Introduction

Tirzepatide, a long-acting glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a long-acting GLP-1 receptor agonist are highly effective newer generation medications for the management of obesity. Little is known about the efficacy of tirzepatide as against semaglutide in adults with obesity but without type-2 diabetes mellitus (T2DM).

Aim

To evaluate the efficacy and safety of the maximum tolerated dose of tirzepatide (10 mg or 15 mg) as against the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) in adults with obesity.

Patient Profile

Adult subjects (age ≥ 18 years) without T2DM but with obesity [body mass index (BMI) ≥ 30 kg/m², or BMI ≥ 27 Kg/m² along with at least one pre-specified obesity-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease)].

Methods

Study Design

Treatment Strategy

• The study subjects were randomized 1:1 to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) as subcutaneous injections, once weekly for 72 weeks. 
• Tirzepatide was initiated at a dose of 2.5 mg once weekly and the dose was escalated by 2.5 mg every 4 weeks until a maximum tolerated dose of 10 mg or 15 mg was reached. 
• Semaglutide was initiated at a dose of 0.25 mg once weekly, the dose was escalated every 4 weeks from 0.25 mg to 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg. In case of unacceptable adverse effects with the 2.4-mg dose, the patient continued receiving the 1.7-mg dose as a maintenance dose

Outcomes

Primary Outcome

Secondary Outcomes

• Weight reductions of at least 10%, 15%, 20%, and 25% 
• Change in waist circumference (WC) from baseline to week 72

Results

• A total of 751 subjects were randomized to the study medications, 80.2% of the patients completed the 72-week treatment during the trial. The mean age of the study population was 44.7 years. The mean body weight was 113.0 kg, the mean BMI 39.4 kg/m², and the mean WC 118.3 cm.
• Patients treated with tirzepatide achieved a greater weight reduction, as compared to those treated with semaglutide [efficacy estimand values: -21.6% (tirzepatide) vs -15.4% (semaglutide)](Fig. 1).

Fig. 1: Change in body weight from baseline to week 72 (Efficacy Estimand) 

Table 1: Percentage of patients achieving specific weight reduction (Efficacy Estimand)

Weight reduction target	Tirzepatide Group (n=374) (%)	Semaglutide Group (n=376) (%)	Treatment difference/ relative risk (95% CI)
≥ 10%	86.7	67.3	1.3 (1.2 to 1.4)
≥ 15%	71.2	46.0	1.5 (1.4 to 1.8)
≥ 20%	54.8	31.9	1.87(1.4 to 2.1)
≥ 25%	36.2	19.4	1.9 (1.5 to 2.4)

• Overall, 22.4% of the patients treated with tirzepatide had an at least 30% body weight reduction, as compared 6.9% of those treated with semaglutide, indicating that likelihood of meeting this weight-reduction target with tirzepatide was around 3 times as high as that with semaglutide. In both study groups, the weight reduction was approximately 6% greater among women than among men. 
• Patients treated with tirzepatide achieved greater reductions in WC, as compared to those treated with semaglutide (-20.0 cm vs. -14.7 cm, efficacy estimand) (Fig. 2).

Fig. 2: Change in waist circumference from baseline to week 72 (Efficacy Estimand)

 

Conclusions

• Among participants with obesity but without T2DM, tirzepatide was superior to semaglutide, in terms of reduction in body weight and WC at 72 weeks.
• A higher proportion of patients treated with tirzepatide were more likely to achieve weight loss of at least 10%, 15%, 20%, and 25%.

N Engl J Med. 2025 Jul 3;393(1):26-36.