Lack of evidence to choose second line drug treatments for type 2 diabetes


For people with type 2 diabetes, metformin is the usual choice for first-line drug treatment.  However, there remains some uncertainty as to the best choice for second-line treatments if metformin alone fails to achieve adequate glycaemic control.  This systematic review set out to find out which is the most effective choice.

The reviewers conducted a search of the main bibliographic databases and found 49 randomised trials relevant to the topic.  These studies evaluated the effectiveness of sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 analogues, insulins and insulin analogues, alpha-glucosidase inhibitors and the weight-loss agents orlistat and sibutramine.  The reviewers analysed combination treatments as well as individual drugs being added to metformin.

The outcomes they looked at were:  HbA1c, hypoglycemia, body weight, complications, adverse events, quality of life and patient satisfaction.  All of the data from the trials were combined in a meta-analysis.

Bottom line

This complex and comprehensive review concluded that there was no evidence of significant differences between drug classes.  Further large, longer term studies are needed to resolve this important question.

Appraisal hints

Users of this research should consider:

  • Whether the study populations were sufficiently similar to warrant combined analysis
  • The possible impact of bias from the low quality of many of the studies
  • Whether the short duration of many studies allowed enough time for outcomes to appear
  • Whether new studies have emerged since the review literature search was carried out in June 2009.


The full text of this review is available from the Canadian Agency for Drugs and Technology in Health (CADTH):

McIntosh B, Cameron C, Singh SR, Yu C, Ahuja T, Welton NJ, Dahl M. Second-line therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a systematic review and mixed-treatment comparison meta-analysis. Open Med. 2011;5(1):e35-e48. Epub 2011 Mar 1.

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I am an information scientist with an interest in making knowledge from systematic research more accessible to people who need it. This means you. I've been attempting this in the area of Evidence-Based Health Care since 1995. So far the results have been mixed. For some reason we expected busy clinicians to search databases and appraise papers instead of seeing patients. We also expected publishers to make the research freely available to the people who paid for it.. Ha! Hence The National Elf service.

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