Tirzepatide Research & Studies

Tirzepatide is a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist (RA) whose mechanism of action leads to a greater effect of gastric emptying (GE) than typical GLP-1 RAs. After the first dose of tirzepatide, GE is most substantially delayed. The drug then undergoes tachyphylaxis after subsequent doses. Although data on GLP1-RAs have historically demonstrated a lack of impact on bioavailability of oral hormonal contraceptives, manufacturer recommendations for tirzepatide indicate an interaction exists.

Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment.

The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.

Obesity has become a global public health concern and China has the largest number of affected people worldwide.

Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist used for the treatment of type 2 diabetes. Efficacy and safety of adding tirzepatide vs prandial insulin to treatment in patients with inadequate glycemic control with basal insulin have not been described.

Type 2 diabetes mellitus (T2DM) is the most common form of diabetes and is a chronic and progressive illness. Millions of Americans have T2DM and many patients do not achieve the recommended blood glucose levels. Glucagon-like peptide 1 (GLP-1) based therapy is an established treatment for the management of T2DM and is recommended early in the treatment algorithm. GLP-1 therapy is associated with better glycemic control, weight reduction, and favorable cardiovascular outcomes. Tirzepatide (Mounjaro™) is a novel dual glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist. Evidence from five SURPASS clinical trials has demonstrated that tirzepatide has potent glucose lowering and weight loss with adverse effects comparable to GLP-1 receptor agonists. This paper gives an overview of tirzepatide and SURPASS clinical trials.

The combination of glucagon-like peptide-1 (GLP-1) with other gut hormones including the glucose-dependent insulinotropic polypeptide (GIP) has been explored to complement and enhance further the GLP-1 effects on glycemia and weight loss. Tirzepatide is the first dual GLP-1/GIP receptor co-agonist which has been approved for treatment of type 2 diabetes mellitus (T2DM) based on the findings from the SURPASS program. The SURPASS trials assessed the safety and efficacy of tirzepatide in people with T2DM, from monotherapy through to insulin add-on in global populations, with another two trials dedicated to Japanese population. Over periods of treatment up to 104 weeks, once weekly tirzepatide 5 to 15 mg reduced glycosylated hemoglobin (1.87% to 3.02%), body weight (5.4 to 12.9 kg) and improved multiple cardiometabolic risk factors (including reduction in liver fat, new-onset macroalbuminuria, blood pressure, and lipids) across the T2DM spectrum. Tirzepatide provided better efficacy than placebo and other commonly used glucose-lowering medications such as semaglutide 1 mg, dulaglutide, insulin degludec, and glargine. All tirzepatide doses were well tolerated with similar side-effect profile to the GLP-1 receptor analogues. In people without diabetes, tirzepatide 5 to 15 mg once weekly for the treatment for obesity (SURMOUNT-1) resulted in substantial reductions in body weight (16.5% to 22.4%) over 72 weeks. Overall, the SURPASS program and SURMOUNT-1 study suggest that tirzepatide is marking a new era in T2DM and/or obesity management through dual agonism of gut hormones.

Tirzepatide is a new molecule capable of controlling glucose blood levels by combining the dual agonism of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) receptors. GIP and GLP1 are incretin hormones: they are released in the intestine in response to nutrient intake and stimulate pancreatic beta cell activity secreting insulin. GIP and GLP1 also have other metabolic functions. GLP1, in particular, reduces food intake and delays gastric emptying. Moreover, Tirzepatide has been shown to improve blood pressure and to reduce Low-Density Lipoprotein (LDL) cholesterol and triglycerides. Tirzepatide efficacy and safety were assessed in a phase III SURPASS 1-5 clinical trial program. Recently, the Food and Drug Administration approved Tirzepatide subcutaneous injections as monotherapy or combination therapy, with diet and physical exercise, to achieve better glycemic blood levels in patients with diabetes. Other clinical trials are currently underway to evaluate its use in other diseases. The scientific interest toward this novel, first-in-class medication is rapidly increasing. In this comprehensive and systematic review, we summarize the main results of the clinical trials investigating Tirzepatide and the currently available meta-analyses, emphasizing novel insights into its adoption in clinical practice for diabetes and its future potential applications in cardiovascular medicine.

The effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described.

Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20.

Obesity is a chronic disease that results in substantial global morbidity and mortality. The efficacy and safety of tirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in people with obesity are not known.

In a phase 2 trial of once-weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo, the dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide dose-dependently reduced HbA1c and body weight in patients with type 2 diabetes. In this post hoc analysis, inflammation, endothelial dysfunction, and cellular stress biomarkers were measured at baseline, 4, 12, and 26 weeks to evaluate the additional effects of tirzepatide on cardiovascular risk factors. At 26 weeks, tirzepatide 10 and 15 mg decreased YKL-40 (also known as chitinase-3 like-protein-1), intercellular adhesion molecule 1 (ICAM-1), leptin, and growth differentiation factor 15 levels versus baseline, and YKL-40 and leptin levels versus placebo and dulaglutide. Tirzepatide 15 mg also decreased ICAM-1 levels versus placebo and dulaglutide, and high-sensitivity C-reactive protein (hsCRP) levels versus baseline and placebo, but not dulaglutide. GlycA, interleukin 6, vascular cell adhesion molecule 1, and N-terminal-pro hormone B-type natriuretic peptide levels were not significantly changed in any group. YKL-40, hsCRP, and ICAM-1 levels rapidly decreased within 4 weeks of treatment with tirzepatide 10 and 15 mg, whereas the decrease in leptin levels was more gradual and did not plateau by 26 weeks. In this hypothesis-generating exploratory analysis, tirzepatide decreased several biomarkers that have been associated with cardiovascular risk.

Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide.

Despite advancements in care, many people with type 2 diabetes do not meet treatment goals; thus, development of new therapies is needed. We aimed to assess efficacy, safety, and tolerability of novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide monotherapy versus placebo in people with type 2 diabetes inadequately controlled by diet and exercise alone.

To assess the efficacy and tolerability of tirzepatide treatment using three different dose-escalation regimens in patients with type 2 diabetes.

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.