An Overview of Similarities and Differences in Metabolic Actions and Effects of Central Nervous System Between Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) and Sodium Glucose Co-Transporter-2 Inhibitors (SGLT-2is)

Abstract

GLP-1 receptor agonists (GLP-1RAs) and SGLT-2 inhibitors (SGLT-2is) are novel antidiabetic medications associated with considerable cardiovascular benefits therapying treatment of diabetic patients. GLP-1 exhibits atherosclerosis resistance, whereas SGLT-2i acts to ameliorate the neuroendocrine state in the patients with chronic heart failure. Despite their distinct modes of action, both factors share pathways by regulating the central nervous system (CNS). While numerous preclinical and clinical studies have demonstrated that GLP-1 can access various nuclei associated with energy homeostasis and hedonic eating in the CNS via blood–brain barrier (BBB), research on the activity of SGLT-2is remains limited. In our previous studies, we demonstrated that both GLP-1 receptor agonists (GLP-1RAs) liraglutide and exenatide, as well as an SGLT-2i, dapagliflozin, could activate various nuclei and pathways in the CNS of Sprague Dawley (SD) rats and C57BL/6 mice, respectively. Moreover, our results revealed similarities and differences in neural pathways, which possibly regulated different metabolic effects of GLP-1RA and SGLT-2i via sympathetic and parasympathetic systems in the CNS, such as feeding, blood glucose regulation and cardiovascular activities (arterial blood pressure and heart rate control). In the present article, we extensively discuss recent preclinical studies on the effects of GLP-1RAs and SGLT-2is on the CNS actions, with the aim of providing a theoretical explanation on their mechanism of action in improvement of the macro-cardiovascular risk and reducing incidence of diabetic complications. Overall, these findings are expected to guide future drug design approaches.

GLP-1 receptor agonist as a modulator of innate immunity

“…These metabolites are biologically active, can reduce intravascular oxidative stress, inhibit hepatocyte gluconeogenesis and oxidative stress, increase cardiomyocyte activity, promote vasodilation, protect the cardiovascular system, improve cardiac function, thereby directly or indirectly protecting the cardiovascular system ( 80 – 82 ). For example, a number of large-scale clinical trials have demonstrated that GLP-1RA could reduce the risk of cardiovascular events, which has been well reviewed in elsewhere ( 83 , 84 ) and we will not further discuss here.…”

Real‐world glycated haemoglobin changes among type 2 diabetes mellitus patients treated with a maintenance dose of 7 mg or 14 mg of oral semaglutide

“…26,27 In addition, GLP-1 RAs have been shown to have a variety of benefits, including reducing the risk of cardiovascular events, improving microvascular function, and reducing inflammation. [28][29][30][31] While GLP-1 RAs are more costly compared with older glucoselowering agents, lower inpatient and outpatient health care costs among patients have been shown to offset the higher treatment costs, resulting in budget neutrality compared with other glucose-lowering agents. 32 Despite the benefits, the use of these medications has remained limited.…”

“…Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are a recommended first‐line treatment option for T2DM because of their effectiveness in regulating blood glucose levels and the additional benefit of weight reduction 23‐25 with minimal well‐known adverse events 26,27 . In addition, GLP‐1 RAs have been shown to have a variety of benefits, including reducing the risk of cardiovascular events, improving microvascular function, and reducing inflammation 28‐31 . While GLP‐1 RAs are more costly compared with older glucose‐lowering agents, lower inpatient and outpatient health care costs among patients have been shown to offset the higher treatment costs, resulting in budget neutrality compared with other glucose‐lowering agents 32 .…”

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

“…Moreover, GLP-1RAs have been shown to exert many beneficial effects on vascular endothelial cells. For instance, GLP-1RAs were demonstrated to reduce the risk of cardiovascular events (5) by decreasing the blood pressure (6), improving microvascular function, and reducing inflammation (7). Further, GLP-1RAs play a neuroprotective effect by stimulating the differentiation of nerve cells and inhibiting neuroinflammation (8), while they were also reported to inhibit liver inflammation (9).…”