Long-term Efficacy and Tolerability of Add-on Pioglitazone Therapy To Failing Monotherapy Compared With Addition of Gliclazide or Metformin in Patients With Type 2 Diabetes

Charbonnel B, Schernthaner G, Brunetti P, et al. Diabetologia. 2005;48:1093-1104.

It has been well documented that many patients treated with long-term oral glucose-lowering monotherapy experience a progressive impairment in glycemic control over time. The failure of monotherapy has prompted several clinical trials designed to evaluate the effectiveness of combination therapy in maintaining long-term glycemic control. This article examined 2 recent studies on the efficacy, safety, and tolerability of pioglitazone as an add-on oral glucose-lowering agent.

The first randomised, double-blind trial compared the safety and efficacy of pioglitazone and a sulfonylurea (gliclazide) when added to existing metformin therapy. This 2-year study was conducted at 75 centers in 9 European countries and Australia. Patients were randomized to receive either pioglitazone (30-40 mg/day according to tolerability) or gliclazide (160-320 mg/day according to tolerability) in addition to their usual regimen of metformin. The second study compared pioglitazone as add-on therapy with metformin as add-on therapy to existing sulfonylurea treatment. This trial was conducted over a 2 year period at 91 centers in Europe and Canada. Subjects were randomized to add-on therapy with either pioglitazone or metformin for 92 weeks after a 12-week period of forced titration. In both studies, primary efficacy was measured by changes in A1C. Secondary efficacy measures included changes in lipids, insulin, and fasting plasma glucose.

The results of these 2 trials indicate that pioglitazone improves glycemic control and helps to sustain such improvements over a 2-year period. In the pioglitazone plus metformin versus gliclazide versus metformin study, changes in A1C from baseline to week 52 were not significant. However, at week 104 the proportion of patients who achieved a target A1C level of <7.0% was 30.6% in the pioglitazone group and 25.2% in the gliclazide group. The study comparing pioglitazone to metformin as add-on indicated no significant difference between the 2 groups in terms of A1C: at week 104 the proportion of subjects who had achieved A1C levels <7.0% was 30.2% for the pioglitazone group and 28.4% for the metformin group. Pioglitazone caused a significantly greater decrease in triglyceride levels and an increase in HDL levels, whether added to metformin or a sulfonylurea. In terms of serum insulin, pioglitazone caused a sustained decrease in fasting serum insulin in both studies. All treatment regimens were well tolerated, with the majority of adverse events falling in the mild to moderate range.

The data in these studies suggest that a combination of pioglitazone and metformin provide superior sustained glycemic control when compared with gliclazide and metformin. Further, the addition of pioglitazone or a sulphonylurea to metformin or the addition of pioglitazone or metformin to a sulphonylurea decreases A1C and fasting plasma glucose levels beyond those achieved with monotherapy alone. The outcomes of these trials suggest that the potential long-term sustainability and lipid-altering effects of pioglitazone may cause this treatment to become the preferred choice of add-on therapy.