AG, Bristol-Myers Squibb Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca, Pfizer Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Hanmi Pharmaceutical. Research Support; Self; Roche Diagnostics Corporation. Advisory Panel; Self; Roche Diagnostics Corporation. Research Support; Self; Medtronic. Advisory Panel; Self; Medtronic, MannKind Corporation. Research Support; Self; Intrexon. Advisory Panel; Self; Intrexon, Dianax, UCB, Inc.. Research Support; Self; Abbott. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. P. Gillard: None. P.A. Senior: Consultant; Self; Abbott, AstraZeneca. Research Support; Self; AstraZeneca, Prometic Life Sciences Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc., Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., Abbott. Research Support; Self; Viacyte, Inc.. C. Hasslacher: None. E. Araki: Speaker's Bureau; Self; Astellas Pharma US, Inc., MSD K.K., Kowa Pharmaceuticals America, Inc., Sanofi, Novo Nordisk Inc.. Research Support; Self; Astellas Pharma US, Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Takeda Pharmaceuticals U.S.A., Inc., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Sanofi, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama?Pharmaceutical Co. M. Lind: Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eli Lilly and Company. Advisory Panel; Self; MSD K.K.. Research Support; Self; Pfizer Inc.. Consultant; Self; Medtronic. S.C. Bain: Research Support; Self; Novo Nordisk Inc., AstraZeneca. S. Jabbour: None. N. Arya: Employee; Self; AstraZeneca. F.A. Thoren: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca.