Effect of metformin on plasma metabolite profile in the Copenhagen Insulin and Metformin Therapy (CIMT) trial. Issue 7 (2nd May 2018)

• Record Type: Journal Article
• Authors: Safai, N.; Suvitaival, T.; Ali, A.; Spégel, P.; Al‐Majdoub, M.; Carstensen, B.; Vestergaard, H.; Ridderstråle, M.
• Other Names: Lundby‐Christensen L. investigator.; Tarnow L. investigator.; Boesgaard T. W. investigator.; Lund S. S. investigator.; Wiinberg N. investigator.; Perrild H. investigator.; Krarup T. investigator.; Snorgaard O. investigator.; Gade‐Rasmussen B. investigator.; Thorsteinsson B. investigator.; Røder M. investigator.; Mathiesen E. R. investigator.; Jensen T. investigator.; Vestergaard H. investigator.; Hedetoft C. investigator.; Breum L. investigator.; Duun E. investigator.; Sneppen S. B. investigator.; Pedersen O. investigator.; Hemmingsen B. investigator.; Madsbad S. investigator.; Gluud C. investigator.; Vaag A. investigator.; Almdal T. P. investigator.
• Is Part Of: Diabetic medicine. Volume 35:Issue 7(2018)
• Page Start: 944
• Page End: 953
• Publication Date: 2018-05-02
• Subjects: Diabetes -- Periodicals; 616.462
• DOI: 10.1111/dme.13636
• Languages: English
• ISSNs: 0742-3071

Abstract

Abstract: Aim: Metformin is the first‐line treatment for Type 2 diabetes. However, not all people benefit from this drug. Our aim was to investigate the effects of metformin on the plasma metabolome and whether the pretreatment metabolite profile can predict HbA1c outcome. Methods: Post hoc analysis of the Copenhagen Insulin and Metformin Therapy (CIMT) trial, a multicentre study from May 2008 to December 2012, was carried out. We used a non‐target method to analyse 87 plasma metabolites in participants with Type 2 diabetes ( n = 370) who were randomized in a 1 : 1 ratio to 18 months of metformin or placebo treatment. Metabolites were measured by liquid chromatography–mass spectrometry at baseline and at 18‐month follow‐up and the data were analysed using a linear mixed‐effect model. Results: At baseline, participants who were on metformin before the trial ( n = 312) had higher levels of leucine/isoleucine and five lysophosphatidylethanolamines (LPEs), and lower levels of carnitine and valine compared with metformin‐naïve participants ( n = 58). At follow‐up, participants randomized to metformin ( n = 188) had elevated levels of leucine/isoleucine and reduced carnitine, tyrosine and valine compared with placebo ( n = 182). At baseline, participants on metformin treatment with the highest levels of carnitine C10:1 and leucine/isoleucine had the lowest HbA1c ( P ‐interaction = 0.02 and 0.03, respectively). This association was not significant with HbA1c at follow‐up. Conclusions: Metformin treatment is associated with decreased levels of valine, tyrosine and carnitine, and increased levels of leucine/isoleucine. None of the identified metabolites can predict the HbA1c ‐lowering effect of metformin. Further studies of the association between metformin, carnitine and leucine/isoleucine are warranted. What's new?: This is the first randomized controlled trial of metformin vs. placebo to investigate responders to treatment with non‐targeted metabolomics in participants with Type 2 diabetes ( n = 370). Metformin treatment is associated with lower levels of valine and carnitine which are known to be associated with insulin resistance and mitochondrial dysfunction. Paradoxically, metformin is also associated with higher levels of lysophosphatidylethanolamines (LPEs) and leucine/isoleucine which are also known to be associated with diabetes and insulin resistance. None of the identified metabolites predicted a greater benefit of being treated with metformin in this study. Higher levels of leucine/isoleucine under metformin treatment are associated with lower HbA1c .