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

Diabet Med. 2009 Dec;26(12):1242-9. doi: 10.1111/j.1464-5491.2009.02857.x.


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 > or = 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: add-on 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 (HbA(1c)) with pioglitazone than with placebo and more pioglitazone-treated patients achieved HbA(1c) 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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Aged
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Double-Blind Method
  • Female
  • Glycated Hemoglobin / analysis
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Male
  • Metformin / therapeutic use*
  • Middle Aged
  • Pioglitazone
  • Sulfonylurea Compounds / therapeutic use*
  • Thiazolidinediones / therapeutic use*
  • Treatment Outcome


  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Sulfonylurea Compounds
  • Thiazolidinediones
  • Metformin
  • Pioglitazone