Tirzepatide (Mounjaro™): A Review in Type 2 Diabetes

Abstract

Over 3,000 years ago, the ancient Egyptians discussed a condition that was type 1 diabetes. In ancient India, people discovered that they could use ants to test for diabetes by presented urine to them. If the ants came near to the urine, this was a sign that it contained high sugar. They names this condition madhumeha, which means honey urine. During 3rd century, Apollonius of Memphis called the term “diabetes. In the 5th century, people in India and China had work out that type 2 diabetes was common. In 1776 Matthew Dobson suggest that the urine of diabetic patient had sweet taste. In 1910 Sir Edward Albert Sharpey Schafer confirmed that diabetes developed when there was a lack of particular chemical that produced by pancreas and the named it insulin. In 1921 Frederick Benting and Charles worked with two other scientists to purify insulin and produced the first treatment for diabetes. In 1936 sir harold Percival published research between type 1 and type 2 diabetes. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes and is a chronic and progressive illness. Food and Drug Administration introduces mounjaro as a new class of medication for people with type II diabetes in the year 2022. The Food and Drug Administration has approved Mounjaro (tirzepatide) injection as a supplement to diet and exercise to help persons with type 2 diabetes mellitus improve their insulinemic control. The US, EU, Japan, and other countries approve tirzepatide (Mounjaro®), a first-in-class dual incretin agonist of the glucose-dependent insulinotropic polypeptide and (GIP) glucagon-like peptide-1 (GLP-1) receptors, to improve glycaemic control in adults with type 2 diabetes mellitus (T2DM).Tirzepatide was associated with a low risk of clinically significant or severe hypoglycaemia and no increased risk of major adverse cardiovascular events. Adverse events were mostly mild to moderate in severity, with the most common being gastrointestinal events including nausea, diarrhoea, decreased appetite and vomiting. In conclusion, tirzepatide is a valuable addition to the treatment options for T2DM. Type 1 -Genetic factors are the cause of diabetes. When blood sugar levels are excessive, the body does not create enough insulin, resulting in type 1 diabetes, a chronic illness. According to a 2016 study, 5.8% of adults in the nation have diabetes.Type 2: The most prevalent type of diabetes is type 2. When a person's body no longer reacts appropriately to insulin, type 2 diabetes develops. We refer to this as insulin resistance. 37.3 million individuals in 2019 have diabetes, primarily type 2.

Keywords

Trizepatide, mounzaro, diabetes, insulin, Diabetes Mellitus, Carcinoma, Agonist, Insulinotropic, Incertin

Introduction

Our body uses and regulates glucose as a fuel with help of biochemical cycles taking place in body. A chronic illness known as Type 2 diabetes occurs when there is a long-term impairment in the regulation and utilization of glucose, leading to an excess of sugar or glucose in the bloodstream. This may result in immunological, circulatory, and neurological issues that are deadly. Adult-onset diabetes was another name for it.

It Often Develop Too Slowly and Shows Following Symptoms:

 · Increased thirst.

· Fatigue.

· Blurred visions.

· Frequent urination .

· Increased hunger .

· Unintended weight loss.

· Frequent infections.

· Darkened skin usually in armpits and neck.

Primarily It Can Be the Result of 2 Problems -

1. Poor interaction of cells present in muscles and liver with insulin as they don’t take in enough glucose or they become insulin resistant.

2. The pancreas become unable to secrete enough insulin. In May 2022 the FDA approved trizepatide which comes under brand name mounjaro for adults living with Type 2 diabetes. Tirzepatide is  an once  a week  injection but it’s  not an insulin which comes in six different strengths.To lower the risk of side effects it is prescribe..to start with the lowest strength and gradually raise it (if needed). It is also called as a dual glucose-dependent  insulinotropic  polypeptide  (GIP) and glucagon-like  peptide-1  (GLP-1) receptor  agonist.  this  is  the  first  dual  GIP/GLP-1  receptor  agonist. Tirzepatide  acts  like incretins i.e. GIP and GLP-1, these  are two hormones which is naturally  synthesized and secreted by our body.These hormones are known as incretins. This may 2022 FDA approval a drug TIRZEPATIDE (mounjaro). The medication is the first new  diabetes  medications.  Tirzepatide  is  brand  new  type  of  medication  approved  for treatment of type 2 diabetes. Tirzepatide is an injectable medication but it is not a form of insulin. In this article we discuss all the effect and side-effects of this new drug.

