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

David Preiss, Adem Dawed, Paul Welsh, Alison Heggie, Angus G Jones, Jacqueline Dekker, Robert Koivula, Tue H Hansen, Caitlin Stewart, Rury R Holman, Paul W Franks, Mark Walker, Ewan R Pearson, Naveed Sattar, DIRECT consortium group

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)356-363
Number of pages8
JournalDiabetes, Obesity and Metabolism
Volume19
Issue number3
DOIs
Publication statusPublished - Mar 2017

Cite this

Preiss, David ; Dawed, Adem ; Welsh, Paul ; Heggie, Alison ; Jones, Angus G ; Dekker, Jacqueline ; Koivula, Robert ; Hansen, Tue H ; Stewart, Caitlin ; Holman, Rury R ; Franks, Paul W ; Walker, Mark ; Pearson, Ewan R ; Sattar, Naveed ; DIRECT consortium group. / Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes. In: Diabetes, Obesity and Metabolism. 2017 ; Vol. 19, No. 3. pp. 356-363.
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title = "Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes",
abstract = "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.",
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author = "David Preiss and Adem Dawed and Paul Welsh and Alison Heggie and Jones, {Angus G} and Jacqueline Dekker and Robert Koivula and Hansen, {Tue H} and Caitlin Stewart and Holman, {Rury R} and Franks, {Paul W} and Mark Walker and Pearson, {Ewan R} and Naveed Sattar and {DIRECT consortium group}",
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Preiss, D, Dawed, A, Welsh, P, Heggie, A, Jones, AG, Dekker, J, Koivula, R, Hansen, TH, Stewart, C, Holman, RR, Franks, PW, Walker, M, Pearson, ER, Sattar, N & DIRECT consortium group 2017, 'Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes' Diabetes, Obesity and Metabolism, vol. 19, no. 3, pp. 356-363. https://doi.org/10.1111/dom.12826

Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes. / Preiss, David; Dawed, Adem; Welsh, Paul; Heggie, Alison; Jones, Angus G; Dekker, Jacqueline; Koivula, Robert; Hansen, Tue H; Stewart, Caitlin; Holman, Rury R; Franks, Paul W; Walker, Mark; Pearson, Ewan R; Sattar, Naveed; DIRECT consortium group.

In: Diabetes, Obesity and Metabolism, Vol. 19, No. 3, 03.2017, p. 356-363.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Sustained influence of metformin therapy on circulating glucagon-like peptide-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 - Stewart, Caitlin

AU - Holman, Rury R

AU - Franks, Paul W

AU - Walker, Mark

AU - Pearson, Ewan R

AU - Sattar, Naveed

AU - DIRECT consortium group

N1 - © 2016 John Wiley & Sons Ltd.

PY - 2017/3

Y1 - 2017/3

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Blood Glucose

KW - Body Weight

KW - Case-Control Studies

KW - Diabetes Mellitus, Type 2

KW - Double-Blind Method

KW - Fasting

KW - Female

KW - Glucagon-Like Peptide 1

KW - Glycated Hemoglobin A

KW - Humans

KW - Hypoglycemic Agents

KW - Male

KW - Metformin

KW - Middle Aged

KW - Peptides

KW - Postprandial Period

KW - Journal Article

KW - Randomized Controlled Trial

KW - Research Support, Non-U.S. Gov't

U2 - 10.1111/dom.12826

DO - 10.1111/dom.12826

M3 - Article

VL - 19

SP - 356

EP - 363

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 3

ER -