Key Benefits
Biologic Description
Tirzepatide, known also as LY3298176, represents a groundbreaking development in the pharmacological management of type 2 diabetes (T2D) and obesity. It's a synthetic peptide that functions as a dual agonist for both the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. This dual mechanism is significant because it mimics the effects of endogenous GIP while simultaneously promoting cAMP synthesis at the GLP-1 receptor, leading to a synergistic effect. This results in enhanced insulin response and reduced glucagon levels, outperforming the impact of either GIP or GLP-1 therapies when used independently.
Tirzepatide is a 39 amino acid long peptide, which includes a C20 fatty di-acid moiety. This design grants it an extended duration of action, allowing for a once-weekly dosing regimen in humans. Its efficacy and safety in improving blood sugar control have led to its approval by the United States Food and Drug Administration (USFDA) in May 2022 for treating T2D. This marked it as the first dual GLP-1 and GIP receptor agonist for this purpose.
In addition to its application in diabetes, tirzepatide is under investigation for its potential in weight management. Clinical trials have indicated significant and sustained benefits in weight loss, particularly in adults with a Body Mass Index (BMI) of 27 or higher. This is partly attributed to its ability to activate GIP receptors in fat cells, which seems to reduce adipose inflammation and enhance adiponectin production – factors known to reduce fat cell differentiation and increase energy expenditure.
The drug's unique mechanism, encompassing mimicking native GIP at the GIP receptor and displaying a bias at the GLP-1 receptor for cAMP generation over beta-arrestin recruitment, is believed to underlie its effectiveness as an anti-diabetes drug. Tirzepatide has shown superior efficacy in glycemic control and comparable safety to other established T2D treatments in clinical trials. Additionally, its role in increasing serum adiponectin levels – an adipokine linked to lipid and glucose metabolism regulation – suggests potential cardioprotective implications.
Beyond its approved use as a T2D treatment, tirzepatide is available for research to qualified professionals. Its multiple effects, including weight loss, improved glycemic control, and potential cardioprotective benefits, make it a subject of ongoing research and interest. The results of these studies, particularly those investigating its long-term effects and comprehensive cardiovascular outcomes, are eagerly anticipated by the medical community.
Dosage Guidelines
Researchers investigating tirzepatide's efficacy and applications should closely adhere to the dosing recommendations, which are based on the populations typically involved in clinical trials—mainly patients with type 2 diabetes and/or obesity. It's essential to refer to the label recommendations detailed in the Mounjaro (tirzepatide) package insert for accurate dosing guidelines.
For researchers focusing on tirzepatide's potential in inducing weight loss in overweight or obese subjects, the following dosing protocol is suggested, based on available data:
Starting Dose (Weeks 1-4): Begin with a 2.5mg dose per week for the initial four weeks. This introductory phase allows for assessment of tolerability and initial efficacy.
Dose Increase (Weeks 5-24): After the initial period, increase the dose to 5mg per week. Subsequent dose adjustments should be made in 2.5mg increments weekly, based on the individual's response. This phase is crucial for evaluating the optimal dosage for effective weight loss while minimizing side effects.
Frequency of Administration: Tirzepatide should be administered once weekly through a subcutaneous injection. This frequency is based on the drug's pharmacokinetics and ensures sustained efficacy over the treatment period.
The recommended duration for this dosing protocol is between 12 to 24 weeks. This timeframe allows for a comprehensive assessment of the drug's weight loss efficacy and safety profile.
Maximum Dose: According to the Mounjaro dosing guidelines and clinical trial data, the maximum established weekly dose is 15mg. It's important not to exceed this limit to avoid potential adverse effects.
Researchers should continuously consult the latest clinical trials and guidelines while considering any updates or changes in the recommended practices. This protocol serves as a reference and may need adjustments based on individual subject responses and emerging research findings.
Starting Dose
2.5 mg
Per Week
1-4 Weeks
Dose Increase
4-5 mg
Per Week
5-24 Weeks
Side Effects
Tirzepatide is generally well-tolerated according to available data, with no serious adverse effects reported in obese or overweight adults, either with or without type 2 diabetes. However, it's important for researchers to be aware that the administration of tirzepatide may lead to minor side effects, predominantly related to the gastrointestinal tract. These side effects usually resolve upon discontinuation of the therapy or with a reduction in dosage.
Commonly observed side effects include nausea, vomiting, diarrhea, reduced appetite, constipation, indigestion, dyspepsia, abdominal pain, and hypersensitivity reactions. Given tirzepatide's impact on gastric emptying, it is advised against its use in subjects with severe gastrointestinal diseases.
Regarding the safety of tirzepatide, the United States Drug Administration has approved it for the treatment of type 2 diabetes in adults, indicating its safety for this group. In clinical trials, such as the phase 3 SURPASS-1 trial, tirzepatide demonstrated a safety profile on par with other GLP-1 receptor agonists. Additionally, the SURPASS-4 trial indicated no excess cardiovascular risk for patients with type 2 diabetes using tirzepatide. Further research, particularly under the SURMOUNT program, is exploring its use as a weight loss treatment and continues to show a favorable safety profile.
It should not be used in subjects with a history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), due to its association with thyroid C-cell tumors in rodent studies. Additionally, patients receiving insulin or insulin secretagogues alongside tirzepatide should be monitored for hypoglycemia, and those on medications with a narrow therapeutic index should be closely observed due to potential delays in medication absorption caused by the peptide.
References:
FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes
The U.S. Food and Drug Administration approved Mounjaro (tirzepatide) injection to improve blood sugar control in adults with type 2 diabetes, as an addition to diet and exercise. Mounjaro was effective at improving blood sugar and was more effective than the other diabetes therapies with which it was compared in clinical studies.
Publication Date: May 13, 2022
A novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab.
Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, Haupt A. LY3298176,
2018 Dec;18:3-14.
doi: 10.1016/j.molmet.2018.09.009.
Epub 2018 Oct 3. PMID: 30473097;
PMCID: PMC6308032.
The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials
Min T, Bain SC.
Diabetes Ther. 2021;12(1):143-157.
doi:10.1007/s13300-020-00981-0
Tirzepatide Once Weekly for the Treatment of Obesity.
Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A
SURMOUNT-1 Investigators
N Engl J Med. 2022 Jul 21;387(3):205-216.
doi: 10.1056/NEJMoa2206038.
Epub 2022 Jun 4.
PMID: 35658024.