Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort

Abstract

Type 2 diabetes (T2D) is a rising pandemic worldwide. Diet and lifestyle changes are typically the first intervention for T2D. When this intervention fails, the biguanide, metformin, is the most common pharmaceutical therapy. Yet, it's full mechanisms of action remain unknown. In this work, we applied an ultrahigh resolution, mass spectrometry-based platform for untargeted plasma metabolomics to human plasma samples from a case-control observational study of non-diabetic and well-controlled T2D subjects, the latter treated conservatively with metformin or diet and lifestyle changes only. No statistically significant differences existed in baseline demographic parameters, glucose control, or clinical markers of cardiovascular disease risk between the two T2D groups, which we hypothesized would allow the identification of circulating metabolites independently associated with treatment modality. Over 3000 blank-reduced metabolic features were detected, with the majority of annotated features being lipids or lipid-like molecules. Altered abundance of multiple fatty acids and phospholipids were found in T2D subjects treated with diet and lifestyle changes as compared to nondiabetic subjects: changes that were often reversed by metformin. Our findings provide direct evidence that metformin monotherapy alters the human plasma lipidome independent of T2D disease control and support a potential cardioprotective effect of metformin worthy of future study. Significance Statement:This work provides important new information on the systemic effects of metformin in type 2 diabetic subjects. We observed significant changes in the plasma lipidome with metformin therapy, with metabolite classes previously associated with cardiovascular disease risk significantly reduced as compared to diet and lifestyle changes. While cardiovascular disease risk was not a primary outcome of our study, our results provide a jumping-off point for future work into the cardioprotective effects of metformin, even in well-controlled type 2 diabetes.

Integration of Vitreous Lipidomics and Metabolomics for Comprehensive Understanding of the Pathogenesis of Proliferative Diabetic Retinopathy

“…Studies have shown that hypoglycemic agents influence metabolomic and lipidomic profiles in humans . Among diabetic patients with good blood glucose control, the overall lipidomic status of patients taking metformin was closer to that of patients without diabetes when compared with diet and lifestyle interventions . Therefore, given that approximately 50% of PDR patients (24/49) in this study were using oral hypoglycemic agents, this difference in medication use may lead to the identification of fewer differential metabolites and lipids.…”

A Special Section on Clinical Pharmacology—Editorial

“…In the first article, type 2 diabetic patients treated with metformin showed reduced plasma levels of lipid metabolites known to associate with cardiovascular disease risk. Inasmuch as lipidome changes were independent of glycemic control and pre-existing cardiovascular risk, these results suggested that an old drug such as metformin might represent a new cardioprotective agent (Wancewicz et al, 2023). In the second "drug repurposing" article the venerable aspirin, unparalleled game changer in cardiovascular prevention, is reviewed for mechanisms and clinical evidence of preventive effects against colorectal cancer and other cancers of the digestive tract, something that could only be reconciled with the seemingly unlimited ramifications of aspirin-dependent inhibition of cyclooxygenases (Patrono, 2023).…”

Comprehensive Metabolomic Analysis of Human Heart Tissue Enabled by Parallel Metabolite Extraction and High-Resolution Mass Spectrometry

“…Second, it is essential to efficiently detect and identify the extracted metabolites. There are multiple mass spectrometry (MS)-based platforms that can be used for the analysis of metabolites, each having its own unique advantage. − As previously demonstrated, direct infusion workflows can rapidly and reproducibly detect hundreds of metabolites when coupled with ultrahigh-resolution MS. , On the other hand, there are many pathways that contain isomeric metabolites (e.g., leucine and isoleucine) which require the implementation of additional separation strategies prior to MS detection. As a complementary technique, liquid chromatography (LC) separation coupled to high-resolution MS allows for the separation of some structural isomers while providing high-resolution detection. , Moreover, tandem mass spectra (MS/MS) can be generated by using this approach, allowing for fragmentation matching.…”