SGLT2i and GLP-1RA in Cardiometabolic and Renal Diseases: From Glycemic Control to Adipose Tissue Inflammation and Senescence

Abstract

Background. Over the last few years, the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) has increased substantially in medical practice due to their documented benefits in cardiorenal and metabolic health. In this sense, and in addition to being used for glycemic control in diabetic patients, these drugs also have other favorable effects such as weight loss and lowering blood pressure, and more recently, they have been shown to have cardio and renoprotective effects with anti-inflammatory properties. Concerning the latter, the individual or associated use of these antihyperglycemic agents has been linked with a decrease in proinflammatory cytokines and with an improvement in the inflammatory profile in chronic endocrine-metabolic diseases. Hence, these drugs have been positioned as first-line therapy in the management of diabetes and its multiple comorbidities, such as obesity, which has been associated with persistent inflammatory states that induce dysfunction of the adipose tissue. Moreover, other frequent comorbidities in long-standing diabetic patients are chronic complications such as diabetic kidney disease, whose progression can be slowed by SGLT2i and/or GLP-1RA. The neuroendocrine and immunometabolism mechanisms underlying adipose tissue inflammation in individuals with diabetes and cardiometabolic and renal diseases are complex and not fully understood. Summary. This review intends to expose the probable molecular mechanisms and compile evidence of the synergistic or additive anti-inflammatory effects of SGLT2i and GLP-1RA and their potential impact on the management of patients with obesity and cardiorenal compromise.

Figure 1

Proven benefits of SGLT2i and GLP-1RA in the cardiorenal-vascular axis. Strong evidence supports the multiple effects of SGLT2i and GLP-1RA on the cardiovascular disease scenario. Studies show cardio- and renoprotective properties in clinical biomarkers and long-term mortality. SGLT2i: sodium-glucose cotransporter 2 inhibitors; GLP-1RA: glucagon-like peptide 1 agonists.

Figure 2

Role of SGLT2i in obesity, adipose tissue inflammation, and cardiac and kidney disease. In obesity, these drugs modify the insulin : glucagon ratio, where glucagon increases, favoring lipolysis and lipid oxidation, while insulin decreases, causing an increase in endogenous glucose production from amino acids, favoring the process of lipolysis even more. Also, they attenuate the hemodynamic/neurohormonal mechanism in the kidney with positive changes of glomerular filtration rate (GFR), the tubular transport toil, and oxygen consumption. Ultimately, they have a role in the mitigation of inflammation decreasing the recruitment and accumulation of T cells and M1 macrophages, increasing the polarization of M2 macrophages, which release anti-inflammatory cytokines while activating adrenergic receptors in adipocytes, producing thermogenesis by the expression of uncoupling protein (UCP1). Furthermore, they increase adiponectin expression, which promotes the downregulation of SGLT2 and subcutaneous white adipose tissue (WAT) browning by stimulating the proliferation of M2 macrophages. SGLT2i: sodium-glucose cotransporter 2 inhibitors; GFR: glomerular filtration rate; UCP: uncoupling proteins; WAT: white adipose tissue.

Figure 3

Role of GLP-1RA in obesity, adipose tissue inflammation, and cardiac and kidney disease. In obesity, glucagon-like peptide 1 agonist (GLP-1RA) effects are related to its capacity to penetrate the blood-brain barrier and the presence of the glucagon-like peptide 1 receptor (GLP-1R) in different brain regions, resulting in appetite reduction, increase in satiety, and abdominal fullness and a decrease in food cravings. This, in turn, favors a weight loss of 2 to 8 kg on average. In the kidneys, an antioxidant and anti-inflammatory role has been reported. Via the activation of the Sirt1/AMPK/PGC1α signaling pathway, it partially restores the function of renal mitochondria and decreases lipid deposition and inflammation in the kidneys. Lastly, its role has been proven in the mitigation of inflammation since it favors macrophage polarization and adiponectin production while promoting mitochondrial biogenesis and adequate function, as well as adipose tissue browning. GLP-1RA: glucagon-like peptide 1 agonists; GLP-1R: glucagon-like peptide 1 receptor; SIRT1: sirtuin 1; AMPK: AMP-activated protein kinase; PGC1α: Pparg coactivator 1 alpha; WAT: white adipose tissue; ANP: atrial natriuretic peptide.