A total of 485 patients were randomly assigned to the main morning dose and exploratory evening dose cohorts (). In addition, 74 patients were randomly assigned to the exploratory, high-A1C cohort, of which 73 patients took at least one dose of study medication. Demographic and baseline characteristics are shown in .
Demographics and baseline characteristics
In the main cohort, mean A1C reductions were dose ordered and apparent by week 4 and maintained thereafter (A). Mean A1C reductions from baseline at week 24 in the main cohort ranged from −0.58 to −0.89% with dapagliflozin compared with −0.23% with placebo. The reductions were statistically significant with 5 and 10 mg dapagliflozin (P = 0.0005 and P < 0.0001, respectively, vs. placebo). At the end of study, a higher proportion of patients in dapagliflozin arms reached the American Diabetes Association/European Association for the Study of Diabetes target A1C of <7% (41, 44, and 51% with 2.5, 5, and 10 mg dapagliflozin, respectively, vs. 32% with placebo).
Figure 2 Changes in glycemic parameters over time. A: Mean change from baseline in A1C after adjustment for baseline value. B: Mean change from baseline in FPG after adjustment for baseline value. C: Mean change from baseline in body weight after adjustment for (more ...)
Reductions in FPG were apparent as early as week 1. Throughout the study, FPG reductions were more marked in 5 and 10 mg dapagliflozin arms and were statistically significant at week 24 (B, ). Mean body weight decreases were greater with all dapagliflozin doses than with placebo, although they did not reach statistical significance (Fig. 3C, ).
Changes from baseline at week 24 in efficacy parameters, vital signs, and laboratory values
In the exploratory evening dose cohort, changes from baseline in A1C, FPG, and body weight at week 24 were similar to those seen in the main patient cohort (). In the exploratory high-A1C cohort (10.1–12% at enrollment), treatment with dapagliflozin for 24 weeks led to numerically greater reductions in mean A1C and FPG from baseline than those observed in other cohorts (). Subgroup analyses of the main patient cohort by baseline A1C were consistent with the ability of dapagliflozin to cause greater A1C reductions in patients with high baseline A1C. In patients with baseline A1C ≥9%, changes in mean A1C from baseline at week 24 were −1.23 ± 0.98, −1.98 ± 0.90, and −1.90 ± 0.79% with 2.5, 5, and 10 mg dapagliflozin groups, respectively, compared with 0.16 ± 2.50% with placebo.
Treatment with dapagliflozin did not result in any clinically meaningful changes from baseline in serum electrolytes including serum sodium (). There were no clinically relevant changes in any renal function parameter including serum creatinine, blood urea nitrogen, or cystatin C. In addition, there were no clinically relevant changes in mean serum albumin with dapagliflozin treatment. Small, numerical decreases from baseline in high-sensitivity C-reactive protein (placebo-subtracted adjusted mean change from baseline value [SE] ranged from −1.53 [1.06] to −2.67 [1.10] mg/l) and serum uric acid were observed in most dapagliflozin arms. Small, dose-ordered mean increases in hematocrit (up to 2.4%) were observed with dapagliflozin. A decrease in mean seated blood pressure with no notable increase in orthostatic hypotension was observed in the dapagliflozin arms (). Rates of hypotension/dehydration/hypovolemia were similar among placebo and dapagliflozin arms. Treatment with dapagliflozin did not alter the lipid profile of patients, although small numerical increases in HDL cholesterol were noted in all dapagliflozin arms (placebo-subtracted adjusted mean change from baseline value [SE] ranged from 0.02 [0.07] to 0.17 [0.08] mmol/l).
Glucose-to-creatinine ratios were higher with dapagliflozin than with placebo (). Higher values with the evening dose presumably reflect the pharmacokinetic half-life of dapagliflozin. In pooled data from the morning and evening cohorts, changes from baseline in fractional renal glucose excretion at week 24 were significantly related (r = −0.13, P = 0.008) with the corresponding changes in body weight, such that across all study arms greater renal glucose losses were associated with larger decrements in body weight. A similar trend was found for changes in glucose excretion and changes in A1C (P = 0.11).
Adverse events are summarized in . There was one death due to a motor vehicle accident in the 10 mg dapagliflozin group. There were no major episodes of hypoglycemia in this study, and none of the patients discontinued the study medication due to hypoglycemia. An increased incidence in signs and symptoms and other reports suggestive of UTIs and genital infections was noted with dapagliflozin treatment. Safety data in the exploratory evening dose cohort were similar to those in the morning dose cohort. A small number of patients (n = 6) experienced nocturia with the evening dose (one, two, and three patients in the 2.5, 5 or 10 mg dapagliflozin evening dose arms, respectively, and none with the morning dose). There were no other notable differences in the number or type of adverse events reported with the evening dose.