Plasma metabolomic profiling of patients with acute coronary syndrome treated with potent platelet inhibitors

Ticagrelor and prasugrel are key antiplatelet agents used in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Beyond their antiplatelet effects, both drugs exhibit pleiotropic actions that may contribute to side effects. Notably, ticagrelor has been associated with dyspnea in clinical trials. This study aimed to identify metabolomic markers linked to the effects of ticagrelor and prasugrel using targeted metabolomics. Plasma samples from 207 ACS patients treated with either prasugrel (n = 106) or ticagrelor (n = 101) were analyzed for up to 631 metabolites. Several metabolites differed significantly between the groups (p < 0.05). The most notable changes were found in DHEAS (p = 0.0004, FC = -1.66) and 3-Met-His (p = 0.0024, FC = 1.75). After adjusting for risk factors, lysoPC a C17:0, 3-Met-His, and DHEAS remained significantly altered. Subgroup analysis revealed that diabetic patients had distinct metabolic profiles, including elevated TMAO and choline and reduced GUDCA levels, compared to non-diabetics. Additional changes were observed in hexoses, Met-SO, and TCDCA. The findings support a novel hypothesis that ticagrelor-induced dyspnea may be linked to low DHEAS levels. Reduced methionine and Met-SO levels could suggest lower oxidative stress. Moreover, diabetic patients showed a gut microbiome-related metabolic shift associated with a more ischemic profile.