Chemical Formula - C225h348n48o68    

Objectives:

1. Determine which patients, depending on their clinical characteristics and desired course of treatment, are suitable for tirzepatide therapy.
2. Examine the patient's reaction to tirzepatide treatment by tracking weight fluctuations and glycemic control on a regular basis
3. For patients with complicated medical histories or diabetes that is resistant to treatment, choose the best combination therapies or alternate forms of care.
4. Coordinate follow-up consultations and care transitions with interdisciplinary healthcare teams to ensure tirzepatide therapy continuation and track long-term results.
5. Determine which patients are suitable for tirzepatide therapy based on their clinical characteristics and desired course of treatment.
6. Work together with multidisciplinary medical teams to plan follow-up visits and care transitions to ensure tirzepatide therapy continuation and track long-term results.

Indications

FDA-Approved Indications:

Tirzepatide is a novel medication approved by the US Food and Drug Administration (FDA) in May 2022 for treating type 2 diabetes mellitus (T2DM). Tirzepatide is a synthetic polypeptide and dual agonist for the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. Therefore, the drug leads to significantly improved glycemic control and weight reduction in patients with T2DM, maximizing benefits similar to GLP-1 medications such as semaglutide. Current clinical data demonstrated that tirzepatide is superior to placebo in improving hemoglobin A1c (HbA1c) levels. The SURPASS-5 clinical trial showed a -2.11% reduction in HbA1c levels at 5 mg per week dosing, compared to -0.86% with a placebo. At the highest dose of 15 mg per week, tirzepatide lead to a -2.34% reduction in HbA1c. This was demonstrated over 40 weeks. A weight reduction of 5.4 kg was seen with 5 mg of tirzepatide dosing, and a 10.5 kg reduction was observed with 15 mg dosing. This dose-dependent correlation with weight loss is similar to semaglutidea common GLP-1 medication utilized for weight loss management. Comparatively, tirzepatide works similarly to GLP-1 medications but with greater efficacy. Given the weight loss properties and lack of liver toxicity, it is likely to have an indirect role in the treatment of nonalcoholic fatty liver disease. However, further research is needed before the use is approved for metabolic dysfunction-associated steatotic liver disease. The results of the SURPASS trials demonstrate that tirzepatide yields clinically significant improvements in glycemic control and weight loss when compared with other GLP-1 receptor agonists (semaglutide and dulaglutide), insulin degludec, and insulin glargine. Consequently, the American Diabetes Association (ADA) categorizes tirzepatide as a highly effective therapy for achieving glycemic control and weight loss.

Mechanism:

When we eat our body releases two incretins called as GIP and GLP-1 which tell our pancreas to release insulin and help us feel full and this is called as the incretin effect. It helps us to digest our food properly and keep the level of our blood sugar (glucose) stable. But for people with Type 2 diabetes, incretins doesn’t work in a proper way. And tirzepatide mimics what GIP and GLP-1 do in the body. This helps in raising the amount of insulin that our body releases after meals and lowers blood sugar. Tirzepatide makes our body more sensitive to insulin. This helps our body to move sugar from the blood to our cells. In addition, tirzepatide prevents our liver from making more glucose. Tirzepatide is a synthetic polypeptide dual agonist for GLP-1 and GIP. Tirzepatide, "twincretin," exhibits distinct characteristics from GLP-1 receptor agonists. The medication comprises 39 amino acids and is an analog of the gastric inhibitory polypeptide. Functionally, tirzepatide stimulates insulin release from the pancreas and reduces hyperglycemia. In addition, tirzepatide also increases the levels of adiponectin.

