Lilly-authored review restates tirzepatide's mechanism, with a discrepancy

A review article published November 6, 2025, in the journal Diabetes Therapy restates how tirzepatide, the active ingredient in Mounjaro and Zepbound, works in the body. The paper, written by Lilly scientists Galindo and Coskun along with colleagues, describes tirzepatide as a "first-in-class, single-molecule, dual" agonist that activates both the GIP receptor and the GLP-1 receptor ^[1].

The review notes that tirzepatide binds the GLP-1 receptor with roughly 18- to 20-fold weaker affinity than the body's own GLP-1 hormone ^[1]. That figure is notably larger than the roughly 5-fold weaker affinity reported in earlier discovery and receptor-occupancy papers on the same molecule, a gap the new review does not explain ^[1]. The sources provided do not clarify why the numbers differ or which figure should be considered more accurate.

Tirzepatide is approved by the FDA for type 2 diabetes since 2022, for weight management in adults with obesity or overweight since 2023, and for moderate-to-severe obstructive sleep apnea in adults with obesity since 2024 ^[1]. The review also points to newer research areas, including a 2024 New England Journal of Medicine study on tirzepatide in metabolic dysfunction–associated steatohepatitis (MASH), a 2025 study on heart failure with preserved ejection fraction, and a company press release describing cardiovascular protection findings in people with type 2 diabetes and heart disease ^[1]. Tirzepatide's effects on illness and death in people with obesity or overweight without diabetes remain under investigation in an ongoing trial ^[1].

The review explains that both GLP-1 and GIP receptors are found throughout the body, not just in the pancreas. GLP-1 receptors appear in pancreatic beta cells, the gut, nerve cells in the brain and body, the kidney, blood vessels, and the heart ^[1]. The authors say this widespread receptor expression, with some overlap and some differences between the two receptor types, may help explain why tirzepatide has effects on blood sugar, body weight, the heart and kidneys, and lipid levels ^[1].

Why it matters for patients

For people taking Mounjaro or Zepbound, this review does not change how the drug is prescribed or dosed. It is a scientific summary meant for clinicians, not a new clinical trial or a change in FDA labeling. The sources do not report any new safety signal or efficacy finding tied to the affinity numbers themselves.

The discrepancy in the GLP-1 receptor affinity figure is worth noting because it comes from the drug's own manufacturer restating a number differently than in earlier papers from the same company ^[1]. Receptor affinity describes how tightly a drug binds to a receptor compared with the body's natural hormone, which researchers use to understand a drug's mechanism, not necessarily how well it works in practice. Real-world benefits and risks of tirzepatide, as documented in the SURPASS and SURMOUNT trial programs referenced in the review, are unaffected by this specific number ^[1].

Patients or caregivers who follow the science behind these medications may see the 18- to 20-fold figure cited in future summaries or news coverage. It is not yet known from the available sources why this figure differs from the roughly 5-fold figure in the original discovery papers, whether it reflects a different measurement method, a correction, or something else ^[1].

What happens next

The review does not include a timeline for follow-up analysis or correction. The sources do not indicate whether Diabetes Therapy, Lilly, or independent researchers plan to address the discrepancy in receptor affinity figures. Ongoing trials mentioned in the review, including the study on illness and death outcomes in people with obesity without diabetes (NCT05556512), continue separately from this mechanism-focused publication ^[1].