In 2022, when I first started writing ABOM study blogs, one of my earliest posts focused on tirzepatide. The then–hot-off-the-press SURMOUNT-1 trial demonstrated significant weight loss following its initial approval for type 2 diabetes. Since then, numerous additional studies have expanded our understanding of tirzepatide. This blog will review those updates and replace the original post from May 2022.

To begin, let’s review the basics of tirzepatide (Zepbound®). This is a glucagon-like peptide-1/gastric inhibitory hormone (GLP-1/GIP) dual-receptor agonist administered as a subcutaneous injection that results in an average weight loss of approximately 20%, approaching the weight loss seen with metabolic and bariatric surgery. Incretins stimulate insulin secretion in response to carbohydrate ingestion while simultaneously inhibiting glucagon release and do not cause hypoglycemia in the absence of concurrent hypoglycemic agents.

Combining the mechanisms of anti-obesity medications allows for targeting multiple receptors, creating a synergistic effect that enables lower therapeutic dosages, fewer side effects, and greater weight loss. The dual agonist tirzepatide acts synergistically through GLP-1 and GIP pathways, similar to the individual components discussed below:

  • GLP-1 is secreted by enteroendocrine L-cells in the distal small intestine and colon in response to nutrient ingestion. It exerts an incretin effect, enhancing glucose-dependent insulin secretion, suppressing glucagon release to reduce hepatic gluconeogenesis, and slowing gastric and intestinal emptying, which promotes increased satiety.
  • GIP, also referred to as glucose-dependent insulinotropic peptide, is secreted by the duodenum and jejunum (K-cells); it also has an insulin incretin effect and slows gastric emptying.

The side effect profile of tirzepatide is similar to semaglutide and consists mainly of gastrointestinal symptoms, including nausea, diarrhea, and constipation. However, these effects may occur to a lesser extent than with GLP-1 receptor agonists alone, as GIP may help mitigate gastrointestinal side effects. A prior blog has discussed the potential fetal harm associated with tirzepatide (see here), but as a reminder, patients taking oral contraceptives (OCP) should use barrier protection when initiating tirzepatide or for one month after dose escalation due to transient gastrointestinal slowing, which may reduce OCP absorption. Non-oral contraceptive options are not affected. Finally, GLP-1 receptor agonists carry a boxed warning and should be avoided in individuals with a personal or family history of medullary thyroid carcinoma or a personal history of multiple endocrine neoplasia type 2 (MEN2).

Now that we have covered the basics, let’s dive into the landmark trials that established the effectiveness of this medication, starting with the SURPASS trials, which collectively demonstrated that tirzepatide provides robust glycemic control and clinically significant weight loss across a broad spectrum of patients with type 2 diabetes (T2DM). As monotherapy and in combination with other agents, tirzepatide consistently outperformed placebo, was superior to semaglutide 1 mg (the highest dose FDA-approved at that time), and achieved greater A1C and weight reductions compared with basal insulins, with a lower risk of hypoglycemia. In higher-risk populations, additional signals suggested potential renal benefit. These trials reinforced its role as a highly effective dual incretin therapy in T2DM management and leading to the approval of Mounjaro® in 2022.

More recently, in 2025, Mounjaro® has been approved for use in patients with T2DM down to an age of 10 years. The SURPASS-PEDS trial supported this expansion, demonstrating HbA1c reductions of 2.2% and a BMI decrease of 11%.

The SURPASS trials focused on those with diabetes, whereas the SURMOUNT trials focused on effectively treating those with excess adiposity. These trials led to FDA indications for adults with obesity (SURMOUNT 1-5) and obstructive sleep apnea (SURMOUNT-OSA), as summarized in the table below:

A few other notable studies that may ultimately lead to more FDA indications to the tirzepatide label are summarized below:

  • SUMMIT is a phase 3 trial that demonstrated tirzepatide significantly improves outcomes in adults with heart failure with preserved ejection fraction (HFpEF) and obesity. Compared with placebo, tirzepatide reduced the risk of heart failure-related events (including urgent visits, hospitalization, diuretic intensification, or cardiovascular death) by 38%, while also improving heart failure symptoms and physical limitations. In addition, tirzepatide led to substantial weight loss (approximately 14-16%) and improved secondary measures, including exercise capacity and inflammatory markers.
  • SURMOUNT-MMO is a large phase 3, randomized, double-blind, placebo-controlled 5-year trial evaluating whether tirzepatide reduces morbidity and mortality in adults with obesity. The primary endpoint is time to first occurrence of a major adverse outcome, including all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events.
  • SYNERGY-NASH (i.e., MASH) is a phase 2 trial that showed tirzepatide was superior to placebo for MASH resolution without worsening fibrosis, and more than half of treated patients achieved improvement in fibrosis at 52 weeks. This is a major advancement, but given the short duration of one year and smaller sample size (190 participants), longer and larger trials will be needed.

For the ABOM exam, it is not necessary to know the names of specific trials; rather, focus on the key findings that support clinical use and indications. Currently, tirzepatide is FDA-approved for T2DM for those ≥10 years of age and chronic weight management and obstructive sleep apnea in adults. Also, be familiar with trials showing potential benefits over others. For example, when selecting treatment for patients with MASH or heart failure, there is evidence supporting GLP-1/GIP receptor agonists over other oral combination therapies such as naltrexone/bupropion ER.

Finally, be familiar with the expected weight loss associated with each FDA-approved pharmacologic option. Tirzepatide provides approximately 20% total body weight loss for weight management in individuals without diabetes and slightly lower (approximately 12–13%) in those with diabetes, accounting for placebo. It is one of the most potent anti-obesity medications currently available. However, semaglutide 7.2 mg weekly, approved in March 2026, demonstrates comparable weight loss, and the anticipated release of retatrutide in late 2026 to early 2027 is expected to achieve even greater weight reduction, demonstrating approximately 30% weight loss in phase 2 trials.

Sample Question

A 45-year-old woman with obesity presents to clinic to discuss pharmacologic options for weight loss. She is interested in starting tirzepatide. Her medical history is notable for hypertension and migraine headaches. She takes lisinopril daily and has no history of diabetes. Which of the following represents a contraindication to initiating this medication?

A. Uncontrolled hypertension

B. Family history of multiple endocrine neoplasia type 2

C. Use of an ACE inhibitor

D. BMI <30 kg/m²

E. Personal history of papillary thyroid carcinoma

Next Week: Monthly Knowledge Check. This is a review checklist of must-know items for ABOM exams based on the previous four blog topics. In addition, this will include a brief explanation of the correct answers to previous sample questions.

Upcoming: Air Displacement Plethysmography (i.e., Bod Pod), AACE Algorithm for Evaluation and Treatment of Obesity (2025), and Medullary Thyroid Carcinoma

For more practice questions, check out the following:

  • Obesity Medicine Board Review Questions (2026): Q 29, 200, 213, and 279.
  • Obesity Medicine Practice Tests (2026): Qs 293 and 294.

(Copyright 2026) Obesity Medicine Board Review Questions, LLC: obesitymedicinereview.com

Featured image: Modified from VectorStock (image license purchased)

Copyediting by Kelly Smith

Now available: A full line of ABOM study resources with 775+ challenging questions in a mobile or book format. Access to both formats is available in a discounted Ultimate Package, which also includes a Pass Guarantee (if you fail the exam in 2026, you get the 2027 edition free), 50 bonus questions released in August, and the newest book, Obesity Medicine: Sample Questions and Study Blogs, which includes all the updated previous study blogs in a paperback format. Check it out here!