GLP-1 receptor agonists, SGLT-2 inhibitors, and their combination: effects on carotid atherosclerosis regression, oxidative stress, and amyloid-β1-40 in diabetes.

Carotid intima-media thickness (cIMT), amyloid-β1-40 (Aβ1-40), and oxidative stress are markers of vascular aging and cardiovascular risk. We compared the effects of insulin, glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and their combination on the aforementioned markers in type 2 diabetes (T2DM). We prospectively studied 183 metformin-treated T2DM patients, propensity-score-matched to 12-mo treatment with insulin, liraglutide, empagliflozin, or liraglutide plus empagliflozin. Six-segment cIMT and plaque-equivalent lesions (cIMT ≥ 1.5 mm) were assessed at baseline, 6, and 12 mo; plasma Aβ1-40 and malondialdehyde (MDA) were measured. All regimens were associated with reductions in cIMT and Aβ1-40 at 12 mo (P < 0.05). MDA decreased overall with the largest reduction in GLP-1RA-based regimens. Compared with insulin, liraglutide, empagliflozin, and their combination achieved greater reductions in cIMT (-8.2, -5.6, and -10.7% vs. -1.7%, P < 0.05) and in Aβ1-40 (-52.1, -40.3, and -50.7% vs. -30.7%, P < 0.05). Patients achieving cIMT < 1.5 mm at 12 mo was the highest with combination therapy (75%), followed by liraglutide (67%) and empagliflozin (54%) versus insulin (40%; P < 0.05). Patients who regressed <1.5 mm showed greater reduction in Aβ1-40 than those with ≥1.5 mm (-56.2% vs. -25.1%, P = 0.028). Liraglutide, empagliflozin, and their combination induced greater reduction of cIMT (-8.2, -5.6, and -10.7% vs. -1.7%) and Aβ1-40 (-52.1, -40.3, and -50.7% vs. -30.7%; P < 0.05) compared with insulin. cIMT regression was associated with Aβ1-40 and MDA reductions (P < 0.05). In T2DM patients, GLP-1RA and SGLT-2i-particularly in combination-were associated with improvements in carotid atherosclerotic burden, amyloid-related vascular injury, and oxidative stress.NEW & NOTEWORTHY We investigated the effect of insulin, glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and their combination on carotid intima-media thickness (cIMT) and amyloid-β1-40 (Aβ1-40) in diabetes. Twelve-month treatment with GLP-1RA, SGLT-2i, and their combination confers significant reductions in cIMT and Aβ1-40 compared with insulin. cIMT regression was associated with Aβ1-40 and malondialdehyde reductions. Our findings support that newer antidiabetic agents can favorably modify structural and biochemical markers of atherosclerosis.