Metformin is the key factor in elevated plasma growth differentiation factor‐15 levels in type 2 diabetes: A nested, case–control study

Abstract

Produced as a tissue defence response to hypoxia and inflammation, growth differentiation factor-15 (GDF-15) is elevated in people receiving metformin treatment. To gain insight into the relationship of GDF-15 with metformin and major cardiovascular risk factors, we analysed the data from the SUMMIT cohort (n = 1438), a four-centre, nested, case-control study aimed at verifying whether biomarkers of atherosclerosis differ according to the presence of type 2 diabetes and cardiovascular disease. While in univariate analysis, major cardiovascular risk factors, with the exception of gender and cholesterol, increased similarly and linearly across GDF-15 quartiles, the independent variables associated with GDF-15, both in participants with and without diabetes, were age, plasma creatinine, N-terminal pro-brain natriuretic peptide, diuretic use, smoking exposure and glycated haemoglobin. In participants with diabetes, metformin treatment was associated with a 40% rise in GDF-15 level, which was independent of the other major factors, and largely explained their elevated GDF-15 levels. The relatively high GDF-15 bioavailability might partly explain the protective cardiovascular effects of metformin.

Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss

“…Furthermore, clinically relevant dosing of metformin increases serum GDF15 in mice and humans. The finding that metformin acutely increases serum GDF15 is consistent with our previous research 33 and that of others 34 , which show that serum GDF15 is correlated with metformin dose but not with the use of other glucose-lowering therapies in patients with insulin resistance or type 2 diabetes. Our data importantly establish that increases in serum GDF15 are not secondary to other actions of metformin, such as insulin sensitization, glucose-lowering and weight loss.…”

The impact of growth differentiation factor 15 on the risk of cardiovascular disease: evidence from Mendelian randomization study

“…It involved in the progress of in ammatory and oxidative stress [31], which participated in the process of diverse conditions, such as HF, CAD and CDK [32][33][34] and may lead the course of disease to a varying degree. Besides, GDF-15 might be an early warning, a composite sign of disease and a re ection determined by various but general elements [35]. Nevertheless, in our research, MR could avoid confounding factors to clarify causality between exposure (GDF-15 level) and outcome (AF).…”

The impact of growth differentiation factor 15 on the risk of cardiovascular disease: evidence from Mendelian randomization study

“…It involved in the progress of in ammatory and oxidative stress [27], which consist in the process of diverse conditions, such as HF, CAD and CDK [28][29][30] and may lead the course of disease to a varying degree. Besides, GDF-15 might be an early warning, a composite sign of disease and a re ection determined by various but general elements [31]. Nevertheless, in our research, MR could avoid confounding factors to clarify causality between exposure (GDF-15 level) and outcome (AF).…”