Long-term glycaemic effects of pioglitazone compared with placebo as add-on treatment to metformin or sulphonylurea monotherapy in PROactive (PROactive 18)

Abstract
Aims To assess the long-term glycaemic effects, concomitant changes in medications,
and initiation of permanent insulin use (defined as daily insulin use for a period of ≥90
days, or ongoing use at death/final visit) with pioglitazone vs. placebo in diabetic patients
receiving metformin or sulphonylurea monotherapy at baseline in the PROspective
pioglitAzone Clinical Trial in macroVascular Events (PROactive).
Methods In PROactive, patients with Type 2 diabetes and macrovascular disease were
randomized to pioglitazone (force-titrated to 45 mg/day) or placebo, in addition to other
existing glucose-lowering therapies. In a post-hoc analysis, we categorized patients not
receiving insulin at baseline and treated by oral monotherapy into two main cohorts: addon
to metformin alone (n = 514) and sulphonylurea alone (n = 1001). The follow-up
averaged 34.5 months.
Results There were significantly greater reductions in glycated haemoglobin (HbA1c)
with pioglitazone than with placebo and more pioglitazone-treated patients achieved
HbA1c targets, irrespective of the baseline oral glucose-lowering regimen and despite a
decrease in the use of other glucose-lowering agents. Approximately twice as many in the
placebo groups progressed to permanent insulin use than in the pioglitazone groups
across the two cohorts: 3.4% for pioglitazone and 6.5% for placebo when added to
metformin monotherapy and 6.3% and 14.8%, respectively, when added to sulphonylurea
monotherapy. The overall safety of both dual therapies was good.
Conclusions Intensifying an existing oral monotherapy regimen to a dual oral regimen by
adding pioglitazone resulted in sustained improvements in glycaemic control and reduced
progression to insulin therapy. The efficacy and safety of adding pioglitazone to either
metformin monotherapy or sulphonylurea monotherapy were good.