Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes

Aims: To investigate, in the Carotid Atherosclerosis: Metformin for Insulin Resistance (CAMERA) trial (NCT00723307), whether the influence of metformin on the glucagon-like peptide (GLP)-1 axis in individuals with and without type 2 diabetes (T2DM) is sustained and related to changes in glycaemia or weight, and to investigate basal and post-meal GLP-1 levels in patients with T2DM in the cross-sectional Diabetes Research on Patient Stratification (DIRECT) study. Materials and methods: CAMERA was a double-blind randomized placebo-controlled trial of metformin in 173 participants without diabetes. Using 6-monthly fasted total GLP-1 levels over 18 months, we evaluated metformin's effect on total GLP-1 with repeated-measures analysis and analysis of covariance. In the DIRECT study, we examined active and total fasting and 60-minute post-meal GLP-1 levels in 775 people 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 interval [CI] 4.7-39.0), 12 (+26.7%, 95% CI 10.3-45.6) and 18 months (+18.7%, 95% CI 3.8-35.7), an overall increase of 23.4% (95% CI 11.2-36.9; P <.0001) vs placebo. Adjustment for changes in glycaemia and adiposity, individually or combined, did not attenuate this effect. In the DIRECT study, metformin was associated with higher fasting active (39.1%, 95% CI 21.3-56.4) and total GLP-1 (14.1%, 95% CI 1.2-25.9) but not post-meal incremental GLP-1. These changes were independent of potential confounders including age, sex, adiposity and glycated haemoglobin. Conclusions: In people without diabetes, metformin increases total GLP-1 in a sustained manner and independently of changes in weight or glycaemia. Metformin-treated patients with T2DM also have higher fasted GLP-1 levels, independently of weight and glycaemia.