Cardiovascular Protective Properties of GLP-1 Receptor Agonists: More than Just Diabetic and Weight Loss Drugs

Abstract

Owing to their potent glucose-lowering efficacy and substantial weight loss effects, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are now considered part of the frontline therapeutic options to treat both type 2 diabetes mellitus and nondiabetic overweight/obesity. Stemming from successful demonstration of their cardiometabolic modulation and reduction of major adverse cardiovascular events in clinical outcome trials, GLP-1 RAs have since been validated as agents with compelling cardiovascular protective properties. Studies spanning from the bench to preclinical and large-scale randomised controlled trials have consistently corroborated the cardiovascular benefits of this pharmacological class. Most notably, there is converging evidence that they exert favourable effects on atherosclerotic ischaemic endpoints, with preclinical data indicating that they may do so by directly modifying the burden and composition of atherosclerotic plaques. This narrative review examines the underlying pharmacology and clinical evidence behind the cardiovascular benefits of GLP-1 RAs, with particular focus on atherosclerotic cardiovascular disease. It also delves into the mechanisms that underpin their putative plaque-modifying actions, addresses existing knowledge gaps and therapeutic challenges and looks to future developments in the field, including the use of combination incretin agents for diabetes and weight loss management.

Keywords: atherosclerosis; coronary artery disease; diabetes; glucagon-like peptide-1 receptor agonist; incretin; obesity.

Figure 1

Intracellular signalling pathways induced by GLP-1 RA binding to GLP-1R in pancreatic β cells. These result in attenuation of endoplasmic reticulum (ER) stress (pink), inhibition of apoptosis (purple), increased insulin exocytosis (green), β cell proliferation (yellow) and improved glucose handling and homeostasis (white). AC: adenylyl cyclase, AKT/PKB: protein kinase B, AMPK: adenosine monophosphate-activated protein kinase, ATF4: activating transcription factor 4, ATP: adenosine triphosphate, B-raf: serine/threonine–protein kinase B-raf, Ca²⁺: calcium ions, cAMP: cyclic adenosine monophosphate, CREB: cAMP-response element binding protein, c-Src: tyrosine–protein kinase Src, DAG: diacylglycerol, dephosph-eIF2α: dephosphorylated eukaryotic initiation factor 2α, EGFR: epidermal growth factor receptor, Epac2: exchange protein activated by cAMP 2, ERK1/2: extracellular signal-regulated kinase 1/2, FOXO1: forkhead box protein O1, GLP-1R: glucagon-like peptide 1 receptor, GLP-1 RA: glucagon-like peptide 1 receptor agonist, HIF-α: hypoxia-inducible factor 1-α, IGF1R: insulin-like growth factor 1 receptor, IGF2: insulin-like growth factor 2, IP3: inositol 1,4,5-trisphosphate, IP3R: inositol 1,4,5-trisphosphate receptor, Irs2: insulin receptor substrate 2, mTOR: mammalian target of rapamycin, PDX-1: pancreatic and duodenal homeobox 1, PI3K: phosphoinositide 3-kinase, PIP2: phosphatidylinositol (4,5)-diphosphate, PLC: phospholipase C, PKA: protein kinase A, Rap1: Ras-proximate-1, RyR: ryanodine receptor, SUR1: sulfonylurea receptor 1, TCF7L2: transcription factor 7 like 2, VGCC: voltage-gated calcium channel, Wnt: wingless-related integration site. Created with BioRender.com.

Figure 2

Summary of the cardiometabolic benefits of GLP-1 RA therapy. Green upward arrow: increases; Red downward arrow, decreases. Created with BioRender.com.

Figure 3

Putative Molecular Mechanisms for Anti-Atherogenic Effects of GLP-1 RAs. ABCA1: ATP-binding cassette transporter A1, ANG-II: angiotensin-II, AMPK: AMP-activated protein kinase, ANP: atrial natriuretic peptide, Arg-1: arginase-1, ATF6: cyclic AMP-dependent transcription factor-6, CCL2: C–C motif chemokine ligand 2, CCR7: C-C chemokine receptor type 7, CD62p: P-selectin, CD163+ Mac: cluster of differentiation 163+ macrophage, cGMP: cyclic guanine monophosphate, CRP: C-reactive protein, eNOS: endothelial nitric oxide synthase, FOXO3a: forkhead transcription factor O subfamily member 3a, HTN: hypertension, iNOS: inducible nitric oxide synthase, IFN-γ: interferon-γ, IL-1β: interleukin-1β, IL-6: interleukin-6, IL-10: interleukin-10, IRE1α: inositol-requiring enzyme 1, JNK: c-Jun N-terminal kinase, KLF2: Krüppel-like factor 2, LDL-C: low-density lipoprotein cholesterol, MAPK: mitogen-activated protein kinase, Mφ: macrophage, M1: M1 macrophage, M2: M2 macrophage, MMP: matrix metalloproteinase, MCP-1: monocyte chemoattractant protein-1, NLRP3: nucleotide-binding domain (NOD)-like receptor protein 3, NO: nitric oxide, PERK: protein kinase R-like ER kinase, PKG: protein kinase G, RAGE: receptor for advanced glycation end-products, ROS: reactive oxygen species, SIRT1: sirtuin 1, STAT1: signal transducer and activator of transcription 1, STAT3: signal transducer and activator of transcription 3, TAG: triacylglyceride, TIMP: tissue inhibitor of metalloproteinases, TNF-α: tumour necrosis factor-α, VASP: vasodilator-stimulated phosphoprotein, VCAM1: vascular cell adhesion protein 1, VSMC: vascular smooth muscle cell. Green upward arrow, increases. Red downward arrow, reduces. Red cross, inhibits. Created with BioRender.com.