The sustained influence of metformin therapy on circulating GLP-1 levels in individuals with and without type 2 diabetes

David Preiss (Lead / Corresponding author), Adem Dawed, Paul Welsh, Alison Heggie, Angus G. Jones, Jacqueline Dekker, Robert Koivula, Tue H. Hansen, The DIRECT consortium, Caitlin Stewart, Rury R. Holman, Paul W. Franks, Mark Walker, Ewan R. Pearson, Naveed Sattar

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Aims: Small, short studies suggest metformin influences the glucagon-like peptide (GLP)-1 axis in individuals with and without type 2 diabetes (T2DM). In the Carotid Atherosclerosis: Metformin for insulin ResistAnce (CAMERA) trial (NCT00723307) we investigated whether this effect is sustained and related to changes in glycaemia or weight. In the cross-sectional DIabetes REsearCh on patient straTification (DIRECT) study, we investigated basal and post-meal GLP-1 levels in diabetic patients.

Materials and methods: CAMERA was a double-blinded randomized placebo-controlled trial of metformin in 173 participants without diabetes. Using six-monthly fasted total GLP-1 levels over 18 months, we evaluated metformin's effect on total GLP-1 with repeated-measures and ANCOVA analyses. In DIRECT, we examined active and total fasting and 60-minute post-meal GLP-1 levels in 775 patients recently diagnosed with T2DM treated with metformin or diet, using Student's T-tests and linear regression.

Results: In CAMERA, metformin increased total GLP-1 at 6 (+20.7%, [95% confidence intervals 4.7-39.0%]), 12 (+26.7% [10.3-45.6%]) and 18 months (+18.7% [3.8-35.7%]), an overall increase of 23.4% (11.2-36.9%; p < 0.0001) versus placebo. Adjustment for changes in glycaemia and adiposity, individually or combined, did not attenuate this effect. In DIRECT, metformin was associated with higher fasting active (39.1% [21.3-56.4%]) and total GLP-1 (14.1% [1.2-25.9%]) but not post-meal incremental GLP-1. These changes were independent of potential confounders including age, sex, adiposity and HbA1c.

Conclusions: In non-diabetic individuals, metformin increases total GLP-1 in a sustained manner and independently of changes in weight or glycaemia. Metformin-treated diabetic patients also have higher fasted GLP-1 independent of weight and glycaemia.

Original languageEnglish
Pages (from-to)356-363
Number of pages8
JournalDiabetes, Obesity & Metabolism
Issue number3
Early online date13 Nov 2016
Publication statusPublished - Mar 2017


  • antidiabetic drug
  • GLP-1
  • metformin


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