Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study

Henry RR, Rosenstock, Edelman S, et al. Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study. Diabetes Care. 2014; Epub ahead of print. DOI: 10.2337/dc13-2955. 


Dapagliflozin has the potential to improve glycemic control as an adjunct to insulin therapy in patients with type 1 diabetes. Maladaptive reabsorption of glucose may perpetuate hyperglycemia in these subjects.

Dapagliflozin is a highly selective, orally active inhibitor of sodium-glucose cotransporter 2 (SGLT2) that reduces hyperglycemia by inhibiting renal glucose reabsorption independently of insulin. It has been shown to improve glycemic control and attenuate insulin-associated weight gain without increasing rates of major hypoglycemia in patients with type 2 diabetes.

 
This phase 2a pilot study assessed the potential of dapagliflozin for treatment of type 1 diabetes as an adjunct to insulin, a high percentage of patients in all treatment groups experienced at least one episode of hypoglycemia with no relationship to dapagliflozin dose. Data on adverse events:
  • One hypoglycemia event on day 6 in the dapagliflozin 10 mg group was major, which was related to the subject’s failure to reduce insulin dosing as instructed
  • One genitourinary infection occurred in each of the placebo and dapagliflozin 1-, 2-, 5-, and 10-mg groups
  • There were no apparent effects of dapagliflozin on fluid intake, body weight, or blood pressure
  • Total daily urine output tended to show numeric increases in all groups (larger increase in the placebo group)
 
Results for pharmacokinetics and pharmacodynamics:
  • Steady-state pharmacokinetic results showed that both Cmax and AUCt appeared to be dose proportional across all dose groups for both dapagliflozin and its major inactive metabolite, dapagliflozin 3-O-gluronide (D3OG)
  • Dapagliflozin was rapidly absorbed after oral administration, with median time of maximal observed plasma concentration (Tmax) ranging from 0.50 to 1.00 hour across dose groups
  • The pharmacodynamic parameter analyzed was the mean change from baseline in 24-hour urine glucose levels at day 7
    • Consistent with the mechanism of action of dapagliflozin, a dose-dependent increase in 24-hour urine glucose level was observed, but this was not statistically tested.
    • In contrast, the 24-h urine glucose level decreased in the placebo group
     
 
Results for changes in average daily glucose and insulin use:
  • No differences in levels between the placebo and dapagliflozin groups were observed for mean glucose measurements derived from 7-point glucose monitoring
    • Mean glucose level was based upon 7-point central laboratory glucose monitoring obtained before and after each meal and at bedtime
     
  • Among the dapagliflozin groups, the following dose-related trends were suggested: fasting plasma glucose, daily average glucose (DAG), SD of DAG, and mean amplitude of glucose excursion showed greater numeric reductions at day 7 with the dapagliflozin 5 and 10 mg doses versus the lower dapagliflozin doses
    • However, the 95% CIs of the mean for all dapagliflozin doses overlapped those of placebo
     
  • The dapagliflozin 5 and 10 mg doses were associated with reductions in the mean percentage change from baseline at day 7 in total insulin dose of -19.3% (95% CI -30.1 to -6.8) and -16.2% (95% CI -29.4 to -0.5), respectively
    • However, the 95% CIs for all dapagliflozin doses overlapped those for placebo
     

About the study 
This 2-week randomized, double-blind, parallel-group, placebo-controlled, exploratory phase 2a pilot study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of dapagliflozin vs placebo in subjects with type 1 diabetes inadequately controlled with insulin. Standardized diets and guidance on insulin dose adjustment were given during the inpatient treatment period (week 1). Subjects were treated with insulin monotherapy prior to study initiation, either by multiple daily injections consisting of long-acting (basal) plus short-acting prandial (bolus) insulin or continuous subcutaneous insulin infusion pump. Insulin dose was not proactively reduced at study drug initiation, however, subjects and investigators were advised to adjust insulin dosing as needed to avoid hypoglycemia and ensure patient safety. Safety and tolerability data were analyzed after 14 days of exposure; PK, PD, and efficacy data were collected over the first 7 days.
 
 
All slides available for download in the Slide Library. 

SGLT2 inhibitors, including dapagliflozin, are not FDA-approved for the treatment of type 1 diabetes in the United States

 
 
  

Any pharmacologic agents discussed are approved for use in the United States by the U.S. Food and Drug Administration (FDA) unless otherwise noted. Consult individual prescribing information for approved uses outside of the United States. 

November 2014 

This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.  

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Last Modified: 12/9/2014