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Review
. 2024 Jun 24:15:1402583.
doi: 10.3389/fendo.2024.1402583. eCollection 2024.

Tirzepatide against obesity and insulin-resistance: pathophysiological aspects and clinical evidence

Salvatore Corrao  1   2 , Chiara Pollicino  1 , Dalila Maggio  1 , Alessandra Torres  1 , Christiano Argano  1
Affiliations
Review

Tirzepatide against obesity and insulin-resistance: pathophysiological aspects and clinical evidence

Salvatore Corrao et al. Front Endocrinol (Lausanne). .

Abstract

Obesity is a chronic, multifactorial disease in which accumulated excess body fat has a negative impact on health. Obesity continues to rise among the general population, resulting in an epidemic that shows no significant signs of decline. It is directly involved in development of cardiometabolic diseases, ischemic coronary heart disease peripheral arterial disease, heart failure, and arterial hypertension, producing global morbidity and mortality. Mainly, abdominal obesity represents a crucial factor for cardiovascular illness and also the most frequent component of metabolic syndrome. Recent evidence showed that Tirzepatide (TZP), a new drug including both Glucagon Like Peptide 1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) receptor agonism, is effective in subjects with type 2 diabetes (T2D), lowering body weight, fat mass and glycated hemoglobin (HbA1c) also in obese or overweight adults without T2D. This review discusses the pathophysiological mechanisms and clinical aspects of TZP in treating obesity.

Keywords: GIP; GLP - 1; Tirzepatide; arterial hypertension; clinical trials; insulin-resistance; obesity; pathophysiology.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Tirzepatide’s pathway signaling. TZP binds its receptor, leading to the activation of adenylyl cyclase-cAMP-protein kinase A (PKA) pathway and thus stimulating glucose metabolism (glycolysis and Krebs Cycle). The increase of intracellular ATP levels hesitates in the closure of plasma membrane K+ channels, thus triggering β-cell depolarization. Due to depolarization, voltage-gated Ca2+ channels become open, favoring the entrance of Ca2+ into the cell, which concomitantly stimulates the releasing of calcium from the endoplasmic reticulum. This leads to the release of insulin into the bloodstream. Additionally, PKA stimulates insulin gene transcription, leading to insulin synthesis. αs, in vivo-subunit; ADP, adenosine diphosphate; ATP, adenosine triphosphate; β/γ, G protein β/gamma subunits; cAMP, cyclic adenosine monophosphate; GIP-R/GLP-1R, gastric inhibitory polypeptide receptor/glucagon-like peptide 1 receptor; PKA, adenylyl cyclase-cAMP-protein kinase A.
Figure 2
Figure 2
Tirzepatide’s effects on various organs.
Figure 3
Figure 3
(A) The SURPASS Program (SURPASS1–6). TZP, Tirzepatide; FSG, Fasting serum glucose; BW, Body Weight; HbA1c, Glycated Hemoglobin; T2D, Type 2 Diabetes; SMBG, self-monitored blood glucose; WC, waist circumference; HOMA2-IR, homeostasis model assessment–insulin resistance. (B) The SURPASS Program (J-mono, J-combo e AP) TZP, Tirzepatide; FSG, Fasting serum glucose; BW, Body Weight; HbA1c, Glycated Hemoglobin; T2D, Type 2 Diabetes; SMBG, self-monitored blood glucose; WC, waist circumference; HOMA2B-Insulin, homeostasis model assessment B–insulin; HOMA2S-Insulin, homeostasis model assessment S–insulin; TEAEs, treatment-emergent adverse events; SAEs, serious Adverse Event(s).
Figure 4
Figure 4
Tirzepatide’s effects on body weight and in HbA1c (SURPASS 2).
Figure 5
Figure 5
The Surmount Program. TZP, Tirzepatide; BW, Body Weight; WL, Weight Loss; WC, waist circumference; SBP, Systolic Blood Pressure; DBP, Diastolic Blood Pressure.
Figure 6
Figure 6
(A) Tirzepatide’s Effects on Systolic Blood Pressure (SURMONT 3). (B) Tirzepatide’s Effects on Diastolic Blood Pressure (SURMONT 3).
See this image and copyright information in PMC

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