Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, appeared to help improve glucose control as an adjunct to insulin in patients with inadequately controlled type 1 diabetes, an industry-funded trial found.
Researchers performed a double-blind, randomized, parallel-controlled study at 143 sites in 17 countries to examine the safety and efficacy of dapagliflozin when added to adjustable insulin therapy. Patients were eligible for the trial if they were 18 to 75 years of age, had type 1 diabetes that was inadequately controlled (defined as an HbA1c level ≥7.7% and ≤11.0%), and had been prescribed insulin for at least two months. The study used an eight-week lead-in period to optimize diabetes management and to determine variability in blood glucose profiles as well as frequency of hypoglycemic events. Patients were then randomly assigned to receive oral dapagliflozin, 5 mg or 10 mg once daily, or matched placebo.
The full analysis set, made up of all randomly assigned patients who received at least one dose of the study medication, was used to assess the primary efficacy outcome, which was the change in HbA1c level after 24 weeks of treatment. The safety analysis set included the full analysis set plus another 55 patients who were erroneously, nonrandomly allocated to only dapagliflozin groups. The results of the study, which was funded by AstraZeneca and Bristol-Myers Squibb, were published online Sept. 14 by Lancet Diabetes & Endocrinology.
A total of 833 patients were assigned to treatment groups and were included in safety analyses. Two hundred seventy-seven patients were assigned to dapagliflozin, 5 mg; 296 patients were assigned to dapagliflozin, 10 mg; and 260 patients were assigned to placebo. Of these 833 patients, 778 were included in the full analysis set (259, 259, and 260 patients in each treatment group, respectively). More women than men were assigned to receive 5 mg of dapagliflozin (57% vs. 43%), but otherwise all groups had similar baseline and demographic characteristics. Mean HbA1c level at baseline was 8.53%. All patients were given a combined home glucose and ketone meter and instructed to measure glucose four times daily and ketones whenever glucose concentrations were consistently elevated.
At week 24, both the 5-mg and 10-mg doses of dapagliflozin were associated with significant decreases in HbA1c level versus placebo (−0.42% for the 5-mg dose and −0.45% for the 10-mg dose, respectively; P<0.0001 for both comparisons), as well as with decreases in body weight (−2.96% and −3.72% vs. placebo, respectively; P<0.0001 for both comparisons) and significant reductions in total daily insulin dose. The most common adverse events were nasopharyngitis, urinary tract infection, upper respiratory tract infection, and headache. Hypoglycemia occurred in 79%, 79%, and 80% of the 5-mg, 10-mg, and placebo groups, respectively; severe hypoglycemia occurred in 8%, 6%, and 7%, respectively. The study drug was discontinued due to hypoglycemia in two patients, one in the 5-mg group and one in the placebo group. Four patients in the 5-mg group (1%), five patients in the 10-mg group (2%), and three patients in the placebo group (1%) developed diabetic ketoacidosis.
The authors acknowledged that the treatment period was relatively short, that patients with common comorbid conditions were excluded from the study, and that outcomes of sensitivity analyses should be considered when examining overall efficacy, among other limitations. However, they concluded that oral dapagliflozin as add-on therapy appeared to yield improvements in HbA1c and weight loss in patients with type 1 diabetes that was inadequately controlled with insulin.
“Overall, similarly to studies in type 2 diabetes, dapagliflozin was well tolerated when used as an add-on to adjustable insulin, with no new safety signals identified,” the authors wrote. “Our results suggest that dapagliflozin is a promising adjunct treatment to insulin in patients with type 1 diabetes.”
The author of an accompanying comment said that the study provides encouraging short-term data supporting the efficacy of adjunct therapy with SGLT2 inhibitors in patients with type 1 diabetes and may also offer insights on minimizing ketoacidosis, since rates of that complication were low. The comment author also observed that ketoacidosis in the 10-mg group might have been more severe as all five of the participants with ketoacidosis discontinued the trial, whereas only one of the four participants in the 5-mg group and none of the three in the placebo group discontinued. The comment author also pointed out that a 28-week extension phase of the trial is under way and noted that follow-up exceeding a year would be preferred, since effects of adjunct therapies in type 1 diabetes are often short-lived. Based on the current study's results, he wrote, “adjunct therapy with SGLT2 inhibitors might be appropriate for individuals who have a good understanding of the early warning signs of ketoacidosis, undertake regular home monitoring (including of blood ketones), and have a high level of self-monitoring and communication with their diabetes team.”