Glucagon-Like Peptide-1 Based Therapies: A New Horizon in Obesity Management

Abstract

Obesity is a significant risk factor for health issues like type 2 diabetes and cardiovascular disease. It often proves resistant to traditional lifestyle interventions, prompting a need for more precise therapeutic strategies. This has led to a focus on signaling pathways and neuroendocrine mechanisms to develop targeted obesity treatments. Recent developments in obesity management have been revolutionized by introducing novel glucagon-like peptide-1 (GLP-1) based drugs, such as semaglutide and tirzepatide. These drugs are part of an emerging class of nutrient-stimulated hormone-based therapeutics, acting as incretin mimetics to target G-protein-coupled receptors like GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon. These receptors are vital in regulating body fat and energy balance. The development of multiagonists, including GLP-1-glucagon and GIP-GLP-1-glucagon receptor agonists, especially with the potential for glucagon receptor activation, marks a significant advancement in the field. This review covers the development and clinical efficacy of various GLP-1-based therapeutics, exploring the challenges and future directions in obesity management.

Keywords: Glucagon; Glucagon-like peptide-1 receptor agonists; Glucose-dependent insulinotropic polypeptide; Multiagonist; Obesity.

Fig. 1.

Effects of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon on various vital organs and tissues. Modified from Lim et al. [37], with permission from Elsevier. ANP, atrial natriuretic peptide; BMD, bone mineral density.

Fig. 2.

Structures of formulations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and glucose-dependent insulinotropic polypeptide/ GLP-1RA. Modified from Tschop et al. [36]. GIP, glucose-dependent insulinotropic polypeptide.

Fig. 3.

Comparison of bodyweight (A) and abdominal visceral fat (B) from baseline to week 68 for semaglutide 2.4 mg, semaglutide 1.7 mg, and placebo in Janpanese and Korean people with obesity. Adapted from Kadowaki et al. [49], with permission from Elsevier. VFA, visceral fat area.