Effect of Metformin on Metabolites and Relation with Myocardial Infarct Size and Left Ventricular Ejection Fraction after Myocardial Infarction

Background - Left ventricular ejection fraction (LVEF) and infarct size (ISZ) are key predictors of long-term survival after myocardial infarction (MI). However, little is known about the biochemical pathways driving LV dysfunction after MI. To identify novel biomarkers predicting post-MI LVEF and ISZ, we performed metabolic profiling in the GIPS-III randomized clinical trial (Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction). We also investigated the metabolic footprint of metformin, a drug associated with improved post-MI LV function in experimental studies. Methods and Results - Participants were patients with ST-segment-elevated MI who were randomly assigned to receive metformin or placebo for 4 months. Blood samples were obtained on admission, 24 hours post-MI, and 4 months post-MI. A total of 233 metabolite measures were quantified using nuclear magnetic resonance spectrometry. LVEF and ISZ were assessed 4 months post-MI. Twenty-four hours post-MI measurements of high-density lipoprotein (HDL) triglycerides (HDL-TG) predicted LVEF (β=1.90 [95% confidence interval (CI), 0.82 to 2.98]; P=6.4×10-4) and ISZ (β=-0.41 [95% CI, -0.60 to -0.21]; P=3.2×10-5). In addition, 24 hours post-MI measurements of medium HDL-TG (β=-0.40 [95% CI, -0.60 to -0.20]; P=6.4×2×10-5), small HDL-TG (β=-0.34 [95% CI, -0.53 to -0.14]; P=7.3×10-4), and the triglyceride content of very large HDL (β=-0.38 [95% CI, -0.58 to -0.18]; P=2.7×10-4) were associated with ISZ. After the 4-month treatment, the phospholipid content of very large HDL was lower in metformin than in placebo-treated patients (28.89% versus 38.79%; P=7.5×10-5); alanine levels were higher in the metformin group (0.46 versus 0.44 mmol/L; P=2.4×10-4). Conclusions - HDL triglyceride concentrations predict post-MI LVEF and ISZ. Metformin increases alanine levels and reduces the phospholipid content in very large HDL particles. Clinical Trial Registration - URL: https://clinicaltrials.gov/ct2/show/NCT01217307. Unique Identifier: NCT01217307.