Class of Compound:

Peptide

Mechanism of Action:

Notable Studies:

Tirzepatide Once Weekly for the Treatment of Obesity

What is Tirzepatide?

Tirzepatide, or LY3298176, is a unimolecular dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist that is under study for its glycemic control and weight loss benefits.

Tirzepatide is based on the human GIP hormone and has a length of 39 amino acids. It includes a C20 fatty di-acid moiety that provides extended duration and allows for once-weekly dosing in humans.

Following extensive clinical testing, including against comparable treatments, tirzepatide was approved in May 2022 by the United State Food and Drug Administration (USFDA) as a type 2 diabetes (T2D) treatment. It became the first dual GLP-1 and GIP receptor agonist indicated for T2D.

Tirzepatide is now in clinical trials to establish its safety and efficacy as a weight loss treatment in adults with a body mass index (BMI) of 27 or greater, with the initial results suggesting that it provides significant and sustained weight management benefits.

While it is now an approved prescription medication for T2D patients, tirzepatide is also available as a reference material to credentialed professionals wishing to conduct research on this novel GLP-1/GLP agonist.

What Does Tirzepatide Do?

Tirzepatide is a potent instrument for controlling both weight and blood sugar, thanks to its dual GLP-1/GLP action. Researchers have found that its dual receptor agonism produces a synergistic effect for significantly enhanced insulin response and glucagonostatic activity, versus administering either GIP or GLP-1 monotherapy.

GIP and GLP-1 are the two primary incretin hormones that the intestine secretes upon ingestion of glucose or nutrients, with the effect of stimulating insulin secretion from pancreatic beta cells. Tirzepatide has similar affinity at the GIP receptor as native GIP, but has five times lower GLP-1 receptor affinity compared to native GLP-1. In the latter, tirzepatide has a preference for cAMP signaling over beta-arrestin recruitment .

This biased agonism of tirzapetide and unique GLP-1 signaling are believed to underlie its efficacy in enhancing insulin secretion.In fact, clinical trials have demonstrated tirzepatide’s superior efficacy and comparable safety as a glucose lowering agent when compared to established T2D treatments.

Researchers should also note tirzepatide’s ability to significantly increase adiponectin, an adipokine linked to lipid and glucose metabolism regulation. Increases of serum adiponectin have been associated with weight loss, exercise, and improved nutrition. Researchers believe that this particular mechanism of tirzepatide has cardioprotective implications.

Tirzepatide Benefits | Clinical Trials

While tirzepatide has already been approved as a safe and effective treatment of type 2 diabetes, researchers are now intrigued by its potential weight loss and cardioprotective benefits.

Clinical trials to investigate these uses are ongoing until at least 2024. Accordingly, we will summarize only the results published as of the date of writing.

 Tirzepatide and Weight Loss: The ability of tirzepatide to induce weight loss is at least partially explained by its mechanism of activating GIP receptors in fat cells, resulting in decreased adipose inflammation and increased adiponectin, both associated with reduced fat cell differentiation and increased energy expenditure .

In view of the global obesity crisis and the fairly limited treatment options on the market, Eli Lilly and Company, as tirzepatide patent holder, kicked off a clinical development program to test tirzepatide as a weight control agent in late 2022. Called SURMOUNT, the program is set to include four global phase 3 trials to evaluate tirzepatide’s safety and efficacy as an adjunct weight loss treatment in obese and overweight adults, defined as those with a BMI of ≥ 27.

The first trial numbered over 2,500 participants and confirmed the peptide’s efficacy in inducing weight loss in obese and overweight patients. Study authors observed average weight reductions of 16% for patients on tirzepatide 5mg/weekly, 21.4% for tirzepatide 10mg/weekly, and 22.5% for tirzepatide 15mg/weekly, over the course of 72 weeks. The remaining trials are set to conclude in 2023.

 Tirzepatide as a T2D Treatment: BAs discussed, tirzepatide’s dual GLP-1/GLP action sets it apart as a T2D treatment.

Researchers believe that its unique mechanism of action, summarized as mimicking native GIP at the GIP receptor while exhibiting bias at the GLP-1 receptor for cAMP generation over beta-arrestin recruitment, underlies its efficacy as an anti-diabetes drug.

Research has shown that tirzepatide is superior to other diabetes therapies like semaglutide and dulaglutide in terms of glycemic control and weight loss. For example, researchers discovered that tirzepatide was more effective than semaglutide at lowering hemoglobin A1c and causing weight loss in T2D patients.

On the basis of its comparative effectiveness, the USFDA has approved tirzepatide as an adjunct treatment for improving blood sugar control in adults with T2D, as an addition to doctor-supervised diet and exercise .

 Tirzepatide and Cardioprotective Benefits: Research surrounding GLP-1 shows that the incretin hormone is key to directly regulating risk factors like hypertension and obesity, while indirectly regulating risk factors like inflammation and endothelial cell dysfunction. It is thus believed that tirzepatide’s selective targeting of the GLP-1 receptor may slow the development and progression of cardiovascular complications, particularly in diabetic patients.

In a 26-week study on T2D patients, once-weekly tirzepatide injections improved lipoprotein biomarkers associated with insulin resistance and cardiovascular risk, while reducing triglycerides, suggesting a net lowering of the patients’ risk of heart disease.

A pending cardiovascular outcomes study should provide a more accurate picture of the cardioprotective benefits of tirzepatide, pitting it against the GLP-1 receptor agonist dulaglutide.

Definition

Tirzepatide (LY3298176) was developed as a dual agonist to both GLP-1 and gastric inhibitory polypeptide (GIP) receptors (Frias et al., 2018). Similar to GLP-1, GIP is an incretin hormone that functions to induce insulin secretion.