incretins and Carotid-Stenosis

Topics: Absorptiometry, Photon; Adaptor Proteins, Signal Transducing; Aged; Bone Density; Bone Remodeling; Carotid Intima-Media Thickness; Carotid Stenosis; Cell Adhesion Molecules; Collagen Type I; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Incretins; Intercellular Signaling Peptides and Proteins; Metformin; Peptide Fragments; Peptides; Postmenopause; Procollagen; RANK Ligand; Sulfonylurea Compounds; Ultrasonography, Doppler

Diabetes mellitus (DM) is a known risk factor for myocardial infarction (MI); however, data regarding MI subtypes in people with diabetes are limited. In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (n = 9,340), liraglutide significantly reduced the risk of major adverse cardiovascular (CV) events (composite of CV death, nonfatal MI, or nonfatal stroke) versus placebo in patients with type 2 DM and high CV risk. Liraglutide also reduced risk of first MI (292 events with liraglutide vs 339 with placebo). This post hoc analysis characterized MIs (first and recurrent) occurring in LEADER, by treatment arm and regarding incidence, outcome, subtype, and troponin levels. A total of 780 MIs (first and recurrent) were reported, with fewer in the liraglutide-treatment group than in the placebo-treatment group (359 vs 421, p = 0.022). Numerically fewer MIs were associated with CV death with liraglutide than with placebo (17 vs 28 fatal MIs, p = 0.28). Symptomatic MIs in both arms were mainly non-ST-segment elevation MI (555/641) and spontaneous MI (518/641). Numerically greater proportions of symptomatic MIs were associated with troponin levels ≤5× or ≤10× the upper reference limit with liraglutide versus placebo (p = 0.16 and p = 0.42, respectively). At baseline, more liraglutide-treated patients than placebo-treated patients with MI during the trial had a history of coronary artery bypass graft (p = 0.008), and fewer had peripheral arterial disease in the lower extremities (p = 0.005) and >50% stenosis of the coronary artery, the carotid artery, or other arteries (p = 0.044). In conclusion, this analysis showed that liraglutide reduces the incidence of MIs in patients with type 2 DM at high CV risk and may impact the clinical outcomes of MI.

Topics: Carotid Stenosis; Coronary Stenosis; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Incidence; Incretins; Liraglutide; Myocardial Infarction; Non-ST Elevated Myocardial Infarction; Peripheral Arterial Disease; ST Elevation Myocardial Infarction; Troponin

Glucagon like peptide 1 (GLP-1) analogues and dipeptidyl peptidase IV (DPP-4) inhibitors reduce atherosclerosis progression in type 2 diabetes mellitus (T2DM) patients and are associated with morphological and compositional characteristics of stable plaque phenotype. GLP-1 promotes the secretion of adiponectin which exerts anti-inflammatory effects through the adaptor protein PH domain and leucine zipper containing 1 (APPL1). The potential role of APPL1 expression in the evolution of atherosclerotic plaque in TDM2 patients has not previously evaluated.. The effect of incretin therapy in the regulation of adiponectin/APPL1 signaling was evaluated both on carotid plaques of asymptomatic diabetic (n=71) and non-diabetic patients (n=52), and through in vitro experiments on endothelial cell (EC).. Atherosclerotic plaques of T2DM patients showed lower adiponectin and APPL1 levels compared with non-diabetic patients, along with higher oxidative stress, tumor necrosis factor-α (TNF-α), vimentin, and matrix metalloproteinase-9 (MMP-9) levels. Among T2DM subjects, current incretin-users presented higher APPL1 and adiponectin content compared with never incretin-users. Similarly, in vitro observations on endothelial cells co-treated with high-glucose (25mM) and GLP-1 (100nM) showed a greater APPL1 protein expression compared with high-glucose treatment alone.. Our findings suggest a potential role of adiponectin/APPL1 signaling in mediating the effect of incretin in the prevention of atherosclerosis progression or plaque vulnerability in T2DM.

Topics: Adaptor Proteins, Signal Transducing; Adiponectin; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Carotid Stenosis; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endarterectomy, Carotid; Endothelium, Vascular; Female; Glucagon-Like Peptide 1; Humans; Incretins; Italy; Male; Oxidative Stress; Plaque, Atherosclerotic; Risk Factors; Secondary Prevention; Signal Transduction