AIM: Dapagliflozin could benefit type 2 diabetics
“Nearly one in four patients with type 2 diabetes mellitus eventually requires insulin therapy because of progressive deterioration of glycemic control,” John P.H. Wilding, DM, of the University Hospital Aintree in Liverpool, U.K., and colleagues wrote. “However, patients with inadequately controlled diabetes despite substantial doses of insulin are particularly challenging to treat.”
In January, the FDA put a hold on AstraZeneca and Bristol-Myers Squibb's dapagliflozin for the treatment of type 2 diabetes and asked for clinical data that showed a better assessment of the risk-benefit profile. The drug is under development to be used as an adjunct treatment to diet and exercise and is being looked at to help improve glycemic control in diabetic patients. Additionally, the agency requested clinical trial data from ongoing studies to help determine the next step for the drug application.
To understand the safety of dapagliflozin, a sodium-glucose cotransporter inhibitor, in type 2 diabetes patients whose insulin is poorly controlled with or without antidiabetic drugs, Wilding et al conducted a 24-week randomized, placebo-controlled trial at 126 centers in Europe and North America between April 30, 2008, and Nov. 19, 2009. The study included 808 patients. The patients received at least 30 U of insulin per day. The patients were assigned to a 1:1:1:1 ratio to receive placebo or 2.5 mg, 5 mg or 10 mg of dapagliflozin once daily for 48 weeks.
The authors used the change in HbA1c from baseline to week 24 as the study’s primary endpoint.
Wilding et al reported mean duration of insulin therapy to be six years and the mean daily insulin dose to be 77.1 U. Of the 808 patients enrolled, 17 percent were on long-acting basal insulin and 83 percent were using a sliding scale bolus. Fifty percent of patients received other drugs, mostly metformin, in addition to insulin. The mean baseline HbA1c level was reported to be 8.53 percent; mean fasting plasma glucose was reported to be 9.9 mmol/L.
After evaluation, a rapid decrease in mean HbA1c levels was seen during the first eight weeks with dapagliflozin. These differences were greater in patients taking dapagliflozin compared with placebo at 24 weeks. This difference was maintained over the 48-week period. HbA1c levels were reduced by 0.54 percent in patients administered 10 mg of dapagliflozin compared with those administered placebo at 48 weeks.
HbA1c levels decreased 0.79 percent to 0.96 percent with dapagliflozin compared with 0.39 percent with placebo at 24 weeks. The daily insulin dose decreased 0.63 to 1.95 U with dapagliflozin and increased to 5.65 U with placebo.
Patients administered dapagliflozin saw a decreased body weight; body weight increased for patients on placebo.
Additionally, at 24 weeks, 9.7 percent to 11.2 percent of patients administered dapagliflozin needed insulin up-titration or discontinued the study due to poor glycemic control. Patients administered dapagliflozin had higher incidences of hypoglycemic events compared with those administered placebo. These rates were 60.4 percent in the 2.5 mg group, 55.7 percent in the 5 mg group and 53.6 percent in the 10 mg group compared with 51.8 percent in those administered placebo.
“In our 48-week study, dapagliflozin improved glycemic control, prevented insulin dose escalation, and produced significant and sustained weight loss,” the authors wrote.
Diabetes has been known to increase the incidence of genital infection and urinary tract infection in women. In the current study, the authors found dapagliflozin to be associated with increased symptoms of genital infection and urinary tract infection during the first 24 weeks of study.
The researchers cited the fact that insulin doses were not titrated to target as a limitation of the study.
“In conclusion, in patients whose type 2 diabetes mellitus was inadequately controlled with insulin therapy, adding dapagliflozin reduced HbA1c levels and weight over 48 weeks without increasing overall insulin dose; however, increased rates of minor hypoglycemia were noted. Conversely, patients for whom placebo was added to insulin therapy had a progressive increase in insulin dose and weight.,” the authors summed. “These data suggest that dapagliflozin may offer a new treatment option for patients receiving insulin therapy whose type 2 diabetes remains inadequately controlled.”
"Dapagliflozin, the first in the class of selective renal sodium-glucose cotransporter inhibitors, offers a novel, insulin-independent mechanism of action for diabetes treatment," wrote Steven A. Smith, MD, of the Mayo College of Medicine in Rochester, Minn., in an accompanying editorial. "Dapagliflozin seems to be less effective in patients with renal disease," Smith added. He noted that future drug approval would most likely be restricted to patients with normal or only minimally repaired renal function.
"Studies with long-term follow-up are needed to determine the true effect of dapagliflozin on renal disease and controlled or uncontrolled glycemia in diabetes," Smith concluded.