ADA: SGLT2 Inhibitor Works in Type 1 Diabetes as Add-on to Insulin

An investigational agent for type 2 diabetes may also work as add-on therapy in type 1 disease….

Robert Henry, MD, of the University of California San Diego, and colleagues reported during a late-breaking poster session that, in a phase IIa trial, patients taking dapagliflozin had improved glycemic control and required less insulin than those on placebo.

Dr. Henry stated that, "We were able to show improvements in both fasting and postprandial glucose, a reduction in excursions of glucose, and a reduction in the need for insulin." "There was hypoglycemia, but it was present in both placebo and drug therapy." "For those patients having trouble getting to goal, this would be an opportunity to just take a pill and help reduce their A1c."

He added that the mechanism of dapagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, would be beneficial in type 1 disease because it is effective even in patients who have impaired kidney function. Its main mechanism of action is to block renal reabsorption of glucose, spilling more blood sugar into the urine.

The FDA declined to approve dapagliflozin in January 2012, citing concerns with breast and bladder cancer risks. It approved another SGLT2 inhibitor, canagliflozin (Invokana), in March. Dapagliflozin drugmakers Bristol-Myers Squibb and AstraZeneca said they will re-submit their application to the FDA by the end of summer.

For their study, Henry and colleagues conducted a 2-week, randomized, double-blind, parallel-group, placebo-controlled, exploratory phase IIa trial looking at the safety and tolerability of dapagliflozin in patients with type 1 diabetes who weren’t well controlled on insulin (mean HbA1c 8.5%).

A total of 70 patients were randomly assigned to either placebo or to one of four daily doses of dapagliflozin (1 mg, 2.5 mg, 5 mg, 10 mg) in addition to their regular insulin regimen; 62 completed the trial. As expected, Henry said, there was a dose-dependent increase in urine glucose for patients on the drug.

Overall, the data suggested the potential for reduced glycemic levels and diminished glycemic variability with dapagliflozin compared with placebo, he reported.

For instance, there was a significant drop in fasting plasma glucose (FPG) from baseline compared with placebo:

• 1 mg: -26.3%
• 2.5 mg: -19.6%
• 5 mg: -42.2%
• 10 mg: -35.7%
• Placebo: -8.1%

But the mean daily plasma glucose derived from 7-point glucose measurements trended downward in all treatment groups, with no differences for the dapagliflozin groups compared with placebo.

On the other hand, there were greater reductions in total daily insulin dosing by the end of the study with all dapagliflozin doses compared with placebo:

• 1 mg: -16%
• 2.5 mg: -11.1%
• 5 mg: -19.3%
• 10 mg: -16.2%
• Placebo: 1.7%

Adverse events were similar across all groups; notably, hypoglycemia occurred to a similar extent in all groups, Henry said, not just among patients taking dapagliflozin.

The researchers also reported positive urine ketones in all treatment groups, though they generally weren’t associated with symptoms and tended to be higher in the 5-mg and 10-mg groups. However, Henry noted, few patients had genitourinary effects, a troublesome side effect of this class of drugs.

The study was limited by its small population size, and the results will best be used for future research hypotheses, Henry said.

Practice Pearls:

• In this 2-week randomized, placebo-controlled phase 2a pilot study, dapagliflozin was associated with lower glycemic levels and reduced daily insulin dosing in patients with type 1 diabetes.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Henry RR, et al "Exploring the potential of dapagliflozin in type 1 diabetes: Phase 2a pilot study" ADA 2013; Abstract 70-LB.