Comparison of Pioglitazone (Actos) (15 mg and 30 mg) with Placebo as an Add-on to Insulin
Study Design
This was a multicentre, randomised, double-blind, placebo-controlled study of the safety and efficacy of 2 doses of pioglitazone (Actos) (15 or 30 mg) in combination with insulin compared with insulin alone in patients with type 2 diabetes mellitus whose glucose levels were poorly controlled with their current insulin therapy. Patients who participated in this study were 30 to 75 years of age inclusive, had an HbA1c value greater than or equal to 8.0%, had received insulin therapy of at least 30 units/day for 4 months or longer, and were on a stable, fixed dose of insulin for at least 30 days before the study (with or without metformin, acarbose, or a sulphonylurea).
The primary efficacy variable was change from Baseline in HbA1c. The secondary efficacy variables were HbA1c responder rate defined as a percentage of patients achieving a clinically relevant target value, fasting plasma glucose (FPG), fasting C-peptide, triglycerides, and cholesterol (total, high density lipoprotein (HDL) cholesterol, and low density lipoprotein (LDL) cholesterol. Comparisons between placebo plus insulin and each of the 2 pioglitazone (Actos) plus insulin treatment groups, with respect to changes in the primary and secondary variables, were performed using the Dunnett test with estimates of means and variances obtained from a 2-way ANCOVA model. A total of 566 patients were randomly assigned to treatment and included in the intent-to-treat (ITT) population. Mean age at Baseline was 57 years, and mean body mass index (BMI) was 33.6 kg/m2. Most patients were Caucasian (73%), and slightly more than half (53%) were female. Baseline systolic blood pressure was slightly higher for the groups who received pioglitazone (Actos) plus insulin than for the group who received placebo plus insulin, but there were no differences among the treatment groups with respect to any other baseline variable.
Results
All treatment groups had statistically significant mean decreases from Baseline in HbA1c throughout the study, and both groups of patients who received pioglitazone (Actos) plus insulin had a statistically significantly greater reduction in HbA1c than the group of patients who received placebo plus insulin. At Endpoint (Week 16), those who received 15 mg of pioglitazone (Actos) plus insulin had a mean reduction in HbA1c that was 0.73% (95% CI, -100, -0.47) beyond that observed in the placebo plus insulin group, and the group who received 30 mg of pioglitazone (Actos) plus insulin had a reduction that was 1.00% (95% CI, -1.27, -0.74) beyond that observed with placebo plus insulin. The reduction in HbA1c levels was reflected in the number of HbA1c responders, as 31.6% of the patients who received placebo, 69.5% who received 15 mg of pioglitazone (Actos), and 75.1% who received 30 mg of pioglitazone (Actos) exhibited a 0.6 percentage point decrease in HbA1c, a reduction in HbA1c to a level of 6.1% or lower, or both, without requiring an increase in daily insulin dose of 25% or more.