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Latest breakthrough of Tirzepatide (Mounjaro) and its impressive potential in weight loss

On May 13, 2022, the U.S. Food and Drug Administration (FDA) approved Tirzepatide (brand name: Mounjaro), which is to be used as a supplement to exercise or diet to improve glycemic control in adults with type 2 diabetes.

Tirzepatide is a dual receptor agonist for glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The molecule activates the body’s GIP and GLP- 1 receptors, which are natural incretin hormones.

Mounjaro is in injectable form which is administered through subcutaneous injection. The medicine features a low injection frequency and needs to be administered only once a week. The product will be available in 6 different doses, with 2.5mg, 5mg, 7.5mg, 10mg, 12.5mg and 15mg being packed in an auto-injector device: a pre-filled pen containing a hidden needle, giving patients a visual “no” needle form and eliminates the need to handle needles.

Glucose-dependent insulin-stimulating polypeptide (GIP), also known as intestinal inhibitory peptide, is a member of incretin, which is an important metabolic hormone in the human body. The chemical plays an important physiological role in human body. The main functions include:

1) stimulating insulin release and glucagon secretion
2) inhibiting gastric acid and pepsin secretion
3) inhibiting gastric motility and emptying, etc.

GIP cells, and the level of GIP in serum will increase significantly. Hyperinsulinemia will appear subsequently.

Glucagon-like peptide -1 (GLP-1) is also an incretin, which can stimulate insulin secretion according to the level of glucose. GLP-1 induced insulin secretion accounts for about 50%-70% of the total insulin secretion in human body.

GLP-1 exist in islet beta cells in the pancreas. It promotes the proliferation and differentiation of beta cells in islets, inhibiting their apoptosis, promote the regeneration and repair of islet beta cells, and as a result improve the function of beta cells. It can also act on islet α cells to reduce postprandial glucagon secretion in a glucose concentration-dependent manner, reduce the decomposition of liver glycogen, and reduce postprandial blood sugar. It can also participate in the homeostasis of blood sugar in the body by acting on multiple pathways, such as delaying gastric emptying, suppressing appetite, etc.

Glucose metabolism in human body is influenced by intestinal hormones, namely insulin-releasing peptide (GIP) and glucagon-like peptide-1 (GLP-1), which cooperate with each other to release insulin and regulate insulin resistance and reduce liver metabolic actions such as fat accumulation and postprandial vascular response.

GIP mainly mediates detrimental metabolic effects, while GLP-1 mainly mediates beneficial metabolic effects. Therefore, the combination of the two can regulate blood sugar in a better and more phenomenal way.

Both GIP receptor and GLP-1 receptor are hot targets for new diabetes drug research in recent years. When used in combination, the regulation of the GIP circuit is expected to further promote weight loss, improve the efficacy of the treatment of type 2 diabetes and reduce gastrointestinal adverse reactions. GLP-1 receptor agonists can enhance insulin secretion, inhibit glucagon secretion, delay gastric emptying, suppress appetite, and reduce the food. The above effects lead to a lower blood sugar.

At present, there are many GLP-1 receptor agonists, which can be roughly divided into long-acting and short-acting. Long- acting GLP-1 receptor agonists include loxenatide (Fulaimi), exenatide microspheres, semaglutide, albiglutide, dulaglutide, etc.; short-acting GLP-1 receptor agonists include exenatide, beiraglutide, and liraglutide.

The FDA approval of Mounjaro’s hypoglycemic efficacy was based on the results of the Phase 3 SURPASS study, which includes injectable semaglutide (GLP-1 receptor agonist) 1mg, insulin glargine and insulin degludec active agents (two long-acting insulin analogs).

Mounjaro delivered excellent and consistent glycated hemoglobin (A1C) reduction rates across all comparators across the SURPASS study, which was designed to evaluate the efficacy of Mounjaro in adults with a broad range of type 2 diabetes that can be treated in clinical practice.

The trial evaluated the efficacy of 5mg, 10mg and 15mg Mounjaro alone or in combination with commonly prescribed diabetes medications including metformin, SGLT2 inhibitors, sulfonylureas and insulin glargine. Among participants in the SURPASS program, average glycated hemoglobin (A1C) reductions are:
1.8% to 2.1% in patients using Mounjaro 5mg
1.7% and 2.4% in patients using Mounjaro 10mg and 15mg

In addition, glycated hemoglobin (A1C) levels were reduced by 1.6% compared to placebo in the group of patients randomized to receive the maximum recommended dose of 15 mg in Mounjaro monotherapy, and by 1.5% compared with placebo when used in combination with long-acting insulin. In comparison studies with other diabetes drugs, the maximum recommended dose group had a 0.5% reduction in glycated hemoglobin (A1C) compared to semaglutide, a 0.9% reduction compared to insulin degludec, and a 1.0% reduction compared to insulin glargine

Although not for weight loss, the mean change in body weight was a key secondary endpoint across all SURPASS studies. Participants in this study reported a mean BMI of 32-34kg/m2 at enrollment, and participants who received Mounjaro lost an average of approximately 5kg (Mounjaro 5mg users) to 11kg (Mounjaro 15mg users).

In addition, Mounjaro also has a good performance in reducing blood lipids. In another study endpoint, all 3 doses of Mounjaro (5mg, 10mg, 15mg) results in a favorable change from baseline in fasting lipids in 52 weeks. Among them, participants who used the highest dose of Mounjaro (15mg) had a 5.6% reduction in total cholesterol, a 22.5% reduction in triglycerides, a 7.9% reduction in low-density lipoprotein (LDL) cholesterol, and a 21.8% reduction in very low-density lipoprotein (VLDL) cholesterol. High-density lipoprotein (HDL) cholesterol increased by 10.8%. Therefore, Mounjaro also has a good effect on reducing the risk of cardiovascular disease.

In Mounjaro’s clinical trial, at least 5% of participants reported adverse reactions, including nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion, and stomach or abdominal pain. Mounjaro’s label contains a boxed warning about thyroid C-cell tumors.

Mounjaro has not been studied in patients with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes, and is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with type 2 multiple endocrine neoplasia syndrome symptomatic patients.

1. Regarding indications: Since the current GLP-1 receptor agonist liraglutide was launched in 2005, the number of weekly administrated GLP-1RA medications has reached 4. The mainstream semaglutide has diabetes/obesity in Europe and the United States. While in China, no Obesity indication, but only diabetes (+ cardiovascular benefit) indication was allowed. Eli Lilly’s Tirzepatide is estimated to be approved with diabetes/obesity in China.

2. Regarding the significance of weight loss effect for Tirzepatide: previously, the best weight loss data came from the STEP 8 study comparing semaglutide and liraglutide, which was published in JAMA in January this year. The study showed that the weekly administration of semaglutide can significantly reduce the body weight of patients by 15.8%. Now with the latest data from Tirzepatide 15mg, a significantly reduction of body weight by an average of 22.5% is realized, which is really amazing.

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