The Head-to-Head Battle: SURMOUNT-5 Results
For years, patients and clinicians have wondered: between tirzepatide (Zepbound/Mounjaro) and semaglutide (Wegovy/Ozempic), which is truly more effective? The SURMOUNT-5 trial—the first randomized head-to-head comparison—now provides a definitive answer.
Trial Design
The SURMOUNT-5 study was an open-label, controlled phase IIIb trial with rigorous methodology:
- Participants: 751 adults with obesity but without type 2 diabetes
- Randomization: 1:1 ratio to either medication
- Dosing: Maximum tolerated doses
- Tirzepatide: 10 mg or 15 mg weekly
- Semaglutide: 1.7 mg or 2.4 mg weekly
- Duration: 72 weeks
- Primary Endpoint: Percent change in body weight
Primary Results: Tirzepatide Wins
The results were unambiguous:
| Metric | Tirzepatide | Semaglutide |
|---|---|---|
| Mean Weight Loss | 20.2% | 13.7% |
| Absolute Weight Loss | 22.8 kg (50 lbs) | 15.0 kg (33 lbs) |
| Statistical Significance | p<0.001 | Reference |
This represents a 47% greater relative weight loss with tirzepatide—a clinically meaningful difference that exceeded many predictions.
Secondary Endpoints
Tirzepatide demonstrated superiority across all five key secondary endpoints:
Weight Loss Thresholds Achieved
| Threshold | Tirzepatide | Semaglutide |
|---|---|---|
| ≥10% weight loss | 85.8% | 72.5% |
| ≥15% weight loss | 69.3% | 52.1% |
| ≥20% weight loss | 53.4% | 30.5% |
| ≥25% weight loss | 31.6% | 16.1% |
Nearly one-third of patients on tirzepatide lost at least a quarter of their body weight—a result previously seen only with bariatric surgery.
Waist Circumference
Tirzepatide was also superior for waist circumference reduction, an independent predictor of cardiometabolic risk.
Safety Comparison
The tolerability profile favored tirzepatide:
| Safety Metric | Tirzepatide | Semaglutide |
|---|---|---|
| GI Adverse Events Leading to Discontinuation | 2.7% | 5.6% |
| Most AEs Severity | Mild-Moderate | Mild-Moderate |
| Timing of Most AEs | During dose escalation | During dose escalation |
Most adverse events in both groups were gastrointestinal (nausea, vomiting, diarrhea) and occurred during the dose escalation phase. However, significantly fewer tirzepatide patients discontinued due to these effects.
Why the Difference?
The superior efficacy of tirzepatide likely stems from its dual mechanism of action:
Semaglutide: Single-Target Approach
- GLP-1 receptor agonist only
- Enhances insulin secretion
- Reduces appetite via hypothalamic signaling
- Slows gastric emptying
Tirzepatide: Dual-Target Approach
- GLP-1 receptor agonist AND
- GIP (glucose-dependent insulinotropic polypeptide) receptor agonist
- The combination produces synergistic effects on:
- Appetite suppression
- Energy expenditure
- Fat metabolism
- Insulin sensitivity
Important Caveats
Sex Differences
Weight loss was approximately 6% lower in men than women in both treatment groups. This trial included 35% men—higher than most obesity trials—which may explain why overall results were slightly lower than previous studies of both medications.
Open-Label Design
The trial was open-label, meaning participants knew which medication they received. While this could theoretically bias subjective outcomes, the objective weight measurements remain reliable.
Cost and Access
Both medications remain expensive without insurance coverage, and availability continues to be challenging due to high demand and manufacturing constraints.
Cardiovascular Implications
A post-hoc analysis examined 10-year cardiovascular disease risk reduction:
- Both medications significantly reduced predicted cardiovascular risk
- Tirzepatide showed numerically greater risk reduction
- For patients with elevated baseline cardiovascular risk, the difference between medications may be clinically meaningful
Clinical Decision-Making
When Tirzepatide May Be Preferred
- Patients targeting substantial weight loss (>20%)
- Those who experienced significant GI side effects on semaglutide
- Patients with comorbidities requiring maximal weight reduction
- When cardiovascular risk reduction is a priority
When Semaglutide May Be Preferred
- Patients satisfied with 10-15% weight loss
- Those with insurance coverage only for semaglutide
- Patients who have responded well to semaglutide previously
- When oral formulation is desired (Rybelsus)
Market Implications
The SURMOUNT-5 results have significant market implications:
- Prescribing Trends: September 2025 data shows tirzepatide has already become the most commonly prescribed first-time GLP-1 medication, overtaking semaglutide
- Competition: These results increase pressure on Novo Nordisk to develop next-generation compounds
- Pricing: The proven superiority may influence future pricing strategies
What This Means for Patients
For individuals considering GLP-1 therapy for obesity, the SURMOUNT-5 trial provides actionable information:
- Tirzepatide produces significantly greater weight loss in a head-to-head comparison
- Both medications are effective—even the "losing" medication produced 13.7% weight loss
- Tolerability may be better with tirzepatide based on discontinuation rates
- Individual response varies—some patients may respond better to semaglutide despite population-level differences
- Access and cost remain practical concerns that may influence real-world choices
Conclusion
The SURMOUNT-5 trial represents a pivotal moment in obesity medicine. Tirzepatide's demonstrated superiority—with 47% greater weight loss and better tolerability—establishes it as the more effective option for patients seeking maximal weight reduction.
However, the remarkable efficacy of both medications underscores the transformative impact of GLP-1 receptor agonists on obesity treatment. For the first time, pharmaceutical approaches can produce weight loss previously achievable only through surgery.
As research continues and additional formulations emerge (including oral tirzepatide in development), the obesity treatment landscape will continue evolving. What remains clear is that personalized medicine—matching the right patient to the right medication—will be essential for optimizing outcomes.
This article is for educational purposes only. Medication decisions should be made in consultation with qualified healthcare providers based on individual circumstances.