| 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. |
| History | Tirzepatide is a 39-amino acid synthetic peptide developed by Eli Lilly and Company. Its design is based on the sequence of a natural glucose-dependent insulinotropic polypeptide (GIP) and simultaneously activates the glucagon-like peptide-1 (GLP-1) receptor, hence the name "twincretin." The drug first entered clinical research in 2016, with Eli Lilly initiating a Phase I clinical trial to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics in obese or overweight subjects with related comorbidities. Subsequently, a Phase II trial further clarified its dose-response relationship and demonstrated significant blood glucose-lowering and weight-loss effects. Phase III clinical trials, including the SURPASS and SURMOUNT series, covered comparisons with placebo and active control drugs (such as semaglutide, insulin glargine, and insulin degludec), confirming its superior efficacy in the treatment of type 2 diabetes and obesity. In May 2022, Tirzepatide, marketed under the brand name Mounjaro®, was approved by the U.S. FDA for the treatment of type 2 diabetes, becoming the first and only approved GIP/GLP-1 dual receptor agonist . Subsequently, the drug was approved under the brand name Zepbound® for weight management. Throughout the development process, Eli Lilly remained the sole original developer of the drug, and no individual scientists specifically involved in the drug design have been disclosed in publicly available literature. The structure of Tirzepatide extends its half-life to approximately 5 days by introducing α-aminoisobutyric acid (Aib) to replace alanine at positions 2 and 13 to prevent DPP-4 degradation, and by covalently binding to a C20 eicosanedioic acid via a γGlu-(AEEA-AEEA) linker at position 20 lysine residue, enabling once-weekly dosing. |
| 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® 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]. |
| 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 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. |
| 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]. |
| References | [1] Calley, J. and W. Dhillo. “Effects of the Hormone Kisspeptin on Reproductive Hormone Release in Humans.” 2014. 0. |
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