Tirzepatide
Contents
What is Tirzepatide?
Tirzepatide (also known as tirz) is part of the second generation of GLP-1 agonists, demonstrating dual action by mimicking the functions of both GLP-1 and GIP. It has emerged as a groundbreaking medication for type 2 diabetes and weight loss treatment. In this article, we explain what GLP-1 and GIP are, how tirzepatide works, its uses in clinical practice, and key results from major studies over the past decade.
What are GLP-1 and GIP?
Glucagon-like peptide-1 (GLP-1) is a hormone produced in the gut (specifically by intestinal L-cells) in response to eating. It has several important roles in metabolism and appetite regulation:
- GLP-1 stimulates insulin release from the pancreas when blood sugar is high, helping lower blood glucose levels.
- At the same time, it reduces the release of glucagon from the pancreas, a hormone that normally signals the liver to put more sugar into the bloodstream.
- GLP-1 also slows down stomach emptying, meaning food is digested more slowly and glucose from meals enters the bloodstream gradually.
- In addition, GLP-1 acts on the brain to increase feelings of fullness (satiety) and reduce appetite after eating.
Through these combined actions, our natural GLP-1 hormone helps keep blood sugar in check and tells us to eat less, especially after meals. However, in conditions like type 2 diabetes, the GLP-1 response may be blunted or insufficient.
GIP (Glucose-Dependent Insulinotropic Polypeptide) is the other major “incretin” hormone from the gut, secreted by K-cells in the small intestine when we eat. Like GLP-1, GIP has important metabolic roles:
- It stimulates insulin secretion in a glucose-dependent manner (meaning it mainly works when blood sugar is elevated). In fact, GIP typically accounts for a large portion of the insulin released after meals in healthy people. However, in people with type 2 diabetes, the insulin-releasing effect of GIP is often impaired.
- Unlike GLP-1, GIP by itself has little effect on appetite – GLP-1 greatly reduces appetite and food intake, whereas GIP alone has not shown significant impact on food intake.
Together, GLP-1 and GIP are the body’s key messengers in the “incretin effect,” helping the pancreas respond to meals by increasing insulin. GLP-1 has the added benefit of suppressing appetite and slowing down the movement of food in the digestive tract, contributing to reduced hunger sensation. These insights led scientists to develop peptides that leverage these hormones for diabetes and weight loss research.
How Does Tirzepatide Work?
Tirzepatide is a dual GLP-1 and GIP receptor agonist – in other words, it binds to and activates the same receptors that GLP-1 and GIP normally activate. By stimulating both incretin pathways at once, tirzepatide boosts the effects on insulin release, glucagon suppression, and appetite regulation beyond what a GLP-1–only drug would do. This unique dual-incretin approach has earned tirzepatide the nickname “twincretin” (twin incretin) in the medical research literature.
What is Tirzepatide Used for?
- Type 2 Diabetes Mellitus (T2DM): Tirzepatide was approved by the U.S. FDA in May 2022 for adults with type 2 diabetes, under the brand name Mounjaro™. It’s indicated to improve blood sugar control in T2DM, in addition to diet and exercise. Patients take it once weekly by injection, titrating the dose upward over time. Tirzepatide has shown such robust effects that the American Diabetes Association (ADA) now classifies it as a “highly effective” option for both glucose lowering and weight loss in their consensus treatment guidelines.
- Obesity and Weight Management: In late 2023, the FDA approved tirzepatide for chronic weight management in adults with obesity or overweight, under a new brand name Zepbound™. This approval was based on impressive clinical trial results showing dramatic weight loss. Tirzepatide is used alongside diet and exercise to help achieve and maintain weight loss. The idea of using a diabetes drug for weight loss is not new (several GLP-1 agonists paved the way), but tirzepatide’s amount of weight loss has turned heads in the medical community. Many experts now view it as a promising option for patients with obesity, even those without diabetes. In fact, tirzepatide’s weight-loss efficacy in trials rivals that of some bariatric surgeries in percentage terms, offering a medical (non-surgical) tool to induce major weight reduction.
- Other Potential Uses: Beyond diabetes and obesity, tirzepatide is being studied for a range of metabolic and cardiovascular benefits. There is interest in whether it can help prevent type 2 diabetes in people with prediabetes. In fact, a trial over 3 years showed that tirzepatide led to significant weight loss and many participants with prediabetes returned to normal blood sugar status.
Tirzepatide is also undergoing a large cardiovascular outcomes trial to see if it can reduce heart attacks, strokes, or cardiovascular deaths in people with diabetes (results are pending). Given that GLP-1-based drugs have shown heart and kidney benefits in some studies, there is optimism that the dual action of tirzepatide might confer similar or even greater protection – but we will await the evidence.
Side Effects of Tirzepatide
Like other medications in its class, tirzepatide can cause side effects, and the most common are gastrointestinal (GI) symptoms. In trials, a significant number of patients experienced nausea, vomiting, diarrhea, or constipation, especially during the initial dose-escalation phase. These side effects are usually mild to moderate and tend to improve over time as the body adjusts.
Aside from GI issues, other side effects reported include loss of appetite (which is somewhat intended), occasional dizziness, fatigue, or injection-site reactions (e.g. mild redness or itching where the shot is given). A few people (especially those with diabetes on other meds) experienced episodes of hypoglycemia (low blood sugar). Notably, the risk of significant hypoglycemia with tirzepatide alone is low, since it won’t trigger insulin if blood sugar isn’t elevated. But if a patient is also on insulin or a sulfonylurea, doctors often reduce the doses of those when starting tirzepatide to avoid lows.
One side effect that seen research trials was alopecia (hair loss) – around 3–5% of participants reported some hair loss or thinning. This sounds alarming, but it was generally mild and is believed to be related to the rapid weight loss (significant weight loss from any cause can trigger temporary hair thinning due to the stress on the body). Ensuring adequate nutrition (protein, vitamins) during weight loss is important.
Safety considerations: Tirzepatide comes with a boxed warning (similar to other GLP-1 agonists) about a potential risk of thyroid C-cell tumors. This is based on rodent studies in which extremely high doses caused a specific type of thyroid tumor. No cases of this cancer have been seen in human trials, but as a precaution, tirzepatide is not given to patients with a personal or family history of medullary thyroid carcinoma or MEN-2 syndrome.
Tirzepatide Dosing Protocol (for Research)
Tirzepatide is a well-studied medication, and therefore dosing protocols in the research setting have been well-established. The most common research protocol for tirzepatide involves once weekly injection under the skin (subcutaneous injection). The dosing protocol is as follows:
- 1Weeks 1-4: 2.5 mg once weekly
- 2Week 5-8: 5 mg once weekly
- 3Week 9-12: 7.5 mg once weekly
- 4Week 13 -16: 10 mg once weekly
- 5Week 17-20: 12.5 mg once weekly
- 6Week 21 and beyond: 15 mg once weekly
- Note: Titrating to the maximum dose is not required to achieve intended research outcomes.
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