In the context of a dose-titration scheme designed to optimize efficacy and minimize hypoglycemic episodes with glipizide, this head-to-head comparison study demonstrated that the novel SGLT2 inhibitor dapagliflozin produced a long-term HbA1c
mean reduction at 52 weeks that was numerically identical and statistically noninferior to the sulfonylurea glipizide in patients poorly controlled with metformin monotherapy. This comparable long-term efficacy of dapagliflozin with a sulfonylurea, considered potent glucose-lowering agents (2
), was achieved with >10-fold fewer hypoglycemic episodes along with sustained weight loss. In contrast, weight increased and hypoglycemic episodes were more frequent with glipizide.
The pattern of HbA1c
change over time was substantially different between dapagliflozin and glipizide treatment (). The pattern with glipizide—rapid initial response, followed by gradual increase—is typical of that observed with sulfonylureas (6
). In contrast, dapagliflozin response was initially smaller during titration but thereafter was sustained during the maintenance period such that it was identical to glipizide response at 52 weeks. It is interesting to speculate whether the durability of HbA1c
control with dapagliflozin will outlast that of glipizide during longer-term follow-up of these patients. In this population with a relatively low baseline mean HbA1c
(~7.7%), clinically meaningful reductions of >0.5% were achieved by both agents. A higher baseline HbA1c
, as observed in other clinical efficacy studies of antidiabetic agents, generally predicts larger drops in response to treatment, whichever agent is tested (17
Weight loss with dapagliflozin was progressive during the first 6 months and stabilized during the latter half of the study. This may have resulted from glucosuria-induced fat loss, fluid loss associated with osmotic diuresis, or a combination of both. Studies of body composition are underway to assess the relative contributions of fat and fluid loss to the changes in TBW observed with dapagliflozin.
Dapagliflozin reduced blood pressure. The mechanism for this effect is unclear but may involve osmotic diuresis or sodium loss. Although modest rises in hematocrit and blood urea nitrogen occurred, no meaningful changes were noted in electrolytes, serum creatinine, heart rate, or proportions of patients experiencing orthostatic hypotension to indicate dehydration. The estimated glomerular filtration rate and concentrations of cystatin-C did not show meaningful changes. In addition, AEs of renal impairment or failure—excluding those of decrease in creatinine clearance calculated using current body weight values at each study visit—were not over-represented with dapagliflozin. Taken together, these data suggest that dapagliflozin treatment was not associated with clinically relevant dehydration or impairment in kidney function.
Patients with type 2 diabetes are at higher risk of fungal genital infections and UTIs compared with the general population (19
). Dapagliflozin-treated patients, especially women, reported an increase in events suggestive of genital infections and lower UTIs compared with glipizide-treated patients. For conservative pharmacovigilance purposes with this first-in-class agent, events suggestive of genital infection and UTI were reported spontaneously and in response to questions proactively posed to patients that were related to the signs and symptoms of these infections. Not all of these suggestive events could be confirmed as infections (). Variable reports of these events have been noted in previous studies with dapagliflozin (13
); hence, further analyses using pooled data are required to better evaluate potential risk factors for genital and UTIs with SGLT2 inhibitors such as dapagliflozin.
In conclusion, this head-to-head comparison of dapagliflozin versus glipizide added to metformin in type 2 diabetic patients inadequately controlled with metformin monotherapy demonstrated similar glycemic efficacy at 52 weeks but markedly divergent effects on weight and hypoglycemia. Whereas glipizide treatment led to weight gain and more hypoglycemic episodes, dapagliflozin produced significant weight loss and significantly fewer hypoglycemic episodes. Dapagliflozin treatment was generally safe and well tolerated, but events suggestive of genital and lower UTIs were observed more frequently in this study. Dapagliflozin is a potential valuable alternative to sulfonylureas as add-on therapy when metformin monotherapy fails to maintain adequate glycemic control.