TIRZEPATIDE (MOUNJARO®️) AS A DUAL GIP/GLP-1 AGONIST: PHARMACOLOGICAL BASIS AND MECHANISMS OF ACTION

Abstract

Tirzepatide (Mounjaro®) represents one of the most significant advances in metabolic pharmacotherapy in recent decades by introducing, for the first time, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. The physiological rationale for this strategy is based on the restoration and amplification of the so-called "incretin effect," a mechanism by which intestinal hormones modulate insulin secretion after food intake. In individuals with type 2 diabetes mellitus, this axis is profoundly compromised, contributing to persistent hyperglycemia, insulin resistance, and progressive weight gain.

GLP-1 plays a central role in glycemic regulation by stimulating glucose-dependent insulin secretion, inhibiting glucagon release, delaying gastric emptying, and activating hypothalamic satiety centers. GIP, although also a potent insulin secretagogue, additionally has relevant metabolic effects in adipose tissue, modulating lipid storage, insulin sensitivity, and energy balance. Studies demonstrate that, despite the GIP resistance observed in type 2 diabetes, pharmacological activation of this receptor in conjunction with GLP-1 restores some of its physiological activity, promoting metabolic effects superior to those obtained by isolated GLP-1 stimulation.

Tirzepatide was structurally designed to mimic both incretin hormones, exhibiting high affinity for both receptors and resistance to enzymatic degradation by dipeptidyl peptidase-4, which gives it a prolonged half-life and enables weekly administration. Its pharmacokinetics allow for stable plasma levels, favoring sustained activation of peripheral and central incretin axes. In the pancreas, this effect results in increased glucose-dependent insulin secretion and glucagon suppression, reducing both fasting and postprandial blood glucose. In the gastrointestinal tract, gastric emptying is slowed, which contributes to a lower glycemic load after meals. In the central nervous system, the activation of GLP-1 and GIP receptors in hypothalamic nuclei reduces appetite and intensifies the feeling of satiety, promoting a spontaneous decrease in caloric intake.

In addition to glycemic control, tirzepatide has a direct impact on lipid metabolism and adipose tissue. Activation of the GIP receptor improves glucose uptake by adipocytes and favors fatty acid oxidation, while GLP-1 reduces lipogenesis and metabolic inflammation, creating a hormonal environment conducive to sustained weight loss. These effects explain why clinical trials demonstrate significant reductions in both glycated hemoglobin and body mass, often greater than those obtained with isolated GLP-1 agonists.

Thus, tirzepatide is consolidating itself as a new generation metabolic therapy, capable of acting simultaneously on the main pathophysiological axes of type 2 diabetes and obesity. By integrating the pancreatic, gastrointestinal, central, and adipose effects of incretins, this drug redefines the treatment paradigm for these conditions, offering a more comprehensive, effective, and physiologically aligned approach to the complexity of human metabolism.