Limited evidence for GLP-1 analogs as second line treatment for type 2 diabetes

A syringe

There remains considerable uncertainty as to the next step for treatment of type 2 diabetes that has not been successfully controlled using metformin.  A recent systematic review looked at this issue.

Clinical question:

In type 2 diabetes inadequately controlled on metformin alone, what additional therapy improves glycemic control?

The reviewers also looked at potential adverse events, including hypoglycemia and body weight.

The evidence:

The reviewers found 39 studies, including 17,680 patients.  They conducted a network meta-analysis of this data and found that glucagon-like peptide-1 (GLP-1) analogs improved HbA1C more than sulfonylureas, glinides, thiazolidinediones, a- glucosidase inhibitors and DPP-4 inhibitors.  They did not increase the risk of hypoglycemia and reduced body weight.

The reviewers concluded:

Biphasic insulin, GLP-1 analogs and basal insulin were ranked the top 3 drugs in terms of A1C reduction.

Appraisal hints:

Users of this research should consider:

  • The reviewers only searched PubMed and the Cochrane Library.  It is likely that they missed important research.
  • Did they perform blind, independent assessment of the quality of the studies and extraction of the source data?
  • Was there an explicit protocol specified in advance of the review that was adhered to throughout and whose results were reported in full?
  • Does it make sense to combine the results of these different studies on different populations?  Were the studies consistent in their use of co-interventions?
  • Did the reviewers investigate the impact of possible heterogeneity?
  • There was a lot of uncertainty around the estimates of benefit, suggesting that more research is needed in order to improve the precision.
  • Did the reviewers consistently report adverse outcomes?  There are safety concerns around GLP-1 analogs with respect to thyroid tumours and pancreatitis.
  • What outcomes matter to your patient?


Liu SC, Tu YK, Chien MN, Chien KL. Effect of antidiabetic agents added to metformin on glycemic control, hypoglycemia and weight change in patients with type 2 diabetes: a network meta-analysis. Diabetes Obes Metab. 2012 Apr 9.

See also:

An older systematic review of second line therapies found no significant benefit on glycemic control (full text available):

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):e35-48. Epub 2011 Mar 1.

Read the FDA’s assessment of risk vs benefit for GLP-1 analogs:

Parks M, Rosebraugh C.  Weighing Risks and Benefits of Liraglutide — The FDA’s Review of a New Antidiabetic Therapy. N Engl J Med 2010; 362:774-777.

You can also read the NICE Health Technology Assessment, which does not recommend GLP-1 analogs for second line treatment, and browse related items on The Diabetes Elf.

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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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