Of the 221 patients with severe renal impairment randomized in the trial, 178 patients (100 in the vildagliptin group and 78 in the placebo group) were receiving insulin treatment at baseline. summarizes the baseline demographic and background characteristics in the randomized population. These insulin-treated patients with severe renal impairment had a mean age of 64 years (with over half of the participants ≥ 65 years of age), mean HbA1c of 7.7%, mean estimated GFR of approximately 21 mL/min/1.73 m2 and mean body mass index of 30 kg/m2. They had longstanding type 2 diabetes (mean duration of known type 2 diabetes was about 19 years), with a mean duration of insulin use of about 5 years. The majority of patients were receiving basal insulin at baseline, alone or in a basal/bolus regimen. The mean insulin dose at baseline was approximately 53 U/day in patients randomized to vildagliptin and about 50 U/day in those randomized to placebo, and did not change meaningfully in either group during the study. Fewer than 15% of patients were receiving an oral antidiabetic agent in addition to insulin, primarily sulfonylureas. The treatment groups were generally well balanced with respect to baseline characteristics.
Patient baseline demographic and background characteristics by treatment (randomized population)
depicts the time course of mean HbA1c during 24 weeks of treatment with vildagliptin 50 mg once daily or placebo added to prior insulin therapy. HbA1c values were consistently lower in the vildagliptin compared with the placebo group at all post-baseline visits. In the vildagliptin group, the AMΔ HbA1c from baseline (7.7% ± 0.1%) to endpoint was −0.9% ± 0.4%, while in the placebo group baseline HbA1c averaged 7.8% ± 0.1% and the AMΔ was −0.3% ± 0.4%. The between-treatment difference in AMΔ HbA1c (vildagliptin – placebo) was −0.6% ± 0.2% (P < 0.001).
Time course of mean HbA1c in patients with severe renal impairment receiving insulin therapy.
The percentage of patients (with baseline HbA1c ≥ 7.0%) achieving endpoint HbA1c < 7.0% in the vildagliptin group (33/73 patients, 45.2%) was twice that in the placebo group (13/57 patients, 22.8%, P = 0.008). Further, in patients with high baseline HbA1c > 8.0%, the absolute reduction in HbA1c with vildagliptin (baseline 9.0%, AMΔ −1.4% ± 0.3%, n = 30) was greater than in the overall study population, while there was a minor decrease with placebo (baseline 8.9%, AMΔ −0.2% ± 0.3%, n = 29), resulting in a between-group difference in AMΔ (vildagliptin – placebo) of −1.1% ± 0.3% (P = 0.001). In patients with baseline HbA1c > 9.0%, the decrease in HbA1c with vildagliptin was still larger (baseline HbA1c 9.5%, n = 15, AMΔ HbA1c −1.8% ± 0.5%), as was the between-treatment difference (−2.2% ± 0.7%, P = 0.008).
Fasting plasma glucose also decreased with vildagliptin plus insulin treatment. Baseline fasting plasma glucose averaged 8.1 ± 0.3 mmol/L in the vildagliptin group, and the AMΔ fasting plasma glucose was −2.4 ± 1.1 mmol/L. The between-treatment difference was −0.8 ± 0.4 mmol/L; however, this did not achieve statistical significance (P = 0.063).
The hypoglycemia profile was generally similar between vildagliptin and placebo when added to insulin. In the vildagliptin group, 19/100 patients (19.0%) experienced a total of 36 hypoglycemic events. In the placebo group, 11/78 patients (14.1%) experienced a total of 36 hypoglycemic events. Thus, in the placebo group, of the patients reporting any hypoglycemic event, a higher percentage reported two or more events (72.7% with placebo versus 47.4% with vildagliptin). Severe hypoglycemia was reported at a similarly low rate in the two groups (2.0% with vildagliptin and 2.6% with placebo).
Body weight remained constant in the vildagliptin group; baseline body weight averaged 82.2 ± 1.9 kg and the mean body weight at week 24 was 82.1 ± 2.2 kg. In the placebo group, baseline body weight was 78.7 ± 1.7 kg and at week 24 body weight averaged 79.4 ± 1.9 kg.
The overall adverse event profile was also similar in the two treatment groups, and there were no notable differences in the subgroup of insulin-treated patients with severe renal impairment compared with the overall study population that was previously reported. The percentage of patients receiving vildagliptin in combination with insulin and experiencing one or more adverse event, severe adverse event, or adverse event leading to discontinuation were 79.0%, 19.0%, and 10.0%, respectively. The corresponding percentages for the placebo plus insulin group were 76.9%, 24.4% and 6.4%, respectively. Apart from hypoglycemia, the most common specific adverse events were edema, hyperhidrosis, and dizziness. They were reported by similar percentages of patients in the vildagliptin and placebo groups. Two patients receiving vildagliptin (2.0%) and four patients receiving placebo (5.1%) died during the study: none of the deaths were suspected to be related to study medication.
There was no deterioration of renal function in either group after 24 weeks of treatment. The mean estimated GFRs at baseline were 21.8 ± 0.5 and 20.7 ± 0.8 mL/min/1.73 m2 in the vildagliptin and placebo group, respectively, and were 20.9 ± 0.7 and 19.3 ± 1.1 mL/min/1.73 m2 at week 24.