Growth Differentiation Factor 15 as a Novel Biomarker for Metformin

Abstract

OBJECTIVEMetformin is a commonly used glucose-lowering drug. However, apart from glycemic measures, no biomarker for its presence or dose has been identified. RESEARCH DESIGN AND METHODSA total of 237 biomarkers were assayed in baseline serum from 8,401 participants (2,317 receiving metformin) in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Regression models were used to identify biomarkers for metformin use. RESULTSGrowth differentiation factor 15 (GDF15) was strongly linked to metformin, such that the odds of metformin use per SD increase in level varied from 3.73 (95% CI 3.40, 4.09) to 3.94 (95% CI 3.59, 4.33) depending on the other included variables. For the remaining 25 linked biomarkers, the odds ranged from 0.71 to 1.24. A 1.64 ng/mL higher GDF15 level predicted a 188-mg higher metformin dose (P < 0.0001). CONCLUSIONSGDF15 levels are a biomarker for the use of metformin in people with dysglycemia, and its concentration reflects the dose of metformin.Metformin is currently the most widely used glucose-lowering agent in the world that effectively lowers glucose levels; reduces incident diabetes (1); modestly reduces weight; and may reduce the occurrence of ischemic heart disease, mortality, and some malignancies (2). Whereas its glucometabolic effects are partially due to activation of the AMP-activated protein kinase (3), some of its other effects may be mediated by novel pathways. To identify nonglycemic biomarkers for such pathways, we screened a large panel of 237 markers, covering major physiological pathways that were assayed in baseline serum samples collected in 8,401 participants (;28% of whom were receiving various doses of metformin) in the recently completed Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. RESEARCH DESIGN AND METHODSThe ORIGIN trial recruited 12,537 people with diabetes, impaired glucose tolerance, or impaired fasting glucose levels who had additional cardiovascular (CV) risk factors (4). Prior to randomization, 8,494 participants (68%) provided baseline blood samples that were spun, separated, aliquoted, frozen (within 2 h of collection), and transported to the Population Health Research Institute Biobank in Hamilton, Ontario, Canada, where they were stored in nitrogen vapor-cooled tanks at 2160°C. A

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

“…We also showed that metformin use was associated with elevated GDF-15 plasma levels and demonstrated that its contribution largely explains the consistent finding of increased plasma GDF-15 levels in T2D. 8 When all the relevant variables were entered into a multivariate model, a similar pattern was observed in both study groups and in the whole cohort, with NT-proBNP, age and serum creatinine emerging as the strongest predictors ( Table 1). The major difference was in the strength of the association with metformin in participants with T2D, which was much greater than and also independent of any other variable, being responsible for a 40% rise in GDF-15 level.…”

“…Although still observed after adjusting for ongoing statin therapy, the achieved LDL cholesterol levels are likely to inversely reflect the overall cardiovascular risk of the patients. We also showed that metformin use was associated with elevated GDF‐15 plasma levels and demonstrated that its contribution largely explains the consistent finding of increased plasma GDF‐15 levels in T2D …”

“…Although elevated GDF‐15 plasma levels have been consistently found in T2D, no information is available on whether the degree of metabolic control has an impact per se, and whether this is caused by the higher prevalence of cardiovascular and/or kidney disease in people with T2D or by a different sensitivity to known major GDF‐15 modulators. Information with regard to the effect of the different glucose‐lowering treatments is also limited; interestingly, in the ORIGIN trial, among 237 serum biomarkers, the only one associated with metformin treatment was GDF‐15 …”

“…Information with regard to the effect of the different glucose-lowering treatments is also limited; interestingly, in the ORIGIN trial, among 237 serum biomarkers, the only one associated with metformin treatment was GDF-15. 8 Despite its anti-apoptotic, antihypertrophic and anti-inflammatory actions, as a clinical biomarker GDF-15 appears to reflect the severity of cardiovascular disease (CVD) 9 rather than the extent of the activation of the protective mechanisms observed in vitro. Nevertheless, if metformin is able to upregulate GDF-15 circulating levels independently of other factors, this might represent a mechanism through which the drug exerts its effect in terms of CVD protection.…”

GDF15 and the beneficial actions of metformin in pre-diabetes

“…Although many mechanisms of action for the insulin sensitizing actions of metformin have been proposed 4 , few if any of these would explain the beneficial weight loss promoting effects of the drug which continue to be recognised 5 . A recent observational epidemiological study 6 noted a robust association of metformin use with circulating levels of GDF15, a peptide hormone produced by cells responding to a wide range of stressors 7 . GDF15 acts through a receptor complex solely expressed in the hindbrain, through which it suppress food intake [8][9][10][11] .…”