Long-term glycaemic control with metformin-sulphonylurea-pioglitazone triple therapy in PROactive (PROactive 17)

Diabet Med. 2009 Oct;26(10):1033-9. doi: 10.1111/j.1464-5491.2009.02816.x.


Aims: We assessed the long-term glycaemic effects and the safety profile of triple therapy with the addition of pioglitazone vs. placebo in patients with Type 2 diabetes treated with combined metformin-sulphonylurea therapy in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive).

Methods: In a post-hoc analysis, we identified patients treated with metformin plus sulphonylurea combination therapy and not receiving insulin at baseline (n = 1314). In those patients, we compared the effects of pioglitazone (force-titrated to 45 mg/day, n = 654) vs. placebo (n = 660) on glycated haemoglobin (HbA(1c)) reduction, 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).

Results: Significantly greater reductions in HbA(1c) and greater proportions of patients with HbA(1c) at target were noted with pioglitazone vs, placebo, despite a decrease in the use of other oral glucose-lowering agents. There was an approximate twofold increase in progression to permanent insulin use in the placebo group vs. the pioglitazone group: 31.1 vs. 16.1%, respectively, when added to combination therapy. The overall safety of the metformin-sulphonylurea-pioglitazone triple therapy was good.

Conclusions: Intensifying an existing dual oral therapy regimen to a triple oral regimen by adding pioglitazone to the classical metformin-sulphonylurea combination resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The advantages and disadvantages of adding pioglitazone instead of adding basal insulin should be assessed further.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Glycated Hemoglobin / metabolism*
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Metformin / therapeutic use*
  • Middle Aged
  • Pioglitazone
  • Sulfonylurea Compounds / therapeutic use*
  • Thiazolidinediones / therapeutic use*
  • Treatment Outcome


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

Associated data

  • ISRCTN/ISRCTN00174993