Liraglutide Reduces Carotid Intima-Media Thickness by Reducing Small Dense Low-Density Lipoproteins in a Real-World Setting of Patients with Type 2 Diabetes: A Novel Anti-Atherogenic Effect

Abstract

Introduction Liraglutide has several non-glycemic effects, including those on plasma lipids and lipoproteins, contributing to its cardiovascular benefit; however, the exact underlying mechanisms remain unclear. We investigated a novel anti-atherogenic effect of liraglutide in a real-world prospective study on patients with type 2 diabetes (T2DM). Methods Sixty-two patients with T2DM (31 men, 31 women; mean age ± standard deviation 61 ± 9 years) naïve to incretin-based therapies were treated with liraglutide (1.2 mg/day) as add-on therapy to metformin (1500–3000 mg/day) for 4 months. Laboratory analyses included the assessment of lipoprotein subclass profile by gel electrophoresis (Lipoprint; Quantimetrix Corp., Redondo Beach, CA, USA). Carotid intima-media thickness (cIMT) was assessed by Doppler ultrasonography. Statistical analyses included the paired t test, Spearman correlation and multiple regression analysis. Results The addition of liraglutide to metformin monotherapy resulted in significant reductions in fasting glycemia, hemoglobin A1c, body mass index, waist circumference, total cholesterol, triglycerides and low-density lipoprotein (LDL)-cholesterol, as well as in cIMT. There was an increase in the large LDL-1 subfraction, with a concomitant reduction in atherogenic small dense LDL-3 and LDL-4 subfractions. Correlation analysis revealed a significant association between changes in cIMT and changes in small dense LDL-3 subfraction ( r = 0.501; p < 0.0001). Multivariate analysis, including all of the measured anthropometric and laboratory parameters, revealed that only changes in the small dense LDL-3 subfraction were independent predictors of changes in cIMT ( p < 0.0001). Conclusion Our findings are the first to show that the vascular benefit of liraglutide in patients with T2DM is associated with reductions in atherogenic small dense LDL. This effect is independent of glycemic control and body weight reduction and may represent one of the key mechanisms by which liraglutide is able to reduce cardiovascular events. Trial Registration ClinicalTrials.gov: NCT01715428.

Effect of liraglutide on expression of inflammatory genes in type 2 diabetes

“…It has been hypothesized that the underlying mechanism of this beneficial GLP-1 RA effect is an preventive effect of GLP-1 RAs on atherosclerotic plaque formation 7 and/or anti-inflammatory actions of GLP-1 RAs. Hence, clinical studies have suggested that GLP-1 RA treatment reduces small dense low-density lipoproteins 8 , carotid-intima media thickness 8 , 9 , specific microRNAs involved in vascular inflammation and cardiovascular metabolism 10 , oxidative stress 11 and circulating inflammatory markers 12 – 14 . The inflammatory markers reduced by GLP-1 RA in clinical studies in humans, include circulating plasma levels of tumor necrosis factor (TNF)-α 15 , interleukin (IL)-1β, IL-6 and cluster of differentiation 163 (CD163) 16 .…”

Novel Therapeutical Approaches to Managing Atherosclerotic Risk

“…Liraglutide and semaglutide significantly attenuated plaque lesion development in Apolipoprotein E (ApoE)−/− and LDL-R−/−) deficient mice; semaglutide treatment improved leukocyte recruitment, leukocyte rolling, adhesion/extravasation, cholesterol metabolism, lipid-mediated signaling, extracellular matrix protein turnover, and plaque hemorrhage [ 66 ]. Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome [ 67 ] and, very recently, it has been shown a novel anti-atherogenic effect of liraglutide in patients with type-2 diabetes: the decrease in subclinical atherosclerosis by a reduction in atherogenic small, dense LDL particles [ 68 ]. Semaglutide treatment significantly lowered fasting and postprandial lipid metabolism vs. placebo [ 69 ].…”

Incretin-based therapies in 2021 – Current status and perspectives for the future

“…On this basis, GLP1-RAs are now clearly identified by scientific guidelines as a treatment of choice for T2DM; yet, the adoption of such international recommendations is still suboptimal, and this contributes negatively to what we perceive as clinical inertia [24,25]. Since atherosclerotic CVD is predominant in T2DM patients, it should be also considered that some GLP1-RAs, such as liraglutide and semaglutide, have shown direct antiatherosclerotic effects that help explaining the beneficial cardiovascular outcomes [26][27][28]. Some interesting novel findings have been discussed during the recent 81st Annual Scientific Sessions of the American Diabetes Association where, for instance, the data on efficacy, safety, and tolerability of the dual GIP and GLP-1 receptor agonist tirzepatide were presented.…”