TRZ (GLP-1/GIP)

Mechanism of Action
TRZ is a dual incretin agonist targeting both GLP-1 and GIP receptors. This synthetic 39-amino-acid peptide activates both receptors, mimicking endogenous incretin hormones. As a result, it enhances glucose-dependent insulin secretion and reduces appetite.
GLP-1 receptor activation stimulates insulin release, suppresses postprandial glucagon, delays gastric emptying, and promotes satiety via hypothalamic pathways. GIP receptor agonism also enhances insulin secretion and may provide additional metabolic and weight-regulating benefits.
Preclinical studies demonstrated that TRZ is more potent than GLP-1 receptor agonists alone in improving glycemic control and reducing body weight. Although GIP signaling has historically been considered impaired in type 2 diabetes, combined activation with GLP-1 appears to restore responsiveness. TRZ has greater affinity for the GIP receptor and shows preferential cAMP signaling at the GLP-1 receptor, which may contribute to strong insulinotropic effects with less tachyphylaxis. It also increases adiponectin levels, improving insulin sensitivity and metabolic homeostasis.
Clinical Uses
TRZ was initially developed for type 2 diabetes mellitus and was approved by the FDA in 2022 as the first dual GIP/GLP-1 receptor agonist, marketed as Mounjaro®. It is indicated as an adjunct to diet and exercise, often after metformin, producing substantial reductions in HbA1c and body weight. In many cases, it reduces the need for basal insulin.
Due to its pronounced weight-loss effects, TRZ was further evaluated for obesity and approved by the FDA in October 2023 under the brand name Zepbound® for chronic weight management in adults with obesity (BMI ≥30) or overweight (BMI ≥27) with weight-related comorbidities. It is currently considered one of the most effective pharmacologic treatments for obesity.
In clinical practice, TRZ is used for:
• Type 2 diabetes: Significant HbA1c reduction as monotherapy or in combination therapy.
• Obesity or overweight with comorbidities: Clinically meaningful weight loss when lifestyle interventions alone are insufficient.
It is also being investigated for obesity-related conditions such as obstructive sleep apnea, nonalcoholic steatohepatitis (NASH), and cardiovascular risk reduction.
Side Effects and Precautions
The safety profile of TRZ is similar to that of GLP-1 receptor agonists. The most common adverse effects are gastrointestinal, including nausea, vomiting, diarrhea, constipation, decreased appetite, and dyspepsia. These symptoms typically occur during treatment initiation or dose escalation, so gradual titration is recommended. Most cases are mild to moderate and transient.
TRZ carries a low risk of hypoglycemia when used alone; however, the risk increases when combined with insulin or sulfonylureas, requiring dose adjustments. A small increase in heart rate (approximately 2–4 beats per minute) has been observed. Long-term cardiovascular safety continues to be evaluated.
Scientific Evidence and Clinical Trials
The SURPASS (type 2 diabetes) and SURMOUNT (obesity) clinical trial programs demonstrated the high efficacy of TRZ. In type 2 diabetes, SURPASS trials showed HbA1c reductions of up to −2.6% and weight loss of up to ~11.7 kg, outperforming several other antidiabetic agents, including semaglutide 1 mg. Many patients achieved near-normal glycemic levels.
In obesity, the SURMOUNT-1 trial demonstrated average weight reductions of 15–21% over 72 weeks, with more than 50% of participants losing at least 20% of their initial body weight. These results approach those typically seen with bariatric surgery. Improvements were also observed in blood pressure, lipid profiles, glycemic parameters, and quality of life. Discontinuation rates due to gastrointestinal side effects were low, and no significant increase in serious adverse events was observed compared with placebo.
References – TRZ (GLP-1/GIP)
Jastreboff AM et al. (2022). SURMOUNT-1. N Engl J Med, 387(3), 205–216.
Nauck MA & D’Alessio DA (2022). Tirzepatide, a dual GIP/GLP-1 receptor agonist. Cardiovasc Diabetol, 21:169.
MedlinePlus. Tirzepatide Injection – Drug Information (2025).