Metabolic effects of pioglitazone in combination with insulin in patients with type 2 diabetes mellitus whose disease is not adequately controlled with insulin therapy: Results of a six-month, randomized, double-blind, prospective, multicenter, parallel-group study

Abstract

Type 2 diabetes mellitus (DM) is a progressive disease. Initial therapy begins with dietary and lifestyle modifications. However, as the disease progresses, glycemic control becomes more difficult to attain, often requiring > or =1 oral antihyperglycemic medication (OAM), and finally the addition of insulin to the OAMs and insulin monotherapy. This study was designed to determine the effect of pioglitazone 30 mg plus insulin (PIO + INS) versus placebo plus insulin (PLB + INS) on glycemic control, the serum lipid profile, and selected cardiovascular risk factors in patients with type 2 DM whose disease was inadequately controlled with insulin therapy alone despite efforts to intensify such treatment. This was a 6-month, randomized, double-blind, prospective, multicenter, placebo-controlled, parallel-group study. Patients with type 2 DM and a glycosylated hemoglobin (HbA(1c)) value > or =7.5% who were using insulin (with or without OAMs) entered a 3-month insulin intensification phase to achieve blood glucose targets with insulin monotherapy. After insulin intensification, those patients with HbA(1c) values > or =7.0% were randomized to PIO + INS or PLB + INS. The primary end point was the change in HbA(1c) from baseline. Cardiovascular risk markers (highly sensitive C-reactive protein [hs CRP] and plasminogen activator inhibitor-1 [PAI-1]) were measured at baseline and end point. Of the 289 patients randomized to treatment (mean [SD] age, 58.9 [7.1] years; 164 women, 125 men), 142 received PIO + INS and 147 received PLB + INS. A total of 263 patients completed the study. After 6 months, PIO + INS reduced mean HbA(1c) (-0.69%; P < 0.002) and mean fasting plasma glucose ([FPG] -1.45 mmol/L; P < 0.002) from baseline. PLB + INS produced no significant changes in HbA(1c) or FPG. The between-treatment differences for HbA(1c) (-0.55%; P < 0.002) and FPG (-1.80 mmol/L; P < 0.002) occurred despite a reduction of insulin dose in the PIO + INS group from baseline (-0.16 U/d . kg; P < 0.002). Significant between-group differences were observed for high-density lipoprotein cholesterol (0.13 mM; P < 0.002), triglycerides (ratio of geometric mean [PIO/PLB], 0.871; P < 0.01), atherogenic index of plasma (-0.11; P < 0.002), PAI-1 (-5.10 U/mL; P < 0.001), and hs CRP (-1.47 mg/L; P < 0.05). The rate of clinical and biochemical hypoglycemia (blood glucose <2.8 mmol/L) did not differ statistically between treatment groups, but reported incidences of subjective hypoglycemia occurred more often with PIO + INS than with PLB + INS (90 vs 75; P < 0.05). Edema was more common with PIO + INS than with PLB + INS (20 vs 5 instances, respectively), as was gain (mean [SEM]) in body weight (4.05 [4.03] vs 0.20 [2.92] kg, respectively). Adding pioglitazone to insulin in these study patients with type 2 DM whose disease was inadequately controlled with insulin monotherapy further improved their glycemic control.