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. 2020 Nov;22(11):2151-2160.
doi: 10.1111/dom.14144. Epub 2020 Aug 20.

Benefit/risk profile of dapagliflozin 5 mg in the DEPICT-1 and -2 trials in individuals with type 1 diabetes and body mass index ≥27 kg/m2

Chantal Mathieu  1 , Paresh Dandona  2 , Andreas L Birkenfeld  3   4   5 , Troels Krarup Hansen  6 , Nayyar Iqbal  7 , John Xu  7 , Enrico Repetto  8 , Markus Florian Scheerer  9 , Fredrik Thoren  10 , Moshe Phillip  11   12
Affiliations

Benefit/risk profile of dapagliflozin 5 mg in the DEPICT-1 and -2 trials in individuals with type 1 diabetes and body mass index ≥27 kg/m2

Chantal Mathieu et al. Diabetes Obes Metab. 2020 Nov.

Abstract

Aim: The DEPICT-1 and -2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of dapagliflozin in individuals with type 1 diabetes who were receiving intensive insulin therapy. The DEPICT-1 and -2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of dapagliflozin in individuals with type 1 diabetes. This post-hoc study investigated the safety and efficacy of dapagliflozin in individuals with BMI ≥27 kg/m2 to assess if the benefit/risk ratio associated with dapagliflozin treatment can be further improved than that observed in the overall DEPICT population.

Methods: Changes in glycated haemoglobin (HbA1c) and body weight, percentage change in daily insulin dose and proportion of participants achieving HbA1c reduction ≥0.5% without severe hypoglycaemia were evaluated at weeks 24 and 52. Changes in mean interstitial glucose, mean amplitude of glycaemic excursions and time in target glycaemic range were evaluated at week 24. Safety was assessed until week 56.

Results: Week-52 adjusted mean (SE) change from baseline for HbA1c was -0.26% (0.05) with dapagliflozin versus +0.08% (0.05) with placebo and for body weight was -2.74 kg (0.25) with dapagliflozin versus +0.81 kg (0.26) with placebo. Mean (SE) percentage change in daily insulin dose was -10.5% (1.23) with dapagliflozin versus -1.4% (1.36) with placebo. Time spent in target glycaemic range increased by 2.2 h/day versus placebo. Dapagliflozin was well tolerated, with fewer participants experiencing diabetic ketoacidosis (dapagliflozin, 1.7%; placebo, 1.0%) than dapagliflozin 5 mg receiving participants in the pooled DEPICT populations.

Conclusions: Compared with the pooled DEPICT population, the benefit/risk profile of adjunct dapagliflozin therapy was more favourable in individuals with type 1 diabetes with body mass index ≥27 kg/m2 because of the reduced risk of diabetic ketoacidosis in this population.

Keywords: BMI; DEPICT; DKA; HbA1c; T1D; benefit/risk; body weight; dapagliflozin; type 1 diabetes.

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Conflict of interest statement

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. 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. ALB has served on advisory boards for Novo Nordisk, Sanofi, Merck Sharp and Dohme, AstraZeneca and Boehringer Ingelheim; and has served on speakers bureaux for Novo Nordisk, Sanofi, Eli Lilly, Boehringer Ingelheim and AstraZeneca. TKH has served on advisory boards for Novo Nordisk, Sanofi, Merck Sharp and Dohme, AstraZeneca, Abbott, and Boehringer Ingelheim. NI is an employee of AstraZeneca. JX is an employee and shareholder of AstraZeneca. ER is an employee of AstraZeneca. MFS was an employee of AstraZeneca during the preparation of this manuscript and is currently employed at Bayer pharmaceuticals. FT is an employee of AstraZeneca. 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.

Figures

FIGURE 1
FIGURE 1
Study design for the DEPICT‐1 and ‐2 studies. Total daily insulin dose recommended to be reduced by up to 20% on Day 1, before attempting to titrate back to baseline levels taking into account self‐monitored blood glucose, local guidance and individual circumstances. BMI, body mass index; CGM, continuous glucose monitoring; HbA1c, glycated haemoglobin; LT, long term; R, randomization; ST, short term; T1D, type 1 diabetes; W, week
FIGURE 2
FIGURE 2
Efficacy endpoints in patients with BMI≥27 kg/m2. A, Change from baseline to week 52 in HbA1c, B, change from baseline to week 52 in body weight, C, time in target glycaemic range at week 24, and D, proportion of participants achieving a reduction in HbA1c ≥0.5% without experiencing severe hypoglycaemia at week 24 and week 52. Mixed model included terms for baseline, treatment, study, week, stratum, week*treatment, week*baseline, subgroup, treatment*subgroup, week*subgroup and treatment*week*subgroup. Stratum includes one term for each combination of the three stratification factors on baseline HbA1c, use of personal continuous glucose monitoring system and methods of insulin administration. Bars show SE in Figure 1A,B). aUnadjusted P‐value indicated in Figure 1D and logistic regression adjusted for baseline HbA1c, study and randomization strata. DAPA, dapagliflozin; HbA1c, glycated haemoglobin; T1D, type 1 diabetes
See this image and copyright information in PMC

References

    1. Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT‐1): 24 week results from a multicentre, double‐blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(11):864‐876. - PubMed
    1. Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: the DEPICT‐1 52‐week study. Diabetes Care. 2018;41(12):2552‐2559. - PubMed
    1. Mathieu C, Dandona P, Gillard P, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT‐2 study): 24‐week results from a randomized controlled trial. Diabetes Care. 2018;41(9):1938‐1946. - PubMed
    1. Mathieu C, Rudofsky G, Phillip M, et al. Long‐term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT‐2 study): 52‐week results from a randomized controlled trial. Diabetes Obes Metab. 2020:1–11. 10.1111/dom.14060. - DOI - PMC - PubMed
    1. Dandona P, Mathieu C, Phillip M, et al. Dapagliflozin in Type 1 Diabetes: Pooled Outcomes from DEPICT‐1 and ‐2. San Francisco, CA: American Diabetes Association; 2019.

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