What the compound is
Tirzepatide is a novel dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors (PMID 32730231, PMID 34170647, PMID 35579691). It is under development for conditions such as type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction-associated steatohepatitis (MASH) (PMID 32730231, PMID 38856224).
How it is thought to work
Tirzepatide's mechanism involves activating both GIP and GLP-1 receptors (PMID 32730231). Laboratory studies indicate that it shows a greater degree of engagement with the GIP receptor than the GLP-1 receptor, suggesting an imbalanced action (PMID 32730231, in cells). Pharmacologically, in cell studies, tirzepatide mimics the actions of native GIP at the GIP receptor. At the GLP-1 receptor, it shows a bias towards generating cyclic AMP (cAMP) over recruiting beta-arrestin, and it has a weaker ability to cause GLP-1 receptor internalization compared to GLP-1 itself (PMID 32730231, in cells). Experiments in primary islets (cell studies) suggest that beta-arrestin1 limits the insulin response to GLP-1, but not to GIP or tirzepatide, implying that tirzepatide's biased agonism enhances insulin secretion (PMID 32730231, in cells).
Human evidence so far
In adults with type 2 diabetes, tirzepatide monotherapy was superior to placebo in reducing glycated hemoglobin (HbA1c), fasting serum glucose, and body weight over 40 weeks (PMID 34186022, in humans). In patients with type 2 diabetes, tirzepatide also showed dose-dependent superiority in lowering HbA1c and reducing body weight compared to GLP-1 receptor agonists like semaglutide and basal insulin regimens (PMID 35579691, in humans). Specifically, in a 40-week phase 3 trial, tirzepatide 5 mg, 10 mg, and 15 mg led to greater reductions in HbA1c and body weight than semaglutide 1 mg (PMID 34170647, in humans).
For adults with obesity but without type 2 diabetes, a phase 3b trial showed that tirzepatide resulted in a significantly greater reduction in body weight and waist circumference compared to semaglutide over 72 weeks (PMID 40353578, in humans). Continued treatment with tirzepatide in adults with obesity or overweight maintained and augmented initial weight reduction, whereas discontinuing treatment led to substantial weight regain (PMID 38078870, in humans).
In a phase 2 trial involving participants with metabolic dysfunction-associated steatohepatitis (MASH) and moderate or severe fibrosis, tirzepatide led to a higher percentage of participants achieving MASH resolution without fibrosis worsening, and improvement in fibrosis stage without MASH worsening, compared to placebo over 52 weeks (PMID 38856224, in humans).
The most common adverse events reported across studies were gastrointestinal, generally mild to moderate in severity, including nausea, diarrhea, and vomiting (PMID 34170647, PMID 38078870, PMID 38856224, PMID 40353578, PMID 35579691, in humans).
Open questions and limitations
The cardiovascular safety and efficacy of tirzepatide have not been definitively assessed in a dedicated cardiovascular outcomes trial (PMID 37758044). A randomized, double-blind, active-controlled trial (SURPASS-CVOT) is ongoing to compare tirzepatide to dulaglutide (a GLP-1 receptor agonist with established cardiovascular benefit) on major adverse cardiovascular events (MACE) in people with type 2 diabetes and atherosclerotic cardiovascular disease (PMID 37758044, in humans).
Key terms explained
<b>Glucose-dependent insulinotropic polypeptide (GIP)</b> and <b>glucagon-like peptide-1 (GLP-1)</b> are natural hormones that help regulate blood sugar. <b>Receptor agonists</b> are substances that bind to and activate specific receptors on cells. <b>Glycated hemoglobin (HbA1c)</b> is a measure of average blood sugar levels over the past 2-3 months. <b>Metabolic dysfunction-associated steatohepatitis (MASH)</b> is a progressive liver disease involving inflammation and fat accumulation in the liver. <b>Fibrosis</b> refers to the scarring of liver tissue. <b>Cardiovascular outcome trial (CVOT)</b> is a study designed to evaluate the safety and efficacy of a drug on heart and blood vessel related events. <b>Major adverse cardiovascular event (MACE)</b> is a composite endpoint typically including cardiovascular death, non-fatal myocardial infarction (heart attack), and non-fatal stroke.
