Research Questions!
Do SGLT2 inhibitors alter the pro-atherosclerotic phenotype of circulating exosomes (e.g., levels of pro-inflammatory miRNAs, cytokines, or lipid cargo) in patients with type 2 diabetes (T2D)?!
Is the modulation of exosomal phenotype by SGLT2 inhibitors associated with improvements in atherosclerotic plaque stability (assessed via imaging markers)?!
To what extent do changes in exosomal characteristics mediate the known cardiovascular protective effects of SGLT2 inhibitors in T2D?!
Objectives!
Characterize exosomal content (miRNAs: e.g., miR-155, miR-21; proteins: IL-6, TNF-!; lipids) in T2D patients before and 6 months after initiating SGLT2 inhibitors, compared to a control group on other antidiabetic agents.!
Quantify changes in plaque stability markers (fibrous cap thickness, lipid core size, calcification) via carotid/ coronary imaging in both groups over the same period.!
Statistically evaluate the association between SGLT2 inhibitor-induced exosomal changes and improvements in plaque stability, testing for mediating effects.!
Scientific Rationale!
SGLT2 inhibitors reduce cardiovascular events in T2D, but their mechanisms beyond glycemic control remain incompletely understood. Exosomes, as intercellular messengers, transmit pro-atherosclerotic signals that promote plaque instability. Preclinical studies suggest SGLT2 inhibitors may modulate exosomal release and cargo, but clinical evidence is lacking. This study bridges this gap by linking SGLT2 inhibitor therapy to exosomal phenotype shifts and plaque stability-critical for clarifying non-glycemic mechanisms. By leveraging UK Biobank’s imaging/clinical data and prospective sampling, it explores exosomes as potential mediators and surrogate markers of therapeutic efficacy, enhancing understanding of SGLT2 inhibitors’ cardiovascular benefits and identifying novel targets for risk stratification.
