Effect of dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist on weight loss in subjects with obesity

Abstract

The occurrence of obesity is an increasing issue worldwide, especially in industrialized countries. Weight loss is important both to treat obesity and to prevent the development of complications. Currently, several drugs are used to treat obesity, but their efficacy is modest. Thus, new anti-obesity treatments are needed. Recently, there has been increased interest in the development of incretins that combine body-weight-lowering and glucose-lowering effects. Therefore, a new drug that simultaneously coactivates both the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R) has been developed. Tirzepatide, the first in this class, improves glycemic control by increasing insulin sensitivity and lipid metabolism as well as by reducing body weight. Combining the activation of the two receptors, greater improvement of β-cell function offers more effective treatment of diabetes and obesity with fewer adverse effects than selective GLP-1R agonists. In the present review, we discuss the progress in the use of GIPR and GLP-1R coagonists and review literature from in vitro studies, animal studies, and human trials, highlighting the synergistic mechanisms of tirzepatide.

Keywords: GIP; GIP receptor agonists,; GLP-1; GLP-1R agonists; obesity; tirzepatide; weight loss.

Figure 1

Obesity and co-morbidities: Obesity is distinguished by excess adiposity distributed to many body compartments. The increase of adiposity in pharyngeal soft tissue causes blocked airways during sleep, triggering obstructive sleep apnea; moreover, it causes both osteoarthritis, due to increased mechanical loading on the joints, and gastroesophageal reflux disease, due to an increase in intra-abdominal pressure. The obesity-related proinflammatory state with an increase in cytokines prompts insulin resistance, and together with insulin secretion that increases linearly with the BMI, supports dyslipidemia and T2DM. This obesity-induced chronic inflammation plays an endorsing role in cancer progression due to its promotion of a permissive microenvironment for neoplastic transformation. Furthermore, liposomes augment in hepatocytes that evolve in non-alcoholic fatty liver disease, steatohepatitis, and cirrhosis. Another consequence of obesity is chronic overactivity of the sympathetic nervous system that, together with the previously described consequences of chronic obesity, induces hypertension and increases the risk of heart disease, stroke, and chronic kidney diseases.

Figure 2

Physiological mechanism of incretins and a dual GIP/GLP-1 receptor agonist on weight loss. GLP-1, synthesized in the intestine, binds to its receptor, which is expressed in β-cells, α-cells, the kidneys, the lungs, gastric mucosa, the heart, and the brain. GLP-1-RA improves glucose control and stimulates significant weight loss by reducing gastric emptying, stimulating satiety, and decreasing food intake, and it acts on peripheral and central receptors in the gut and brain. GLP-1-RA reaches the arcuate nucleus, where it stimulates neurons that regulate appetite and express proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcripts (CART), and it indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP). GIP, secreted by K cells of the small intestine, binds to its receptor (GIPR) in the pancreas, adipose tissue (both white and brown adipose tissue), heart, pituitary, adrenal cortex, and some areas of the central nervous system (CNS). In a pharmacological context, GIP induces weight loss by stimulating satiety in the hypothalamus. Tirzepatide, which simultaneously stimulates GIP and GLP-1 receptors, increases general insulin sensitivity, improves glycemic control, and increases weight loss compared to GLP-1-RAs. Tirzepatide increases adiponectin and decreases serum alanine aminotransferase and lipoprotein biomarkers. Moreover, branched-chain amino acids (BCAAs) and their catabolic products are significantly reduced by tirzepatide. Tirzepatide imitates the effect of cold exposure on the amino acid profile in BAT, resulting in improved insulin sensitization, increased metabolic rate, and increased weight loss.