Patient disposition is shown in supplementary Fig. A1. Of the 1,462 patients screened, 743 were randomly assigned and received study treatment and 73% (543 of 743) completed 24 weeks of treatment. A higher incidence of discontinuations occurred in the placebo group (37.4%) versus the saxagliptin groups (22.9, 25.1, and 22.7% in the 25, 5, and 10 mg treatment groups, respectively). Demographic and baseline characteristics were generally similar across all treatment groups (supplementary Table A1, available in an online appendix). For the entire study population, mean age, duration of diabetes, baseline A1C, and baseline FPG were 54.6 years, 6.5 years, 8.0%, and 176 mg/dl, respectively. Daily metformin doses at study entry ranged from 500 to 2,550 mg. A history of being overweight (64.47%) and hypertension (59.08%) were the most commonly reported diabetes-related conditions.
At week 24, treatment with saxagliptin led to clinically and statistically significant reductions in A1C from baseline versus metformin plus placebo (). Differences in adjusted mean change from baseline versus placebo (95% CI) were −0.73% (−0.92 to −0.53), −0.83% (−1.02 to −0.63), and −0.72% (−0.91 to −0.52) for 2.5, 5, and 10 mg saxagliptin, respectively (all P < 0.0001). A1C reductions relative to metformin plus placebo occurred in all saxagliptin treatment groups at week 4, the earliest time point assessed. Maximal A1C reductions were reached at 12 weeks and were sustained through 24 weeks (A).
Key glycemic efficacy end points: changes from baseline
Figure 1 Effect of saxagliptin added to metformin versus placebo added to metformin. A: A1C mean change from baseline values (last observation carried forward [LOCF]) during the 24-week treatment period. B: Mean fasting plasma glucose values (LOCF) during the (more ...)
The percentage of patients achieving A1C <7.0% was comparable for 5 and 10 mg saxagliptin and higher than that for 2.5 mg saxagliptin (). A greater percentage of patients taking saxagliptin achieved A1C <7.0% versus those taking metformin plus placebo. The differences from metformin plus placebo (95% CI) were 20.5% (10.6–30.5), 27.0% (17.0–36.7), and 27.9% (17.7–37.7) for 2.5, 5, and 10 mg saxagliptin, respectively (all P < 0.0001).
As in the overall population, treatment with saxagliptin resulted in A1C reductions from baseline to week 24 in all A1C categories evaluated (baseline A1C <8.0, ≥8.0–<9.0, or ≥9.0%). An interaction of treatment with baseline A1C was observed (P < 0.05) with numerically greater A1C reductions in the higher baseline A1C categories for 2.5 and 5 mg saxagliptin, whereas 10 mg saxagliptin produced similar reductions in the two higher A1C categories. A1C-lowering effects were consistent across treatment groups in all other tested subgroups including duration of diabetes, geographic region, sex, age, ethnicity, and BMI.
Statistically significant FPG reductions at week 24 were observed in all saxagliptin treatment groups versus the metformin plus placebo group (P < 0.0001) (). Differences in adjusted mean change from baseline versus metformin plus placebo (95% CI) were −15.6 mg/dl (−22.5 to −8.5), −23.3 mg/dl (−30.3 to −16.3), and −21.7 mg/dl (−28.8 to −14.7) for 2.5, 5, and 10 mg saxagliptin, respectively. Differences between the effects of saxagliptin and metformin plus placebo on mean FPG were apparent and near maximal as early as week 2 in all saxagliptin treatment groups, with the effect maintained throughout 24 weeks (B).
Statistically significant reductions were seen in the PPG 3-h AUC during the OGTT from baseline to week 24 in all saxagliptin treatment groups versus the metformin plus placebo group (P < 0.0001) (). Differences in adjusted mean change from baseline versus metformin plus placebo (95% CI) were −5,599 mg · min/dl (−7,894 to −3,305), −6,294 mg · min/dl (−8,606 to −3,983), and −4,845 mg · min/dl (−7,153 to −2,537) for 2.5, 5, and 10 mg saxagliptin, respectively. Maximal A1C, FPG, and PPG reductions were observed at the 5 mg saxagliptin dose, without evidence of a dose-response relationship at greater than 5 mg.
There was an overall decrease from baseline in glucose concentration at all time points of the OGTT in the saxagliptin treatment groups at week 24 (C). At the 120-min time point of the OGTT, mean changes from baseline were greater for 2.5, 5, and 10 mg saxagliptin versus metformin plus placebo (−63.9, −62.1, and −40.7 mg/dl; all P ≤ 0.0001 versus −21.0 mg/dl for placebo). The 95% CI for the mean change from baseline excluded zero in all treatment groups.
