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

TY - JOUR

T1 - The sustained influence of metformin therapy on circulating GLP-1 levels in individuals with and without type 2 diabetes

AU - Preiss, David

AU - Dawed, Adem

AU - Welsh, Paul

AU - Heggie, Alison

AU - Jones, Angus G.

AU - Dekker, Jacqueline

AU - Koivula, Robert

AU - Hansen, Tue H.

AU - The DIRECT consortium

AU - Stewart, Caitlin

AU - Holman, Rury R.

AU - Franks, Paul W.

AU - Walker, Mark

AU - Pearson, Ewan R.

AU - Sattar, Naveed

N1 - DP is guarantor for CAMERA data and ERP for DIRECT data. CAMERA was funded by the Chief Scientist Office, Scotland (CZB/4/613). We are grateful to Sara Jane Duffus and Elaine Butler for analysing GLP-1 on the CAMERA samples. The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. ERP holds a Wellcome Trust New Investigator Award (ref 102820/Z/13/Z).

PY - 2017/3

Y1 - 2017/3

N2 - 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.

AB - 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.

KW - antidiabetic drug

KW - GLP-1

KW - metformin

U2 - 10.1111/dom.12826

DO - 10.1111/dom.12826

M3 - Article

C2 - 27862873

SN - 1462-8902

VL - 19

SP - 356

EP - 363

JO - Diabetes, Obesity & Metabolism

JF - Diabetes, Obesity & Metabolism

IS - 3

ER -