• Pharmacokinetics:
• Bioavailability: 80%.
• Elimination half-life: 5 days.
• Excretion: Urine and faeces.
• Absorption: Tirzepatide has a bioavailability of roughly 80%. It may take eight to seventy-two hours to achieve peak serum levels. Tirzepatide takes 8 hours to 72 hours to reach in maximum plasma levels after  subcutaneous  injection. It  has  80  percent absolute  bioavailability  after  subcutaneous (SC) injection in thigh, arms or belly’s subcutaneous tissue.
• Distribution: The mean steady-state volume of distribution (Vd) of tirzepatide is approximately 10.3 L. Tirzepatide is highly bound to plasma albumin (99%).
• Metabolism: Proteolytic cleavage of the peptide structure occurs upon injection. In addition, the C20 fatty diacid composition suffers β-oxidation and amide hydrolysis. Tirzepatide, a modified polypeptide, is metabolized into individual amino acids in the liver and other tissues.
• Elimination: Tirzepatide has a half-life of 5 days, permitting weekly dosing, and is eliminated in urine and feces as metabolites.

Administration

Available Dosage Forms and Strengths:

Dose: There is currently no oral version of tirzepatide; it is delivered by the SQ (subcutaneous) route.

Tirzepatide dosages are available in strengths of:

1. 2.5 mg/0.5 mL.
2. 5 mg/0.5 mL.
3. 7.5 mg/0.5 mL.
4. 10 mg/0.5 mL.
5. 12.5 mg/0.5 mL.
6. 15 mg/0.5 ML.

· Increased thirst

· Fatigue

· Blurred visions

· Frequent urination

· Increased hunger

· Unintended weight loss

· Frequent infections

· Darkened skin usually in armpits and neck

It is prescribed to start with the lowest strength i.e. 2.5 mg per week. After 4 weeks one can increase dose it can be raised up to 5 mg once a week. After that dose can be raised by an  additional  2.5 mg  every 4  weeks  until  our blood  sugar  of  patient is  well-controlled.  The  maximum dose which can be use is 15 mg once a week.

Adult Dosage:

Standard dosing is once weekly; prescribed doses can be increased on follow-up visits based on efficacy, as defined by HbA1c levels, body weight, and adverse effects. The patient's ability to tolerate adverse effects plays a significant role in dosing titration.  The initial dosage of tirzepatide for treatment initiation is 2.5 mg administered SQ once weekly, with the primary goal of initiation rather than glycemic control. After 4 weeks, increase to 5 mg SQ once weekly. For additional glycemic control, escalate the dosage by 2.5 mg after at least 4 weeks on the current dose. The maximum tirzepatide dosage is 15 mg SQ once weekly. If a tirzepatide dose is missed, it should be administered within 4 days (96 hours) if feasible; otherwise, skip the missed dose and return to the regular once-weekly schedule.

Pregnancy Considerations:

Available information on tirzepatide use in pregnant women is inadequate to evaluate for a drug-related risk of congenital disabilities and adverse maternal or fetal outcomes. Exposure to the mother and fetus is associated with poorly controlled diabetes in pregnancy. Animal reproduction studies have shown higher occurrences of external, visceral, and skeletal malformations when exposed to tirzepatide. Potential risks exist to the fetus if ingested during pregnancy. Hence, tirzepatide should only be prescribed to pregnant patients of childbearing age when the benefits outweigh the potential risks and after a thorough discussion of the teratogenic effects. Clinicians should also discuss the decreased efficacy of oral contraceptives and offer non-oral methods for at least 4 weeks after beginning tirzepatide.

Half Life: To increase its half-life to five days and make it administerable once a week, it is conjugated to a 20C fatty diacid and bonded to albumin.

Adverse Effects:

Based on available data, most users do not experience significant adverse drug reactions. The primary adverse effects are gastrointestinal-related, but other side effects have also been infrequently reported. Decreased appetite is frequently reported, though this is a potential contributory etiology of intentional weight loss.

