ArticleJCI insight2020
Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 261 papers, 6 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
261 citing papers in PubMed, 6 syntheses or guidelines pooled it, 445 citations in OpenAlex.
- Divergent Risks of Hematologic Malignancies Associated with GLP-1 Receptor Agonists and SGLT2 Inhibitors: Preliminary Findings from a Pilot Network Meta-Analysis.Biomolecules · 2025Pooled it
- Evaluating biased agonism of glucagon-like peptide-1 (GLP-1) receptors to improve cellular bioenergetics: A systematic review.Diabetes, obesity & metabolism · 2025Pooled it
- Efficacy and safety of tirzepatide for weight loss in patients with obesity or type 2 diabetes: a systematic review and meta-analysis.Frontiers in endocrinology · 2025 · on this mapPooled it
- Evidence that tirzepatide protects against diabetes-related cardiac damages.Cardiovascular diabetology · 2024 · on this mapPooled it
- Tirzepatide as a novel effective and safe strategy for treating obesity: a systematic review and meta-analysis of randomized controlled trials.Frontiers in public health · 2024Pooled it
- GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.Nature genetics · 2023Pooled it
- Efficacy and safety of cAMP signalling-biased GLP-1 analogue ecnoglutide monotherapy versus placebo in patients with type 2 diabetes (EECOH-1): a multi-centre, randomised, double-blind, placebo-controlled, phase 3 trial.Nature communications · 2026Trial
- Gut Hormones and Postprandial Metabolic Effects of Isomaltulose vs. Saccharose Consumption in People with Metabolic Syndrome.Nutrients · 2025Trial
- Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity.Circulation · 2025 · on this mapTrial
- Efficacy and safety of GLP-1 analog ecnoglutide in adults with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 2 trial.Nature communications · 2024Trial
- Weight Loss-Independent Effect of Liraglutide on Insulin Sensitivity in Individuals With Obesity and Prediabetes.Diabetes · 2024Trial
- GLP-1 Receptor Agonist and GIP/GLP-1 Receptor Dual Agonist Therapeutics at the Intersection of Alcohol Use Disorder, Obesity, and Cardiometabolic Dysfunction.Biological psychiatry global open science · 2026Review
- Article
- Effect of GLP-1 receptor agonist on nutrient intake: A narrative review.Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition · 2026Review
- GLP-1 and Dual GIP/GLP-1 Receptor Agonists in Pediatric Obesity: From Neuroendocrine Mechanisms to Clinical Application.International journal of molecular sciences · 2026Review
- Adipose Tissue Remodeling Beyond Weight Loss: New Insights Into Incretin-Based Therapies and Bariatric Surgery.Current obesity reports · 2026Review
- Glycemic and bodyweight effects ofScience advances · 2026Article
- A Sequential Dual GLP-1R/GIPR Agonist-To-Antagonist Molecule Achieves Superior Weight Loss in Obese Mice.Diabetes, obesity & metabolism · 2026Article
- The evolving therapeutic landscape of gut-pancreatic peptide signalling in metabolic disorders: from mono- to multi-agonist therapies.Bioscience reports · 2026Review
- The evolving landscape of obesity pharmacotherapy.Nature reviews. Drug discovery · 2026Review
201 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
18 authors at 3 institutions in 2 countries.
Funding
Abstract
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.