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 (&bgr;=1.90 [95% confidence interval (CI), 0.82 to 2.98]; P=6.4×10−4) and ISZ (&bgr;=−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 (&bgr;=−0.40 [95% CI, −0.60 to −0.20]; P=6.4×2×10−5), small HDL-TG (&bgr;=−0.34 [95% CI, −0.53 to −0.14]; P=7.3×10−4), and the triglyceride content of very large HDL (&bgr;=−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.