Tirzepatide

Description

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.

Uses

Tirzepatide is used with a proper diet and exercise program to control high blood sugar in people with type 2 diabetes.  Controlling high blood sugar helps prevent kidney damage, blindness,  nerve problems, loss of limbs, and sexual function problems.

Definition

Mounjaro® and Ozempic® have distinct active ingredients: tirzepatide and semaglutide, respectively. However, both of these drugs are GLP-1 agonists, which bind to GLP-1 receptors, simulate a feeling of satiety, and signal the pancreas to produce insulin.

Trade name

brand name: Mounjaro

Mechanism of action

It works to stimulate first- and second-phase insulin secretion, and reduces glucagon levels, both in a glucose-dependent manner.  Tirzepatide was also shown to delay gastric emptying, lower fasting and  postprandial glucose concentration, decrease food intake, 4 and reduce body weight in patients with type 2 diabetes.

Pharmacology

Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1 receptor agonists. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with GLP-1 receptor agonism, may result in greater effects on markers of metabolic dysregulation such as body weight, glucose and lipids. Tirzepatide is in phase 3 development for adults with obesity or overweight with weight-related comorbidity and is currently under regulatory review as a treatment for adults with type 2 diabetes. It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction (HFpEF). Studies of tirzepatide in obstructive sleep apnea (OSA) and in morbidity/mortality in obesity are planned as well.

Side effects

The overall safety and tolerability profile of tirzepatide was similar to other incretin-based therapies that have been approved for the treatment of obesity. This said, reported side effects were considerable, especially as dosage levels increased. The most common adverse events were nausea (~30%), diarrhea (~20%), constipation (~15%) and vomiting (~10%).
If tirzepatide gets approved as a both a blood glucose control and anti-obesity agent, it could become a blockbuster drug. However, this isn’t a sure thing. It will have to overcome pricing and reimbursement obstacles, which have plagued similar treatments.

Synthesis

The synthesis process of tirzepatide is as follows: to a reactor was charged dichloromethane (28.6 kg), water (5.4 kg), DTT (4.3 kg), Boc-Fragment 1 + 2 + 3 + 4 (14.3 kg, 8), and TIPS (3.3 kg), resulting in a slurry. The slurry was cooled to less than 10 °C before TFA (162 kg) was added over no more than 1.75 h, resulting in a solution. The solution was warmed to 21 °C and held at this temperature for 3 h. The solution was transferred to a separate reactor, rinsing with TFA (54.3 kg). This solution was cooled to ?10 °C and charged MTBE (125.8 kg) over 2 h. Then, additional MTBE (233 kg) was charged at 17 kg/h, maintaining an internal temperature of less than ?5 °C. The resulting slurry was warmed to 0 °C and then filtered. The wet cake was washed with MTBE (2 × 11 kg/kg relative to 8) and then dried under vacuum at no more than 35 °C to obtain tirzepatide (1, 8.71 kg, 1.81 mol, 81% yield)[1].

Research

Tirzepatide is in phase 3 clinical development at Eli Lilly and Company for blood glucose management in adults with type 2 diabetes, chronic weight management, and obesity-related heart failure with preserved ejection fraction. In addition, Tirzepatide is being studied as a potential treatment for non-alcoholic steatohepatitis (NASH). The molecule comprises a 39 amino acid peptide backbone and a side chain at residue 20. Of the 39 amino acids, 37 are naturally occurring (or coded), while two are noncoded aminoisobutyric acid residues at positions 2 and 13[1].

Mode of action

Tirzepatide has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behaviour has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist. Signaling studies have shown that this is due to tirzepatide mimicking the actions of natural GIP at the GIP receptor. However, at the GLP-1 receptor, tirzepatide shows bias towards cAMP (a messenger associated with regulation of glycogen, sugar and lipid metabolism) generation, rather than β-arrestin recruitment. This combination of preference towards GIP receptor and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion. Tirzepatide has also been shown to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and lipid metabolism, with a maximum increase of 26% from baseline after 26 weeks, at the 10 mg dosage.

Clinical claims and research

Tirzepatide (Eli Lilly), a novel, once-weekly injectable dual glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 RA combination drug, has been developed to treat patients with T2DM. The manufacturer (Eli Lilly) announced the submission of a biologics license application with priority review to the FDA for T2DM on October 27, 2021, with a decision expected in mid-2022.

References

[1] Calley, J. and W. Dhillo. “Effects of the Hormone Kisspeptin on Reproductive Hormone Release in Humans.” 2014. 0.