The study was initiated on May 13, 2009 and ended on February 24, 2010 (data collection complete); recruitment took place between May 13, 2009 and November 13, 2009. A total of 160 patients were randomized to saxagliptin (n = 74) or placebo (n = 86) as add-on therapy to metformin IR and received ≥1 dose during the double-blind phase (Figure 1). All were included in the Randomized Patients Population (efficacy analysis) and the Treated Patients Population (safety analysis), and analyses were by randomized treatment group. Of those randomized and treated with drug, 144 patients (saxagliptin, n = 66; placebo, n = 78) completed 12 weeks of treatment. A similar proportion of patients in both treatment groups (saxagliptin 10.8%, placebo 9.3%) discontinued from the trial. The most common reasons for discontinuation were insufficient glycemic control (2 subjects each group: saxagliptin 2.7%; placebo 2.3%) and poor/noncompliance (2 subjects each group: saxagliptin 2.7%; placebo 2.3%). Patient characteristics are shown in Table 1; 90% were white, 40% were Hispanic or Latino, and the mean (SD) duration of type 2 diabetes was 6.0 (5.30) years.
Extent of exposure
Mean (SD) duration of exposure to study drug was 80.8 (14.55) days for the saxagliptin plus metformin group and 79.7 (17.46) days for the placebo plus metformin group; >80% of patients per group continued study medication for ≥82 days.
At week 12, adjusted mean reductions (95% CI) from baseline in HbA1c were significantly greater (P = 0.006) in the saxagliptin plus metformin group (-0.56% [-0.74 to -0.38]) versus the placebo plus metformin group (-0.22% [-0.39 to -0.06]) (Table 2). There was a progressive decrease in HbA1c to -0.56% in the saxagliptin group throughout the duration of the study (Figure 2A). There were no interactions observed for change from baseline in HbA1c and treatment by baseline HbA1c, gender, age, or ethnicity.
At week 12, adjusted mean reductions from baseline in the first secondary end point, FPG, were numerically greater (-13.73 mg/dL) in the saxagliptin plus metformin group than in the placebo plus metformin group (-4.22 mg/dL) (Figure 2B), though the difference (95% CI) of -9.5 mg/dL (-21.7 to 2.7) at week 12 was not statistically significant (P = 0.12) (Table 2). Accordingly, subsequent secondary end points were analyzed using only summary statistics.
The percentage of patients achieving a therapeutic glycemic response (HbA1c <7%) was numerically greater with saxagliptin plus metformin versus placebo plus metformin (37.5% [29/74] vs 24.2% [19/84]). The difference (95% CI) in the proportions of patients achieving HbA1c <7% versus placebo was 13.2% (1.1 to 25.4). Numerically more patients in the saxagliptin plus metformin group than the placebo plus metformin group achieved HbA1c ≤6.5% (24.6% [19/74] vs 10.7% [8/84]; Table 2). The difference in the proportions of patients achieving HbA1c ≤6.5% versus placebo was 13.8% (3.0 to 24.7).
Other parameters relevant to efficacy
At week 12, a reduction in HbA1c of ≥0.5% was achieved by 51.4% (38/74) and 36.9% (31/84) of patients in the saxagliptin plus metformin group and the placebo plus metformin group, respectively (difference [95% CI], 16.8% [2.3 to 31.3]). A reduction of ≥0.7% was achieved by 40.5% (30/74) and 23.8% (20/84), respectively (difference [95% CI], 14.6% [0.8 to 30.1]).
At week 12, in the saxagliptin plus metformin group and the placebo plus metformin group, 19.2% (14/73) and 3.6% (3/84), respectively, achieved FPG <110 mg/dL, and 37.0% (27/73) and 16.7% (14/84) of patients, respectively, achieved FPG <126 mg/dL.
Few patients in either group discontinued the study because of lack of glycemic control at week 4 (saxagliptin plus metformin, n = 1, 1.4%; placebo plus metformin, n = 1, 1.2%) and week 8 (saxagliptin plus metformin, n = 2, 2.7%; placebo plus metformin, n = 1, 1.2%).
Overall, there were reductions in mean body weight (LOCF) in both treatment groups. Mean change in body weight (95% CI) at week 12 was -0.32 kg (-0.97 to 0.34) for the saxagliptin plus metformin group and -0.40 kg (-0.83 to 0.02) for the placebo plus metformin group.
During the double-blind period, the proportion of patients reporting ≥1 AE (irrespective of investigator-assessed relationship to treatment) was 25.7% (19/74) for the saxagliptin plus metformin group and 39.5% (34/86) for the placebo plus metformin group (Table 3). Treatment-related AEs as identified by the blinded investigator assessment occurred in 1 patient (1.4%) in the saxagliptin plus metformin group (nausea and dizziness; mild in severity) and 3 patients (3.5%) in the placebo plus metformin group (fatigue, increased blood creatine phosphokinase, and insomnia); no deaths occurred in either group during the 12-week double-blind treatment period (Table 3). Apart from hypoglycemia (described below), the most common AEs in the saxagliptin plus metformin group were back pain (2.7% vs 3.5% for placebo plus metformin), hypertension (2.7% vs 2.3%), dizziness (2.7% vs 0), and lymphadenopathy (2.7% vs 0; Table 4). Events with higher incidences in the placebo plus metformin group versus the saxagliptin plus metformin group were gastrointestinal (GI) AEs at the system organ class level (saxagliptin, 4.1%; placebo, 7.0%) and diarrhea (1.4% versus 3.5%). One patient in each treatment group experienced ≥1 serious AE (saxagliptin: myocardial infarction and pulmonary edema; placebo: severe back pain requiring hospitalization, owing to a lumbar strain); neither of these was considered treatment related.
Confirmed hypoglycemia, defined by hypoglycemic symptoms plus a fingerstick glucose value ≤50 mg/dL, occurred in only 1 patient (placebo plus metformin group) during the double-blind period. Hypoglycemia occurred in 4 patients (5.4%) in the saxagliptin plus metformin group and 1 patient (1.2%) in the placebo plus metformin group during double-blind treatment; all were rated mild or moderate in severity. There were no events of serious hypoglycemia, and no patient discontinued the study owing to hypoglycemia during double-blind treatment. Other categories of AEs were identified as being of special interest based on findings observed in the saxagliptin nonclinical and Phase 1 and 2b programs, safety-related concerns reported for other DPP-4 inhibitors, and theoretical considerations related to the mechanism of action of DPP-4. There were 2 such AEs, both in saxagliptin-treated patients. A 63-year-old man, with hypertension, recent death of spouse, and 9-pound weight gain who quit smoking 10 days previously, suffered a non-ST-segment myocardial infarction (the only confirmed major adverse cardiovascular event [MACE] in the trial) with pulmonary edema. A 100% right coronary artery ostial occlusion with collateralization was noted, and the 80%–90% proximal left circumflex artery lesion was treated with percutaneous transluminal coronary angioplasty and a stent. Study medication was resumed and the patient completed the trial. A second patient experienced a severe AE of thrombocytopenia (baseline platelet count of 102 × 103 c/μL fell to 97 × 103 c/μL at the last study visit). The patient was asymptomatic, and the event was deemed not related to treatment. There were no reports of other AEs of special interest, including skin disorders, lymphopenia, thrombocytopenia, localized edema, hypersensitivity, fractures, or pancreatitis. There was no clinically meaningful drug effect on any other laboratory safety parameter, including hematologic, liver, renal, electrolytes, protein, and musculoskeletal parameters.