Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension

Abstract

Background Metabolic dysfunction is highly prevalent in pulmonary arterial hypertension (PAH) and likely contributes to both pulmonary vascular disease and right ventricular (RV) failure in part because of increased oxidant stress. Currently, there is no cure for PAH and human studies of metabolic interventions, generally well tolerated in other diseases, are limited in PAH. Metformin is a commonly used oral antidiabetic that decreases gluconeogenesis, increases fatty acid oxidation, and reduces oxidant stress and thus may be relevant to PAH. Methods and Results We performed a single-center, open-label 8-week phase II trial of up to 2 g/day of metformin in patients with idiopathic or heritable PAH with the co-primary end points of safety, including development of lactic acidosis and study withdrawal, and plasma oxidant stress markers. Exploratory end points included RV function via echocardiography, plasma metabolomic analysis performed before and after metformin therapy, and RV triglyceride content by magnetic resonance spectroscopy in a subset of 9 patients. We enrolled 20 patients; 19/20 reached the target dose and all completed the study protocol. There was no clinically significant lactic acidosis or change in oxidant stress markers. Metformin did not change 6-minute walk distance but did significantly improve RV fractional area change (23±8% to 26±6%, P=0.02), though other echocardiographic parameters were unchanged. RV triglyceride content decreased in 8/9 patients (3.2±1.8% to 1.6±1.4%, P=0.015). In an exploratory metabolomic analysis, plasma metabolomic correlates of ≥50% reduction in RV lipid included dihydroxybutyrate, acetylputrescine, hydroxystearate, and glucuronate (P<0.05 for all). In the entire cohort, lipid metabolites were among the most changed by metformin. Conclusions Metformin therapy was safe and well tolerated in patients with PAH in this single-arm, open-label phase II study. Exploratory analyses suggest that metformin may be associated with improved RV fractional area change and, in a subset of patients, reduced RV triglyceride content that correlated with altered lipid and glucose metabolism markers. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT01884051.

Keywords: insulin resistance; metformin; pulmonary arterial hypertension; right ventricle.

Conflict of interest statement

ARH has served as a consultant to Actelion, Bayer, Complexa, United Therapeutics. She has received grant funding from the Cardiovascular Medical Research and Education Fund and National Institutes of Health and holds stock options with PHPrecisionMed. IMR has received research support from Complexa and Bayer. The remaining authors have no disclosures to report.

Figures

Figure 1. Flow diagram.

DM indicates diabetes mellitus; MRS, magnetic resonance spectroscopy; PAH, pulmonary arterial hypertension; and PFT, pulmonary function test.

Figure 2. Effect of metformin on right ventricular triglyceride content and metabolomic correlates of improvement.

A, Change in myocardial triglyceride content by cardiac magnetic resonance spectroscopy (n=8). Published reference ranges for obesity and diabetes mellitus are shown. 28 , 29B, Plasma metabolomic pattern was compared pre‐ and postmetformin therapy and segregated by ≥50% reduction in right ventricular (RV) triglyceride (Responders) or <50% reduction (non‐responders). Significantly different ratios were identified in several plasma metabolites of relevance to PAH and lipid and glucose metabolism. *P<0.05.

Figure 3. Effects of metformin on plasma metabolome in pulmonary arterial hypertension.

A, Heatmap demonstrating significantly altered pathways after metformin therapy. B, Random Forest analysis of baseline vs end point demonstrating significantly altered metabolites and their pathway.

Figure 4. Pathway analysis to identify key nodes in changed metabolites.