From the 546 originally randomized patients, 476 (87.2%) continued into the 78-week extension period. Of these, 339 (71.2%) completed the 102-week study (Figure ). During the 78-week extension, the completion rate was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3 to 79.8%). This was largely due to more patients in the placebo group (23.5%) withdrawing during the extension period for lack of efficacy, whereas withdrawals were 13.3, 13.9, and 7.6% with dapagliflozin 2.5 mg, 5 mg, and 10 mg, respectively. Demographics and baseline characteristics were balanced between treatment groups as reported previously [9
The mean HbA1c at baseline of all 546 randomized patients was 8.06%. At week 102, the adjusted mean change from baseline in HbA1c was 0.02% (95% CI: -0.20 to 0.23) for placebo and -0.48% (95% CI: -0.68 to -0.29),-0.58% (95% CI: -0.77 to -0.39), and-0.78% (95% CI: -0.97 to -0.60) for dapagliflozin 2.5 mg, 5 mg, and 10 mg, respectively (Table ). The reductions in HbA1c with dapagliflozin were dose dependent and statistically significant compared to placebo at week 102 (Figure ). When excluding data after rescue, 20% (28/137) of patients in the placebo group had observed data for HbA1c at week 102, compared to 26% (36/137), 34% (47/137), and 42% (57/135) of patients receiving dapagliflozin 2.5 mg, 5 mg, and 10 mg, respectively. At week 102, the proportion of patients achieving HbA1c <7% was 20.7 (95% CI: 14.0 to 27.3), 26.4, (95% CI: 19.4 to 33.4), and 31.5% (95% CI: 23.7 to 39.3) for dapagliflozin 2.5 mg, 5 mg, and 10 mg, respectively, vs 15.4% (95% CI: 9.5 to 21.3) for placebo (Table ); the adjusted proportion of patients achieving HbA1c <7% was statistically significant for dapagliflozin at 5 mg (P = 0.0202) and 10 mg (P = 0.0014) compared to placebo. Adjusted mean change from baseline in FPG was -0.58 mmol/l (95% CI: -0.97 to -0.19) for placebo and -1.07 mmol/l (95% CI: -1.42 to -0.72), -1.47 mmol/l (95% CI: -1.78 to -1.16), and -1.36 mmol/l (95% CI: -1.65 to -1.07) for the dapagliflozin 2.5 mg, 5 mg, and 10 mg, respectively, at week 102 (Table ). Adjusted mean change from baseline in FPG was statistically significant for dapagliflozin 5 mg (P = 0.0003) and 10 mg (P = 0.0012) compared to placebo. The proportions of patients rescued or discontinued for failing to achieve glycemic targets were 60.6% (83/137) for placebo and 51.8% (71/137), 46.0% (63/137), and 42.2% (57/135) for dapagliflozin 2.5 mg, 5 mg, and 10 mg, respectively, at week 102.
Change from baseline in efficacy parameters
Figure 2 Change from baseline in (A) glycated hemoglobin (HbA1c), (B) urinary glucose:creatinine ratio, and (C) body weight for placebo (circles), dapagliflozin 2.5 mg (squares), dapagliflozin 5 mg (triangles), and dapagliflozin 10 mg (diamonds) groups all plus (more ...)
As shown in Figure , large increases in the urinary glucose:creatinine ratio for the dapagliflozin groups were dose dependent and maintained through to week 102. For total body weight, when excluding data after rescue therapy, the adjusted mean value decreased from baseline with dapagliflozin (-2.16 kg to -3.38 kg) and with placebo (-0.67 kg) through week 102. When including data after rescue, recognizing that pioglitazone was the primary rescue medication, the adjusted mean value still decreased from baseline with dapagliflozin (-1.10 kg to -1.74 kg) but increased with placebo (1.36 kg) through week 102, and differences between the dapagliflozin groups versus placebo were statistically significant at 102 weeks (Table , Figure ).
The proportions of patients who reported at least one adverse event were similar across dapagliflozin groups and the placebo group when including data after rescue (Table ). During the 78-week extension, three deaths occurred (Table ): two in the dapagliflozin 2.5 mg group due to cardiopulmonary arrest and myocardial infarction, and one death in the placebo group due to malignant lung neoplasm. All three deaths were reported to be unlikely related or not related to the study treatment as assessed by the investigator. The proportions of serious adverse events through 102 weeks were similar across dapagliflozin groups and the placebo group (Table ). Few patients reported adverse events that led to discontinuation, and the proportion was similar in all treatment groups (Table ). No major episodes of hypoglycemia occurred, and no discontinuations were due to hypoglycemia. The proportion of patients who reported at least one event of hypoglycemia was similar across study groups (Table ).
Adverse and special interest events up to week 102
As shown in Table , signs, symptoms, and other evidence suggestive of urinary tract infection (UTI) occurred at a higher rate in the dapagliflozin 10 mg group (13.3%) compared to placebo (8.0%), dapagliflozin 2.5 mg group (8.0%), and dapagliflozin 5 mg group (8.8%), with one discontinuation (dapagliflozin 2.5 mg). Signs, symptoms and other evidence suggestive of vulvovaginitis, balanitis, and related genital infection (not sexually transmitted) were more common in the dapagliflozin groups (11.7% to 14.6%) than placebo (5.1%) (Table ) with one discontinuation (dapagliflozin 5 mg). Evidence suggestive of UTI or genital infection occurred more frequently in women than in men. These events were mild or moderate in intensity, with >65% occurring in the first 24 weeks. Signs or symptoms suggestive of UTI or genital infection responded to standard treatment typically without interruption of dapagliflozin therapy and rarely led to recurrence. No events of pyelonephritis were reported.
The proportions of renal impairment or failure events (defined by a prespecified list) were higher with dapagliflozin in total than with placebo, but similar proportions between dapagliflozin 10 mg and placebo were reported (Table ). Of the 14 events (in all groups) of renal impairment or failure, 8 consisted of increases in serum creatinine ≥1.5 times the baseline value, or attaining an absolute value of 221 μmol/l. One patient in the dapagliflozin 5 mg group had a serious adverse event of acute renal failure at day 624 due to urinary obstruction that resulted in discontinuation and resolved following prostatectomy. Adverse events of hypotension, or suggestive of dehydration and hypovolemia were infrequent, non-severe, and similar between the placebo and dapagliflozin groups (Table ). Fractures were reported by two patients (1.5%) each in the placebo, dapagliflozin 2.5 mg, and dapagliflozin 5 mg groups, and by three patients (2.2%) in the dapagliflozin 10 mg group during the 102-week study. One patient on dapagliflozin 5 mg with a history of hematuria that predated randomization experienced a bladder transitional cell cancer. One patient on dapagliflozin 10 mg was diagnosed with breast cancer within the first year of enrollment.
As shown in Table , no clinically relevant mean changes from baseline in sodium, potassium, creatinine or blood urea nitrogen were apparent in any treatment group through week 102. Mean decreases from baseline in uric acid (46 to 56 μmol/l) were noted in all dapagliflozin groups and were significantly greater versus placebo. Small mean increases in hemoglobin and hematocrit, which were seen by about week 12 with dapagliflozin, remained stable thereafter. Although mean systolic and diastolic blood pressure decreased by 2.1 to 5.1 mmHg and 1.8 to 2.5 mmHg, respectively, at 24 weeks in patients receiving dapagliflozin (2.5 mg, 5 mg, and 10 mg) versus 0.2 and 0.1, respectively, for placebo [9
], smaller decreases from baseline were observed at 102 weeks in mean systolic and diastolic blood pressure with dapagliflozin therapy.
Summary of laboratory parameters