Patient disposition is shown in Fig. 2. In brief, 728 patients were enrolled: 249 received dapagliflozin as monotherapy and 479 received dapagliflozin in combination with other OADs (89% and 85% completed the 52-week monotherapy and combination therapy treatment periods, respectively). The demographics and baseline characteristics were generally balanced across the groups. However, the duration of T2DM was longer in the combination group (Table 1).
At baseline, of the 479 patients in the combination group 122 (25.5%) were taking SUs (glimepiride), 62 (12.9%) DPP-4 inhibitors (sitagliptin), 61 (12.7%) AGIs (acarbose, miglitol, and voglibose), 71 (14.8%) metformin, 64 (13.4%) TZDs (pioglitazone), 49 (10.2%) glinides (mitiglinide and nateglinide), and 50 (10.4%) GLP-1 analogs (liraglutide) (Table 1).
The frequency of AEs observed over the 52-week treatment period with dapagliflozin was 79.1% for the monotherapy group and 72.4% for the combination groups (Table 2) (the range across the combination groups was 63.9–78.9%). AEs were mostly mild or moderate in intensity, and the frequency of serious AEs was 5.6% in the monotherapy group and 3.1% for the combination group (range 1.6–4.8%). Hypoglycemic events were experienced by fewer patients in the monotherapy group vs. the combination therapy group (2.4% and 4.0%, respectively). In the combination therapy subgroups, the frequency of hypoglycemic events was highest in patients receiving SU, glinides, and GLP-1 agonists (6.6, 6.1, and 6.0%, respectively). There were no major hypoglycemic events, and no patient was discontinued from the study due to a hypoglycemic event. The most common AE reported was nasopharyngitis, which was experienced by approximately a quarter of patients in both groups (63 [25.3%] and 116 [24.2%] in monotherapy and combination groups, respectively). Events of urinary tract infection were rare, and rates were similar in the monotherapy and combination therapy groups (3.6% and 2.3%, respectively). Similarly, events of genital infection were rare, and the rates were balanced between monotherapy and combination therapy groups (2.8% and 2.5%, respectively). Rates of renal impairment, fractures, and volume-related events were low and similar in the monotherapy and combination therapy groups (Table 2).
eGFR values declined from week 0 to week 8 in both monotherapy and combination therapy groups (change from baseline, −2.9 and −2.5 mL/min/1.73 m2, respectively) and by week 24 had returned to close to baseline values (change from baseline, 0.5 and 0.1 mL/min/1.73 m2, respectively).
There was no clinically meaningful change in mean values of serum creatinine in either therapy group during the 52-week, open-label treatment period.
Seven of the 728 patients (1%) reported neoplasms (benign, malignant, or unspecified) over the 52-week study period (5 in the monotherapy group and 2 in the combination group). There were two cases of colon cancer (day 55 and day 242) and one each of breast cancer (day 149), rectal cancer (day 70), gastric neoplasm (day 281), metastatic neoplasm (day 321), and squamous cell carcinoma (day 188).
The effects of dapagliflozin on clinical laboratory data are shown in Table 3. Following 52 weeks of treatment with dapagliflozin, urinary glucose increased from baseline in both groups (monotherapy group 2,545.40 mg/dL [141.27 mmol/L]; combination therapy group 2,839.50 mg/dL [157.59 mmol/L]). In both the monotherapy and the combination therapy groups, reductions from baseline were observed in serum uric acid (−0.61 mg/dL [−36.29 µmol/L] and −0.50 mg/dL [–29.74 µmol/L], respectively) and urine albumin (−22.40 mg/L and −25.00 mg/L). Reductions in urine sodium were observed in both the monotherapy and the combination therapy groups (−2.40 mEq/L [−2.40 mmol/L] and −11.10 mEq/L [−11.10 mmol/L], respectively) and increases were seen in parathyroid hormone (0.80 pg/ml [0.80 ng/L] and 5.00 pg/mL [5.00 ng/L]). No meaningful changes from baseline in serum sodium and or potassium were observed in either the monotherapy (0.30 mEq/L [0.30 mmol/L] and –0.03 mEq/L [−0.03 mmol/L], respectively) or combination therapy (0.10 mEq/L [0.10 mmol/L] and −0.03 mEq/L [−0.03 mmol/L]) groups. Over 52 weeks, no change was apparent in serum calcium in either the monotherapy (−0.02 mg/dL [0.00 mmol/L]) or combination therapy (−0.06 mg/dL [−0.02 mmol/L]) group.
Reductions in HbA1c levels from baseline to week 52 with dapagliflozin were the same in the monotherapy and combination therapy groups (−0.7% for both) (Table 4; Fig. 3a). No patients were rescued due to lack of glycemic control in either group. In addition, reductions in HbA1c were similar across each of the individual combination therapies (range −0.5 to −0.9%) (Fig. 4). In both the monotherapy and combination therapy groups, reductions in HbA1c from baseline to week 52 with dapagliflozin were greater in patients with higher baseline HbA1c (Fig. 5a). Similarly, in both groups, the reductions in HbA1c with dapagliflozin were more pronounced in patients with higher baseline kidney function (eGFR) (Fig. 5b). A greater proportion of patients achieved HbA1c levels <7% with dapagliflozin in the monotherapy group (53.4%) versus the combination therapy group (35.1%) (Table 4).
Following treatment with dapagliflozin, total body weight was reduced to a similar degree in the monotherapy and combination therapy groups (Table 4; Fig. 3b). In the monotherapy treatment group, 33.7% of patients achieved a body weight loss of ≥5% compared with 24.1% in the combination therapy group (Table 4).
Body mass index, waist circumference, FPG levels, fasting insulin, and fasting C-peptide were also reduced to a similar extent in the dapagliflozin monotherapy and combination therapy groups (Table 4). SBP and DBP were reduced in both the monotherapy group and the combination therapy groups. Approximately half of all patients in either group with baseline SBP ≥130 mmHg achieved reductions in SBP to <130 mmHg.
Numerical increases were observed in total, LDL, and HDL cholesterol and free fatty acid levels in both the monotherapy and combination therapy groups (Table 4). Triglyceride levels dropped in both therapy groups.
Effect of Up-Titration of Dapagliflozin on Glycemic Control
The first patients were up-titrated from dapagliflozin 5 mg/day to 10 mg/day at week 16. In total, 50/249 patients (20.1%) in the monotherapy group and 177/477 patients (37.1%) in the combination therapy were up-titrated to 10 mg/day dapagliflozin.
Following dapagliflozin up-titration, there was a further mean reduction in HbA1c in patients receiving monotherapy (last pre-titration HbA1c value 7.9 [SD 0.6]: week 8, −0.12%; week 16, −0.07%; week 24, −0.12%), as well as in patients receiving combination therapy (last pre-titration HbA1c value 8.0 [0.6]: week 8, −0.12%; week 16, −0.12%; week 24, −0.11%).
The percentages of patients in the monotherapy and combination therapy groups with FPG of ≥126 mg/dL [≥7.0 mmol/L] before up-titration who achieved FPG of <126 mg/dL [<7.0 mmol/L] at 8 weeks after up-titration (LOCF) were 24.4% and 15.7%, respectively.