This column highlights clinical trial data and landmark trials. Information for obtaining trial data and the references to the published articles are provided to facilitate discussion with your patients/colleagues. The trial is identified by the acronym and the National Clinical Trials Identifier. Primary outcome results are summarized.
Study Title: Efficacy and Safety of Dapagliflozin in Patients with Inadequately Controlled Type 1 Diabetes: The DEPICT-1 52-Week Study
Study title acronym: DEPICT-1
ClinicalTrials.gov identifier: NCT02268214
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.
2. 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.
Sponsor: AstraZeneca and Bristol-Myers Squibb
Study design: A multicenter, three-arm, parallel-group, phase 3 study that enrolled 833 adult participants with type 1 diabetes (T1D), ages 18-75 years with inadequate glycemic control (hemoglobinA1c [A1C] 7.5 to 10.5%) randomized 1:1:1 to treatment with once daily oral dapagliflozin 5 mg (n=277), 10 mg (n=296), or placebo (n=260), as add-on to adjustable insulin therapy. This 52-week blinded intervention study included a 24-week double-blinded short-term study (n=833)2 followed by a 28-week extension study (n=747 of original 833) to provide longer-term safety and efficacy data.
Primary outcomes: Change in A1C, percent change in total daily insulin dose and body weight, from baseline to week 52.
Other outcomes: Secondary outcomes assessed from baseline to week 52 included: 1) proportion of patients achieving an A1C reduction ≥0.5% with or without severe hypoglycemia; 2) proportion of patients with A1C < 7.0%; 3) change in fasting plasma glucose; 4) change in seated systolic blood pressure (SBP) among participants with baseline hypertension; and 5) cumulative safety outcomes data.
Results: Over 52 weeks of treatment, dapagliflozin (5 versus 10 versus placebo) as an adjunct to adjustable insulin therapy resulted in: 1) a clinically relevant reduction in A1C (8.2%, 8.2%, 8.5%; percent change: -0.27%, -0.31%, +0.06%, respectively); 2) a reduction in body weight (weight change: -2.31 kg, -3.65 kg, +0.25 kg; percent change: -2.80%, -4.39%, +0.15%); and 3) a significant reduction in total daily insulin. Additionally, patients treated with dapagliflozin experienced a greater reduction in fasting glucose and were more likely to achieve an A1C <7.0% or a ≥0.5% reduction in A1C without severe hypoglycemia (40.2%, 42.1%, 23.7%, respectively). These improvements came at the cost of slightly higher incidence of adverse events with dapagliflozin (13.4%, 13.5%, 11.5% of patients, respectively). Genital infections (more frequent in females than males) were increased with dapagliflozin (F/M: 21.5%/7.6%, 18.8%/8.6%, 6.3%/0%, respectively). Unlike the initial 24-week data from this trial2, diabetic ketoacidosis (DKA) events were unequivocally more common (4.0%, 3.4%, 1.9%, respectively).
Summary: An increasing number of studies are now reporting on the efficacy of sodium-glucose co-transporter 2 inhibitors as add-on to insulin in T1D over ~24 to 26 weeks of treatment. This study presents longer-term data with dapagliflozin to confirm yearlong improvements in glycemic control without hypoglycemia, accompanied by a sustained decrease in body weight. The increased risk for DKA, evident across a 52-week study (primarily related to missed or interrupted insulin administration), might result from delayed recognition of ketosis at lower glucose values. Therefore, the risk for DKA is a significant concern but perhaps preventable with increased education of both patients and health-care professionals regarding stricter attention to potential ketosis.
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About our experts: Kathryn Thrailkill, MD, Professor of Pediatrics, Division of Pediatric Endocrinology, Barnstable Brown Endowed Chair in Pediatric Diabetes Research, Barnstable Brown Diabetes Center, University of Kentucky, Lexington, Kentucky
Derick Adams, DO, Assistant professor, internal medicine, Division of Endocrinology, Endocrinology Fellowship associate program director, Barnstable Brown Diabetes Center, University of Kentucky, Lexington, Kentucky