TY - JOUR
T1 - Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1)
T2 - 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial
AU - DEPICT-1 Investigators
AU - Dandona, Paresh
AU - Mathieu, Chantal
AU - Phillip, Moshe
AU - Hansen, Lars
AU - Griffen, Steven C.
AU - Tschöpe, Diethelm
AU - Thorén, Fredrik
AU - Xu, John
AU - Langkilde, Anna Maria
AU - Proietto, Joseph
AU - Stranks, Stephen
AU - Chen, Roger
AU - O'Neal, David
AU - Pape, Alexia
AU - Forbes, Mark
AU - Morbey, Claire
AU - Luger, Anton
AU - Hanusch, Ursula
AU - Schnack, Christoph
AU - Fliesser-Goerzer, Evelyn
AU - Hoelzl, Bertram
AU - Ebenbichler, Christoph
AU - Prager, Rudolf
AU - Van Gaal, Luc
AU - Vercammen, Chris
AU - Scheen, Andre
AU - Mathieu, Chantal
AU - Duyck, Francis
AU - Nobels, Frank
AU - Ruige, Johannes
AU - Aggarwal, Naresh
AU - Woo, Vincent
AU - St-Pierre, Bruno
AU - Dumas, Richard
AU - Hramiak, Irene
AU - Elliott, Thomas
AU - Krarup Hansen, Troels
AU - Henriksen, Jan Erik
AU - Gram, Jeppe
AU - Lihn, Aina
AU - Bruun, Jens
AU - Saltevo, Juha
AU - Taurio, Jyrki
AU - Strand, Jorma
AU - Valle, Timo
AU - Nieminen, Sakari
AU - Pietilainen, Kirsi
AU - Guerci, Bruno
AU - Hadjadj, Samy
AU - Miranda-Palma, Bresta
N1 - Funding Information:
PD serves on the advisory boards of AstraZeneca, Novo Nordisk, Sanofi, Boehringer Ingelheim, Merck Intarcia, and AbbVie, and has received research grants from all of these companies, apart from Intarcia. CM serves or has served on advisory boards for Novo Nordisk, Sanofi, Merck Sharp and Dohme, Eli Lilly, Novartis, Bristol-Myers Squibb, AstraZeneca, Pfizer, Janssen Pharmaceuticals, Boehringer Ingelheim, Hanmi Pharmaceuticals, Roche Diagnostics, Medtronic, Mannkind, Intrexon, and UCB, and serves or has served on speakers bureaux for Novo Nordisk, Sanofi, Merck Sharp and Dohme, Eli Lilly, Boehringer Ingelheim, AstraZeneca, and Novartis. CM's institute has received research support for CM from Novo Nordisk, Sanofi, Merck Sharp and Dohme, Eli Lilly, Roche Diagnostics, Abbott, Intrexon, and Novartis. MP's institute has received grants or research support from Medtronic, Novo Nordisk, Roche, Eli Lilly, Merck, Sanofi, Bristol-Myers Squibb, Kamada, AstraZeneca, and Lexicon. MP has received honoraria or consultation fees from Sanofi, Medtronic, Novo Nordisk, and Eli Lilly; has participated in advisory boards for Sanofi, Medtronic, AstraZeneca, and Eli Lilly; and is a stock shareholder in DreaMed Diabetes. LH is an employee and shareholder of Bristol-Myers Squibb. DT has served on advisory boards for AstraZeneca, Amgen, Eli Lilly, Novo Nordisk and Servier; has given lectures for AstraZeneca, Bayer, Eli Lilly, Novo Nordisk, Novartis, Sanofi, and Servier; and has received research grants from AstraZeneca, Bayer, Eli Lilly, Novo Nordisk, Novartis, and Sanofi. FT is an employee of AstraZeneca. JX and AML are employees and shareholders of AstraZeneca. SCG declares no competing interests.
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/11
Y1 - 2017/11
N2 - Background Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. Methods DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18–75 years and had inadequately controlled type 1 diabetes (HbA1c between ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA1c. The primary efficacy outcome was the change from baseline in HbA1c after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. Findings Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA1c was 8·53% (70 mmol/mol; SD 0·67% [7·3 mmol/mol]). At week 24, both doses of dapagliflozin significantly reduced HbA1c compared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was −0·42% [95% CI −0·56 to −0·28; p<0·0001] and for dapagliflozin 10 mg vs placebo was −0·45% [−0·58 to −0·31; p<0·0001]). Among patients in the dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), and placebo (n=260) groups, the most common adverse events were nasopharyngitis (38 [14%] vs 36 [12%] vs 39 [15%]), urinary tract infection (19 [7%] vs 11 [4%] vs 13 [5%]), upper respiratory tract infection (15 [5%] vs 15 [5%] vs 11 [4%]), and headache (12 [4%] vs 17 [6%] vs 11 [4%]). Hypoglycaemia occurred in 220 (79%), 235 (79%), and 207 (80%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups, respectively; severe hypoglycaemia occurred in 21 (8%), 19 (6%), and 19 (7%) patients, respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%) patients in the dapagliflozin 5 mg group, five (2%) in the dapagliflozin 10 mg group, and three (1%) in the placebo group. Interpretation Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycaemic control in patients with inadequately controlled type 1 diabetes. Funding AstraZeneca and Bristol-Myers Squibb.
AB - Background Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. Methods DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18–75 years and had inadequately controlled type 1 diabetes (HbA1c between ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA1c. The primary efficacy outcome was the change from baseline in HbA1c after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. Findings Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA1c was 8·53% (70 mmol/mol; SD 0·67% [7·3 mmol/mol]). At week 24, both doses of dapagliflozin significantly reduced HbA1c compared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was −0·42% [95% CI −0·56 to −0·28; p<0·0001] and for dapagliflozin 10 mg vs placebo was −0·45% [−0·58 to −0·31; p<0·0001]). Among patients in the dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), and placebo (n=260) groups, the most common adverse events were nasopharyngitis (38 [14%] vs 36 [12%] vs 39 [15%]), urinary tract infection (19 [7%] vs 11 [4%] vs 13 [5%]), upper respiratory tract infection (15 [5%] vs 15 [5%] vs 11 [4%]), and headache (12 [4%] vs 17 [6%] vs 11 [4%]). Hypoglycaemia occurred in 220 (79%), 235 (79%), and 207 (80%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups, respectively; severe hypoglycaemia occurred in 21 (8%), 19 (6%), and 19 (7%) patients, respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%) patients in the dapagliflozin 5 mg group, five (2%) in the dapagliflozin 10 mg group, and three (1%) in the placebo group. Interpretation Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycaemic control in patients with inadequately controlled type 1 diabetes. Funding AstraZeneca and Bristol-Myers Squibb.
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U2 - 10.1016/S2213-8587(17)30308-X
DO - 10.1016/S2213-8587(17)30308-X
M3 - Article
C2 - 28919061
AN - SCOPUS:85029446459
VL - 5
SP - 864
EP - 876
JO - The Lancet Diabetes and Endocrinology
JF - The Lancet Diabetes and Endocrinology
SN - 2213-8587
IS - 11
ER -