Semaglutide is Relentlessly Overpowered! Tirzepatide Shows Better Weight Loss and Waist Circumference Reduction in Head-to-Head Comparison

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist developed by Novo Nordisk, which suppresses appetite, reduces calorie intake, and is approved for the treatment of type 2 diabetes and weight loss.

Tirzepatide is a dual agonist developed by Eli Lilly targeting both the glucose-dependent insulinotropic peptide (GIP) receptor and the GLP-1 receptor. It is also approved for the treatment of type 2 diabetes and weight loss. In previous clinical trials, Tirzepatide demonstrated superior weight loss effects compared to Semaglutide, frequently breaking records for drug-induced weight loss.

To better compare the weight loss effects of Tirzepatide and Semaglutide, Eli Lilly launched a head-to-head clinical trial in April 2023, known as SURMOUNT-5. This trial aimed to evaluate the effectiveness and safety of Tirzepatide and Semaglutide in overweight or obese adults with weight-related comorbidities but without diabetes.

On May 12, 2025, the prestigious medical journal The New England Journal of Medicine (NEJM) published a clinical study titled: Tirzepatide as Compared with Semaglutide for the Treatment of Obesity.

This head-to-head clinical trial showed that, compared to the GLP-1 receptor agonist Semaglutide, the GIP and GLP-1 dual agonist Tirzepatide was significantly more effective in weight reduction and waist circumference shrinkage.

In this Phase 3b, open-label, randomized controlled clinical trial, 751 adult participants with obesity but without type 2 diabetes (BMI ≥ 30 or BMI ≥ 27 with at least one obesity-related comorbidity, such as hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease) were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous injections of the maximum tolerated dose of Tirzepatide (10 mg or 15 mg) or Semaglutide (1.7 mg or 2.4 mg) for 72 weeks. The primary endpoint was the percentage change in body weight from baseline to week 72. Key secondary endpoints included the proportion of participants with at least 10%, 15%, 20%, and 25% weight loss, as well as changes in waist circumference from baseline to week 72.

The results showed that, at week 72, the Tirzepatide group achieved an average weight loss of 20.2% (22.8 kg), while the Semaglutide group achieved 13.7% (15.0 kg); the Tirzepatide group had an average reduction in waist circumference of 18.4 cm, compared to 13.0 cm in the Semaglutide group.

Additionally, the proportions of participants in the Tirzepatide group who achieved at least 10%, 15%, 20%, 25%, and 30% weight loss were 81.6%, 64.6%, 48.4%, 31.6%, and 19.7%, respectively. This means that Tirzepatide helped over 80% of participants lose at least 10%, over 60% lose at least 15%, nearly half lose at least 20%, nearly a third lose at least 25%, and almost 20% lose over 30%. These results far surpassed the Semaglutide group, where the corresponding figures were 60.5%, 40.1%, 27.3%, 16.1%, and 6.9%.

In terms of safety, the most common adverse events in both the Tirzepatide and Semaglutide treatment groups were gastrointestinal symptoms such as nausea and constipation, most of which were mild to moderate and primarily occurred during dose escalation. The rates of serious adverse events were 4.8% and 3.5%, respectively, and the proportions of participants discontinuing treatment due to adverse events were 3.0% and 4.8%, which were similar for both groups. In terms of injection site reactions, Tirzepatide had more (8.6% vs 0.3%), but no severe injection reactions were observed.

Overall, these results suggest that, compared to the GLP-1 receptor agonist Semaglutide, the GIP and GLP-1 dual agonist Tirzepatide is significantly more effective in reducing weight and waist circumference.

The superior performance of Tirzepatide is attributed to its unique dual-target mechanism of action:

• GLP-1 receptor: Suppresses appetite and delays gastric emptying;
• GIP receptor: Directly regulates fat cell metabolism and enhances energy expenditure.

In other words, compared to Semaglutide's single-target action, Tirzepatide attacks both problems—suppressing appetite and accelerating fat burning—addressing both overeating and insufficient energy expenditure.

Reference

[1]. https://www.nejm.org/doi/full/10.1056/NEJMoa2416394