The most common side effects of Mounjaro include:

1. Nausea.
2. Vomiting.
3. Diarrhea.
4. Thyroid C-Cell tumor.
5. Pancreatitis.
6. Acute gallbladder disease.
7. decreased appetite.
8. Constipation.
9.  Indigestion.
10.  stomach (abdominal) pain.
11. Thyroid C-Cell tumor
12. Pancreatitis
13. Acute gallbladder disease

Gastrointestinal: Up to 10% of patients may have nausea and diarrhea, along with a few rare cases of acid reflux and vomiting. Some people have also complained of constipation. People frequently report feeling less hungry.In addition to a few rare reports of vomiting and acid reflux, up to 10% of patients may experience. Decreased appetite is often reported. Nausea and diarrhea  may occur in up to 10% of patients, in addition to some infrequent reports of vomiting and acid reflux. Constipation has also been reported in some users.

Renal: Acute renal injury has been documented in rare instances, most likely as a result of dehydration from gastrointestinal losses. These can happen to people who are healthy and already have chronic renal disease. Renal damage can probably be avoided by keeping an eye out for symptoms of dehydration.

Uses:

1. Mounjaro is officially approved by the FDA for: Blood sugar (glucose) control in adults with type 2 diabetes, along with diet and exercise.
2. Blood sugar (glucose) control in adults with type 2 diabetes, along with diet and exercise.

Toxicity:

Tirzepatide overdose patients should have their clinical state closely watched for any changes. Patients may need ongoing monitoring because of the lengthy half-life of this medicine. Clinicians should get in touch with poison control; they might need to speak with a toxicologist. Since there is currently no cure for tirzepatide overdose, supportive care is the most effective treatment. Patients with acute pancreatitis present with abdominal pain, serum lipase >3 ULN, and evidence of acute pancreatitis on imaging. American Gastroenterological Association guidelines recommend goal-directed fluid management for patients with acute pancreatitis. Extended monitoring of patients might be warranted following an overdose, given the half-life of tirzepatide, which is approximately 5 days.

Drug-Drug Interactions:

Tirzepatide should not be administered to patients who are on other GLP-1 medications, such as semaglutide or liraglutide. To reduce the risk of hypoglycemia, patients receiving insulin therapy can be started on tirzepatide medication and have their insulin dosage gradually reduced. For four weeks following initiation and each dose escalation with tirzepatide, patients should be recommended to utilize non-oral contraceptive methods or add a barrier contraceptive because the effectiveness of oral hormonal contraceptives is reduced. Tirzepatide affects the absorption of oral medicines taken concurrently by delaying stomach emptying. This is especially important for people who already have delayed stomach emptying because it can make their symptoms worse. Tirzepatide and other oral medicines with narrow therapeutic indices (TIs) or threshold concentrations should be used with caution.

Contraindications:

 Tirzepatide is contraindicated in patients with medullary thyroid cancer. Tirzepatide is also contraindicated in multiple endocrine neoplasia syndrome type-2 (MEN-2). For further information, refer to the boxed warning below. Further more, the use is contraindicated in patients with known severe hypersensitivity to tirzepatide or any excipients, as it has been associated with severe hypersensitivity reactions, including anaphylaxis and angioedema.In patients who have experienced angioedema or anaphylaxis due to GLP-1 receptor agonists, it is important to use tirzepatide cautiously.

Box Warning-

Thyroid C-cell tumours: Data obtained from animal studies have demonstrated the potential for developing medullary thyroid carcinoma. It is unknown whether this would also occur in humans. Given the theoretical risk, tirzepatide should be avoided in those with a personal or family history of medullary thyroid carcinoma. Patients with a history of MEN-2 should also avoid tirzepatide. Patients with other thyroid cancer-related risk factors should be advised of the theoretical risks. Routine serum calcitonin or thyroid ultrasound monitoring is inconclusive for early detection of medullary thyroid cancer.

Warming and Precautions:

To be monitored for lactating mothers, kidney, and pancreas problems, using birth pills and so on.Contraindications are thyroid carcinoma and severe allergic reactions. Relative contraindications also exist, such as gallbladder disease or diabetic retinopathy.Tirzepatide is only approved for those with T2DM and should not be used for those with T1DM. Further more, tirzepatide does not have approval for other forms of diabetes, like latent autoimmune diabetes in adults.

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