Meta-Inflammation and New Anti-Diabetic Drugs: A New Chance to Knock Down Residual Cardiovascular Risk

Abstract

Type 2 diabetes mellitus (DM) represents, with its macro and microvascular complications, one of the most critical healthcare issues for the next decades. Remarkably, in the context of regulatory approval trials, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) proved a reduced incidence of major adverse cardiovascular events (MACEs), i.e., cardiovascular death and heart failure (HF) hospitalizations. The cardioprotective abilities of these new anti-diabetic drugs seem to run beyond mere glycemic control, and a growing body of evidence disclosed a wide range of pleiotropic effects. The connection between diabetes and meta-inflammation seems to be the key to understanding how to knock down residual cardiovascular risk, especially in this high-risk population. The aim of this review is to explore the link between meta-inflammation and diabetes, the role of newer glucose-lowering medications in this field, and the possible connection with their unexpected cardiovascular benefits.

Keywords: cardiovascular diseases; glucagon like peptide 1 receptor agonists; meta-inflammation; sodium-glucose cotransporter 2 inhibitors; type 2 diabetes mellitus.

Figure 1

Mechanisms linking meta-inflammation, diabetes, and cardiovascular disease. Meta-inflammation may induce CAD onset and progression and HF through a low-grade-inflammatory state. The mechanisms involved in the onset of this metabolic-–inflammatory status start from metabolic endotoxemia, with the increase of LPS, leukocyte activation, and local and systemic inflammation. The unfolded protein response also enhances pro-inflammatory action. Finally, both innate and immune responses arouse complex pathways setting the framework for the inflammatory status. CAD, cardiovascular diseases. HF, heart failure.

Figure 2

Bow tie model. The characteristic of bow tie architecture is the ability to draw in a wide variety of inputs, such as self- and non-self-stimuli (free fatty acids, LPS, and oxidized-LDL) into the core of components (toll-like receptors), which can convert the inputs into a wide range of outputs, such as a variety of inflammatory components.

Figure 3

Possible effects of SGLT2i and GLP-1 RA pharmacodynamics. Both drugs act similarly on the SNS, weight loss and endothelial dysfunction, and vasodilatation mechanisms. On the other hand, major differences emerge in the effect on the cardiovascular system. Indeed, SGLT2i lower cardiac afterload and adverse remodeling, while GLP-1 RA contributes to mitigating atherosclerotic progression and ischemia-reperfusion damage. Up arrow stands for an increase in the reported action. Down arrow stands for a decrease in the reported action. SGLT2i, Sodium–glucose cotransporter 2 inhibitors; GLP-1 RA, Glucagon-Like Peptide 1 Receptor Agonists; SNS, sympathetic nervous system.

Figure 4

Molecular mechanisms of new glucose-lowering drugs. SGLT2i proved to reduce endothelial dysfunction and oxidative stress. Furthermore, SGLT2i may decrease platelet activation and vascular smooth muscle cell proliferation and migration. On the other hand, GLP1-RA significantly limits vascular monocyte adhesion and macrophages and metalloproteinases accumulation in the atherosclerotic plaque. Remarkably, both drugs showed a reduction in inflammatory response. SGLT2i, Sodium–glucose cotransporter 2 inhibitors; GLP-1 RA, Glucagon-Like Peptide 1 Receptor Agonists; eNOS, endothelial nitric oxide synthase; NADPH, nicotinamide adenine dinucleotide phosphate; MMPs, metalloprotease; Ox-LDL, oxidized LDL; VSMC, vascular smooth muscle cells.