Tirzepatide outperforms semaglutide for weight loss in people without diabetes

A major 72-week trial shows tirzepatide leads to double-digit weight loss and greater waist reduction than semaglutide, reshaping obesity treatment strategies and offering new hope for patients without diabetes.

Study: Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. Image Credit: Laborant / Shutterstock

In a recent study published in The New England Journal of Medicine, researchers evaluated and compared the weight-reducing effects and safety of tirzepatide and semaglutide in adults with obesity but without type 2 diabetes. The study was funded by Eli Lilly, the manufacturer of tirzepatide.

Background

Can a weekly injection lead to double-digit weight loss? In the fight against obesity, affecting over 650 million adults globally, many people struggle to lose and maintain weight through lifestyle changes alone. Pharmacological advances, particularly with glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide, offer hope.

Tirzepatide, a dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, may provide even greater benefits. While both drugs are approved for weight management, direct comparisons in non-diabetic populations remain scarce.

Clarifying their relative effectiveness is vital for guiding treatment decisions. Additionally, aligning treatment options with patients’ own weight loss goals and preferences is increasingly recognized as important for effective, shared decision-making.

Further research is needed to determine which therapy best supports long-term weight loss in real-world settings.

About the study

This phase 3b, randomized, open-label (unblinded), controlled trial enrolled 750 adults with obesity, defined as having a body mass index (BMI) ≥30, or ≥27 with complications such as hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease.

Participants were randomly assigned to receive once-weekly subcutaneous injections of tirzepatide (10 mg or 15 mg) or semaglutide (1.7 mg or 2.4 mg) for 72 weeks. Dosing began at 2.5 mg for tirzepatide and 0.25 mg for semaglutide, escalating to maximum tolerated doses. Randomization was stratified by sex, baseline BMI, and prediabetes status.

Both groups received counseling on diet and physical activity. Weight and waist circumference were assessed regularly. Safety was monitored through adverse events, especially gastrointestinal symptoms and injection-site reactions. Participants experiencing intolerable side effects could reduce or stop medication, but were followed for outcomes.

The primary outcome was the percent change in body weight at week 72. Key secondary outcomes included the proportion of participants achieving at least 10%, 15%, 20%, or 25% weight loss, and change in waist circumference. Importantly, the study used a statistical approach called a “modified treatment-regimen estimand,” which allowed for valid comparisons between groups by accounting for participants who discontinued the trial drug, changed therapy, or dropped out.

Statistical models accounted for baseline differences and controlled for dropout rates to ensure valid comparisons between treatment groups. Both drugs were titrated to the maximum tolerated dose, reflecting flexible, real-world clinical practice rather than a fixed-dose protocol.

Study Results

Among the 750 enrolled participants, demographic characteristics were similar across groups. The average age was 44.7 years, 64.7% were women, and the mean baseline weight was 113 kg. The mean BMI was 39.4, and the average waist circumference was 118.3 cm.

About half the participants had at least two obesity-related conditions. Notably, this trial included a higher proportion of men (about 35%) compared to prior obesity medication studies, which may influence the absolute magnitude of weight loss observed.

At 72 weeks, participants treated with tirzepatide achieved a mean body weight reduction of 20.2%, compared to 13.7% with semaglutide, a statistically and clinically significant difference. This translates to approximately 22.8 kg of weight loss with tirzepatide and 15 kg with semaglutide.

Participants on tirzepatide were also significantly more likely to achieve higher tiers of weight loss: 81.6% achieved at least 10% weight loss (vs. 60.5% with semaglutide), 64.6% reached 15% (vs. 40.1%), 48.4% reached 20% (vs. 27.3%), and 31.6% reached 25% or more (vs. 16.1%). Additionally, 19.7% in the tirzepatide group achieved 30% weight loss, compared to just 6.9% in the semaglutide group.

Tirzepatide was also more effective in reducing waist circumference, achieving a mean reduction of 18.4 cm compared to 13.0 cm with semaglutide. Improvements in cardiometabolic risk factors such as blood pressure, fasting glucose, and lipid levels were seen in both groups and were strongly linked to the degree of weight loss.

Among participants achieving higher weight loss categories (for example, ≥20%), the improvements in blood pressure and other risk factors were even greater, highlighting that the health benefits scale with the amount of weight lost. The study also found that women tended to lose about 6% more weight than men in both treatment groups, which is important for interpreting results and applying them in practice.

Safety profiles were consistent with known side effects of incretin-based therapies. Gastrointestinal symptoms were the most common adverse events, typically occurring during dose escalation. This included nausea, diarrhea, constipation, and vomiting, and were primarily mild to moderate.

Semaglutide was associated with a higher discontinuation rate due to gastrointestinal issues (5.6%) compared to tirzepatide (2.7%). Injection-site reactions occurred more frequently in the tirzepatide group (8.6%) versus the semaglutide group (0.3%) but did not lead to treatment cessation.

Overall, about 77% of participants in both groups experienced at least one adverse event, though serious adverse events were rare (around 4% in each group). Serious adverse events were uncommon and similar between groups. Notably, a single adjudication-confirmed case of pancreatitis was reported in the semaglutide group.

These results show that tirzepatide not only delivers greater overall weight loss than semaglutide but also helps more patients reach clinically meaningful weight loss milestones. The consistency of benefits across weight, waist circumference, and metabolic health metrics suggests tirzepatide could be particularly useful for patients with severe obesity or multiple health risks.

Additionally, the trial’s diverse enrollment, including 19% Black and 26% Hispanic or Latino participants, supports the generalizability of these findings to a broader population.

Conclusions

To summarize, in adults with obesity but without type 2 diabetes, tirzepatide significantly outperformed semaglutide in reducing both body weight and waist circumference over 72 weeks. A greater proportion of patients on tirzepatide reached key weight loss thresholds, and the treatment was well-tolerated with manageable side effects.

The trial's open-label nature is a limitation, as it may introduce some bias, but the results are consistent with those seen in prior blinded studies. These findings highlight tirzepatide’s value as a highly effective weight management option in this population.

As obesity continues to rise worldwide, having multiple potent treatment choices enables more personalized care. The availability of medications that can help patients achieve their preferred and clinically meaningful weight loss goals may improve adherence and satisfaction. This head-to-head comparison supports tirzepatide’s growing role in clinical practice and may influence future obesity treatment guidelines and shared decision-making between patients and providers.