GLP1 receptor agonists and CAD regression in diabetic patients after ACS

Abstract Background Despite advances in PCI, a significant proportion of ACS patients experience early CAD progression, with an increased risk in diabetics. GLP1 receptor agonists (GLP1-ra), among newer antidiabetic agents, have shown cardiovascular benefits in patients with atherosclerotic disease, but the underlying pathophysiologic mechanism remains unclear. Methods The PROGRESSION study was a single-center, prospective study enrolling patients with non-ST elevation ACS undergoing PCI between 2019 and 2022. To be eligible for inclusion, patients were required to have atherosclerotic plaques in non-culprit lesions (NCL) with diameter stenosis 20%. Coronary computed tomography angiography (CCTA) and blood tests were performed at baseline (during the index hospitalization) and at 1 year follow-up to assess and characterize CAD progression. The present analysis included diabetic patients, stratified by GLP1-ra use at discharge. GLP1-ra–treated patients and randomly-selected controls underwent comprehensive plasma metabolomic, lipidomic, and proteomic analysis at baseline and 1 year. The primary endpoint was the absolute change in NCL plaque burden (ΔPB), with the absolute change in patient percent atheroma volume (ΔPAV) as a key secondary endpoint. PB was calculated for each non-stented, non-hypoplastic (2 mm diameter) NCL without total occlusion or imaging artifacts. Patient PAV was the mean PB across lesions per patient. Results Of 28 diabetic patients, 7 (25%) with 22 NCL were treated with GLP1-ra, and 21 (75%) with 65 NCL received other antidiabetics. At baseline, mean NCL PB was 49.0±16.3%, and median patient PAV was 47.7% (IQR: 42.0, 55.4), with no differences between groups. At 1 year, both ΔPB (-5.8±12.8% vs. -1.1±13.6%, p=0.041) and ΔPAV (-6.1% -7.3, -1.8 vs. -0.7% -2.4, 9.8, p=0.039) were significantly lower in GLP1-ra-treated patients (Fig 1). Change in total atheroma volume was also numerically lower (0.7 mm³ -2.5, 8.7 vs. 25.0 mm³ 4.8, 39.7) in the GLP1-ra cohort, driven by a greater reduction in NCL fibrofatty volume percentage (-2.9±10.1% vs. 1.0±6.8%, p=0.042). Lipidomics analysis revealed a decrease in monoacylglycerol and triacylglycerol and an increase in phosphatidylethanolamine and diacylglycerols in GLP1-ra-treated patients (Fig 2A). Consistently, metabolomics showed a shift from carbohydrate metabolism toward lipid metabolism and hormone regulation, including retinol and steroid biosynthesis. Proteomic analysis demonstrated changes in immune regulation, endothelial function, and structural integrity with GLP1-ra treatment. Conclusion GLP1-ra therapy is associated with a significant CAD regression in diabetic patients at 1 year after an ACS. The effect is supported by consistent lipidomic, metabolomic, and proteomic changes, and suggests a potential role for GLP1-ra in modifying atherosclerosis progression beyond glycemic control.Figure 1