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

  • Andrea Natali
  • Lorenzo Nesti
  • Elena Venturi
  • Angela C. Shore
  • Faisel Khan
  • Kim Gooding
  • Phillip E. Gates
  • Helen C. Looker
  • Fiona Dove
  • Isabel Goncalves
  • Margaretha Persson
  • Jan Nilsson
Publishing year: 2019-02
Language: English
Pages: 412-416
Publication/Series: Diabetes, Obesity and Metabolism
Volume: 21
Issue: 2
Document type: Journal article
Publisher: Wiley-Blackwell

Abstract english

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.


  • Endocrinology and Diabetes
  • Cardiac and Cardiovascular Systems
  • cardiovascular disease
  • GDF-15
  • growth differentiation factor-15
  • metformin
  • type 2 diabetes


  • Cardiovascular Research - Immunity and Atherosclerosis
  • Internal Medicine - Epidemiology
  • ISSN: 1462-8902
E-mail: jan [dot] nilsson [at] med [dot] lu [dot] se

Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00