Better Than Ozempic: Scientists Reveal Most Effective Weight Loss Drug

In a landmark study comparing two prominent anti-obesity medications, tirzepatide and semaglutide, researchers found that tirzepatide significantly outperformed semaglutide in reducing body weight and waist circumference in adults without diabetes.

A new head-to-head study reveals tirzepatide achieves 47% more weight loss than semaglutide in people with obesity but without diabetes, highlighting its superior effectiveness and cardiometabolic benefits.

A groundbreaking new study has revealed that tirzepatide leads to significantly greater weight loss than semaglutide in people living with obesity but without diabetes. Over the course of 72 weeks, participants taking tirzepatide lost an average of 20.2% of their body weight. That’s a 47% greater reduction compared to the 13.7% average weight loss seen with semaglutide.

These results were presented at the 2025 European Congress on Obesity in Malaga, Spain, and published in the New England Journal of Medicine. The study was led by Dr. Louis J. Aronne, Director of the Comprehensive Weight Control Center at Weill Cornell Medicine in New York City.

Both tirzepatide and semaglutide are powerful medications used to help manage obesity. However, this is the first direct comparison of the two in people who do not have type 2 diabetes. The research was sponsored by Eli Lilly & Company, the makers of tirzepatide.

In the trial, 751 adults with obesity but no diagnosis of diabetes were randomly assigned to receive either tirzepatide (at 10 mg or 15 mg) or semaglutide (at 1.7 mg or 2.4 mg). Both medications were given as once-weekly injections for a total of 72 weeks.

The average participant was about 45 years old. Roughly two-thirds were women, and just over three-quarters were White. Most had been living with obesity for around 16 years. At the start of the study, their average body weight was 113 kilograms, with an average body mass index (BMI) of 39.4 and an average waist circumference of 118 centimeters. About half of the group also had two or more obesity-related health conditions.

Efficacy Results: Weight Loss and Waist Reduction

The primary endpoint at week 72 was the percentage change in weight from baseline. Key secondary endpoints included weight reduction targets of at least 10%, 15%, 20%, and 25%, and change in waist circumference from baseline to week 72.

Key inclusion criteria for this trial included being aged 18 years or older, a body-mass index (BMI) of 30 kg/m² or more, or a BMI of 27 kg/m² or more and at least one prespecified obesity-related complication (hypertension, dyslipidaemia, obstructive sleep apnoea, or cardiovascular disease), and experiencing at least one unsuccessful dietary effort for weight reduction. Key exclusion criteria included diagnosis of diabetes, prior or planned surgical treatment for obesity, or if within 90 days before screening they had received treatment with a medication for weight reduction or a GLP-1 receptor agonist, or a change in body weight of more than 5 kg.

The mean percentage change in weight at week 72 was −20.2% with tirzepatide and -13.7% with semaglutide – thus 47% higher for tirzepatide. The mean decrease in waist circumference was −18.4 cm with tirzepatide and -13.0 cm with semaglutide – thus 42% higher for tirzepatide. Participants treated with tirzepatide were 30%, 60%, 80% and twice as likely to achieve the weight reduction targets of 10%, 15%, 20%, and 25%, respectively, compared to semaglutide. A total of 19.7% of the participants in the tirzepatide group had a reduction in body weight of at least 30% (an exploratory end point) as compared with 6.9% of those in the semaglutide group, which indicated that the likelihood of meeting this weight-reduction target with tirzepatide was 2.8 times as high as that with semaglutide.

The most common adverse events for both study treatments were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation.

Weight reduction was around 6% less in males than females for both treatments and is believed to explain the slightly lower weight reduction in the current trial compared with previous trials. The current trial had a higher proportion of males at 35%, especially compared to the STEP non-diabetes trials, which included 19-26% males. The current findings align with results reported for the SURMOUNT and STEP programs as well as recent real-world evidence demonstrating higher weight reduction with tirzepatide than semaglutide.

Mechanism of Action: Why Tirzepatide May Be Superior

Dr Aronne explains: “Although it is a single molecule, tirzepatide pharmacologically activates two metabolic receptors, GIP and GLP-1, which have both overlapping and nonoverlapping expression and function. This dual-agonism activity of tirzepatide may contribute to the greater weight reduction observed with tirzepatide than with semaglutide, a monoagonist used in the current trial.”

The results show that as weight reduction increased there were greater improvements in cardiometabolic risk factors, including blood pressure, and blood fat and sugar levels, with both treatments consistent with previous reports. The authors explain that, while some patients will not necessarily require the higher magnitudes of weight reduction to see clinical benefits overall, these findings support the clinical relevance of the current study as the majority of participants receiving tirzepatide (65%) were able to achieve at least 15% weight loss versus 40% for semaglutide; and nearly a third (32%) achieved at least 25% weight reductions with tirzepatide compared to 16% with semaglutide.

They further explain that the additional 5.4 cm extra reduction in waist circumference with tirzepatide compared with semaglutide is also clinically relevant. In a large pooled analysis of waist circumference and mortality, each 5-cm increase in waist circumference predicted a 7% increase in mortality among men and a 9% increase among women. In alignment with these data, published guidance has emphasized the importance of treating patients with abdominal obesity and aiming for a reduction of at least 4 cm.

The trial has certain strengths and limitations. One strength is the diversity of the participants as 19% reported race as Black-African American and 26% reported ethnicity Hispanic or Latino, representative of the populations in the USA living with obesity. The trial’s approach of using the maximum tolerated dose for both treatments addresses a potentially more meaningful real-world question, compared to a fixed dose approach. However, a limitation is that the trial was not blinded, meaning participants knew which drug and the dose they were receiving. However, the authors explain the consistency of the current findings with previously blinded trials supports their generalizability.

Dr Aronne concludes: “Our study shows that treatment with tirzepatide was superior to semaglutide with respect to reduction in body weight and waist circumference.”

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