Comparison of different drugs as add-on treatments to metformin in type 2 diabetes: a meta-analysis

Diabetes Res Clin Pract. 2008 Feb;79(2):196-203. doi: 10.1016/j.diabres.2007.08.024. Epub 2007 Oct 10.


Background: Metformin is recommended as first-line treatment in type 2 diabetic patients. Several agents can be used as add-on treatments in metformin monotherapy failure. Most available clinical trials on the hypoglycemic efficacy of different drugs were performed either in monotherapy or in combination with agents other than metformin. Aim of the present meta-analysis is to collect available information on the efficacy of different hypoglycemic drugs, in combination with metformin, in patients failing to metformin, or to other oral monotherapies.

Methods: An extensive Medline search, together with manual search of references from retrieved articles, was performed to identify randomized clinical trials comparing the efficacy on HbA1c of different agents, compared with placebo or with other active drugs, in combination with metformin, in patients failing to oral hypoglycemic therapy. HbA1c reduction at 16-36 months was considered for meta-analysis.

Results: A total of 27 clinical trials were retrieved. Combining the results of different placebo-controlled trials, sulphonylureas, alpha-glucosidase inhibitors and thiazolidinediones induced a reduction [95%CI] of HbA1c of 0.85 [0.78; 0.94], 0.61 [0.55; 0.67], 0.42 [0.40; 0.44]%, respectively. In direct comparisons, sulphonylureas induced a greater reduction of HbA1c (of 0.17 [0.16; 0.18]%) than thiazolidinediones, and had a similar effect as insulin.

Conclusions: When combined with metformin, sulphonylureas and alpha-glucosidase inhibitors show a similar efficacy on HbA1c. The effects of drugs used as add-on to metformin monotherapy could be different from those observed in monotherapy.

Publication types

  • Comparative Study
  • Meta-Analysis

MeSH terms

  • Diabetes Mellitus, Type 2 / drug therapy*
  • Drug Therapy, Combination
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Metformin / therapeutic use*
  • Patient Selection
  • Placebos
  • Randomized Controlled Trials as Topic
  • Research Design


  • Hypoglycemic Agents
  • Placebos
  • Metformin