At all doses, saxagliptin demonstrated increases in mean postprandial insulin AUC and C-peptide AUC levels versus metformin plus placebo (supplementary Figure A2a
, available in an online appendix). The change from baseline in postprandial glucagon AUC at week 24 revealed a greater decrease for all saxagliptin doses versus metformin plus placebo without any apparent dose dependency. The 95% CI for the placebo-subtracted adjusted mean change from baseline for postprandial insulin AUC, glucagon AUC, and C-peptide AUC excluded zero for all saxagliptin treatment groups (). β-Cell function, calculated using HOMA-2β (20
), improved in all saxagliptin treatment groups at week 24 (). Differences in adjusted mean changes from baseline versus metformin plus placebo (95% CI) were 11.5% (5.4–17.7), 12.7% (6.6–18.8), and 13.1% (7.0–19.3) for the 2.5, 5, and 10 mg saxagliptin groups, respectively. Patients treated with saxagliptin had decreases in fasting glucagon measurements of greater magnitude than those observed for metformin plus placebo (data not shown, NS). No discernible effects on fasting C-peptide and insulin levels were observed for saxagliptin versus metformin plus placebo.
The early insulin response based on the insulinogenic index, calculated as ΔI0–30 min/ΔG0–30 min, and insulin sensitivity, calculated using the oral glucose insulin sensitivity (OGIS) index, increased in all saxagliptin treatment groups at week 24 (). No significant treatment effect was observed in the HOMA-2 insulin resistance index or the Matsuda index of insulin sensitivity at week 24. Mean changes from baseline in body weight at week 24 were −1.43, −0.87, and −0.53 kg for 2.5, 5, and 10 mg saxagliptin versus −0.92 kg for metformin plus placebo. Effects of saxagliptin on BMI, mean waist circumference, and mean fasting lipid levels were similar to those for metformin plus placebo.
The percentage of patients who discontinued the study for lack of glycemic control or who were rescued for unacceptable glycemic control was approximately 2 times higher for metformin plus placebo (27.4%) versus saxagliptin (14.6, 12.6, and 14.9% for 2.5, 5, and 10 mg saxagliptin, respectively). Consequently, mean duration of exposure to double-blind study medication was similar across the saxagliptin treatment groups (mean range, 150–152 days) but shorter for the metformin plus placebo group (134 days), given that rescued patients were entered directly into the long-term extension.
Treatment with saxagliptin was generally well tolerated across all doses. The percentage of patients who had at least one adverse event was 74.3% (saxagliptin-treated patients) versus 64.8% (metformin plus placebo group), without evidence of a dose-response relationship. Generally, the frequency of the most common adverse events (≥5%) reported in saxagliptin-treated patients was similar to that in the metformin plus placebo group as was the percentage of patients with one or more serious adverse events (). No patients had a serious adverse event that was considered to be treatment related. The overall percentage of patients who had skin-related adverse events was similar for saxagliptin-treated patients (47 patients, 8.3%) and patients in the metformin plus placebo group (14 patients, 7.8%), with no apparent dose-related effects. The incidence of adverse events related to gastrointestinal disorders was similar in patients treated with saxagliptin (23.0%) versus placebo plus metformin (24.0%).
Adverse events in double-blind treatment period: total, serious, deaths, discontinuations, most frequent (≥5%), reported hypoglycemia, confirmed hypoglycemia, and exposure to study medication
The overall frequency of confirmed hypoglycemia during the 24-week treatment period was similar for saxagliptin-treated patients (0.5%) and metformin plus placebo–treated patients (0.6%). No dose relationship was observed among the three saxagliptin groups. All events were of mild or moderate intensity and did not require treatment or medical intervention ().
The 2.5- and 5-mg doses of saxagliptin had no discernible effect on mean absolute lymphocyte count. There was a small numerical decrease from baseline in mean absolute lymphocyte count in the 10 mg saxagliptin group (−0.14 × 103 cells/μl) without evidence of clinical sequelae. Mean lymphocyte counts remained well within normal limits throughout the study. There is no known clinical significance to the findings observed in the 10 mg saxagliptin treatment group. Other safety laboratory parameters, including hematological, hepatic, renal, and musculoskeletal tests, showed no drug-related issues.