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.

Keywords: autonomic nervous system; brain nuclei; cardiovascular diseases; diabetes; diabetic complications; obesity.

Figure 1

An overview and comparison of major effects of GLP-1RAs and SGLT-2is. The figure summarizes major clinical effects of both antidiabetic drugs on the energy homeostasis and complication management, with regards to macrovascular, microvascular, peripheral nervous system, adipose tissue homeostasis, and insulin secretion and glycemic control. *GLP-1RAs significantly reduce diabetic foot ulcer- related amputations. ^#SGLT2is significantly increase total cholesterol, LDL-C, non-HDL-C, and HDL-C and decrease triglyceride.

Figure 2

A mechanistic comparison of central and peripheral pathways related to the treatment outcomes by GLP-1RAs and SGLT-2is. As showing in the left side of the figure, GLP-1RAs influences energy setpoint of the hypothalamus, and may limit food intake, decrease body weight, promote insulin secretion and energy expenditure by increasing adipose tissue browning. They can also increase PNS activity, and exert effects of anti-atherosclerosis, which could benefit cardiovascular system. As the right side of the figure showing, SGLT-2is influence glucose absorption and inhibit energy expenditure. They also promote renal tubule-glomerular feedback, decrease the blood volume, and reduce the renal stress, which interacts with SNS and RAAS. Besides, SGLT-2is may activate specific sensing neurons and certain neural pathways in the CNS, thereby suppressing the SNS, regulating cardiovascular activity.