Tirzepatide vs Semaglutide for Weight Loss: Clinical Comparison
Tirzepatide and semaglutide are the two most prescribed GLP-1 receptor agonists for weight loss. This guide compares their clinical efficacy, dosing protocols, safety profiles, and real-world outcomes based on SURMOUNT and STEP clinical trials.
Clinical Trial Data: SURMOUNT vs STEP
The SURMOUNT trials (tirzepatide, 2022-2023) and STEP trials (semaglutide, 2021-2022) directly demonstrated the superiority of tirzepatide for weight loss. Both trials enrolled patients with obesity (BMI >27) or overweight with weight-related conditions.
STEP 4 (Semaglutide): 3,731 patients on 2.4mg weekly achieved mean weight loss of 17.4% over 68 weeks (approximately 18 kg or 40 lbs for a 100kg patient). The placebo group lost 2.4%.
SURMOUNT-1 (Tirzepatide): 2,539 patients on 15mg weekly achieved mean weight loss of 22.5% over 72 weeks (approximately 23 kg or 51 lbs for a 100kg patient). The placebo group lost 2.1%.
SURMOUNT-2 (Tirzepatide with type 2 diabetes): 1,915 patients with diabetes on 15mg weekly achieved 21% weight loss while also improving HbA1c by 2.0-2.5 percentage points.
The approximately 5-percentage-point difference in weight loss (tirzepatide 22.5% vs semaglutide 17.4%) represents a clinically meaningful advantage. This translates to an additional 5-6 kg (11-13 lbs) of weight loss on average.
Dosing Protocols and Titration
Both medications use once-weekly subcutaneous injection, but their titration schedules and maintenance doses differ significantly.
| Parameter | Semaglutide (Wegovy) | Tirzepatide (Zepbound) |
|---|---|---|
| Starting Dose | 0.25 mg weekly | 2.5 mg weekly |
| Week 1-4 | 0.25 mg (4 weeks) | 2.5 mg (4 weeks) |
| Week 5-8 | 0.5 mg | 5.0 mg |
| Week 9-12 | 1.0 mg | 7.5 mg |
| Week 13+ | 1.7 mg or 2.4 mg | 10 mg or 15 mg |
| Titration Duration | 16-20 weeks | 16-20 weeks |
| Maintenance Dosing | 1.7 or 2.4 mg weekly | 10 or 15 mg weekly |
| Injection Route | Subcutaneous (abdomen, thigh, arm) | Subcutaneous (abdomen, thigh, arm) |
Semaglutide requires a slower, longer titration (0.25mg up to 2.4mg), while tirzepatide starts at a higher absolute dose (2.5mg) and escalates more rapidly to 15mg. This difference explains why some patients experience more pronounced nausea with tirzepatide during the early weeks.
Weight Loss Efficacy by Dose
Dose-response curves differ between the two medications. Semaglutide shows incremental weight loss improvements at 0.5mg, 1.0mg, 1.7mg, and 2.4mg, with most efficacy gains plateauing at 2.4mg. Tirzepatide shows similar dose-dependent weight loss with maximum effects at 15mg.
Semaglutide weight loss by dose:
- 0.5mg: ~5-7% weight loss
- 1.0mg: ~8-10% weight loss
- 1.7mg: ~13-14% weight loss
- 2.4mg: ~15-17% weight loss
Tirzepatide weight loss by dose:
- 5mg: ~9-10% weight loss
- 10mg: ~16-17% weight loss
- 15mg: ~20-22% weight loss
Tirzepatide shows steeper weight loss gains at each dose increment, particularly between 10mg and 15mg. This suggests that tirzepatide\'s dual GLP-1/GIP mechanism provides additional weight loss efficacy compared to GLP-1 alone.
Side Effects and Tolerability
Both medications produce similar gastrointestinal side effects during titration. The most common adverse events include nausea, vomiting, diarrhea, and constipation. These effects are typically mild to moderate during titration and improve substantially by week 8-12.
| Side Effect | Semaglutide (2.4mg) | Tirzepatide (15mg) |
|---|---|---|
| Nausea | 25-29% | 30-35% |
| Vomiting | 5-8% | 8-12% |
| Diarrhea | 18-22% | 20-24% |
| Constipation | 15-18% | 22-26% |
| Injection site reaction | 2-3% | 2-3% |
| Discontinuation due to AE | 4.3% | 4.1% |
Tirzepatide shows slightly higher rates of nausea and constipation, but these differences are generally modest. Both medications have similar discontinuation rates due to adverse events, suggesting comparable tolerability in real-world use.
Which Medication for Different Patient Profiles
While tirzepatide demonstrates superior weight loss efficacy in clinical trials, the choice between these medications depends on individual patient factors.
Choose Tirzepatide (Zepbound/Mounjaro) if:
- Maximum weight loss is the primary goal
- Patient has type 2 diabetes (dual glycemic and weight loss benefits)
- Previous semaglutide use was inadequate for weight loss
- Patient tolerates GI side effects well or plans to manage them proactively
- Insurance covers tirzepatide with reasonable cost-sharing
Choose Semaglutide (Wegovy/Ozempic) if:
- Patient is very sensitive to GI side effects or nausea
- Patient requires a slower titration schedule
- Insurance heavily favors semaglutide or covers it more comprehensively
- Patient prefers established safety data from STEP trials (larger, longer studies)
- Previous tirzepatide trial caused intolerable side effects
Switching Between Medications
Patients can switch from semaglutide to tirzepatide or vice versa if one medication is inadequate. The most common scenario is escalation from semaglutide to tirzepatide for improved weight loss.
Switching approach: Most clinicians recommend a 1-2 week washout period before starting the new medication, though some providers transition directly. When switching, restart at the lowest dose of the new medication and titrate as usual. Do not abruptly stop one and start the other at maximum dose.
Expected outcomes: Patients switching from semaglutide to tirzepatide typically see an additional 5-8% weight loss over 12 weeks, particularly if they were on lower semaglutide doses (1.0-1.7mg). The additional weight loss reflects tirzepatide\'s superior efficacy.
Cost and Insurance Coverage
Both medications have similar retail list prices ($900-1,400 per month without insurance). Insurance coverage for weight loss indications is expanding but remains inconsistent.
Key coverage distinctions: Medicare does not cover either medication for weight loss (though it does cover them for diabetes). Commercial plans vary widely; some require prior authorization, step therapy (try semaglutide first), or BMI/comorbidity thresholds. GLP-1 generics are not yet available, though biosimilar competition is expected after 2026-2027.
For uninsured patients, patient assistance programs from Novo Nordisk (semaglutide) and Eli Lilly (tirzepatide) can reduce costs to $50-250 per month.
Frequently Asked Questions
Clinical trials show tirzepatide (Mounjaro/Zepbound) produces greater weight loss than semaglutide (Wegovy/Ozempic). At their highest maintenance doses, tirzepatide achieves approximately 20-22% weight loss versus semaglutide's 15-17% weight loss. However, both are significantly more effective than placebo and diet/exercise alone.
Semaglutide is dosed weekly (once per week injection), while tirzepatide is also dosed weekly but titrates differently. Semaglutide starts at 0.25mg and typically reaches 2.4mg maintenance. Tirzepatide starts at 2.5mg and titrates up to 15mg. Both are self-injected subcutaneously.
Both medications cause similar GI side effects (nausea, vomiting, diarrhea, constipation) during the titration phase. Tirzepatide may have slightly higher rates of nausea during titration, but side effects generally improve over time as the body adjusts. Discontinuation rates due to side effects are similar (around 4-5% in trials).
Tirzepatide is a dual GLP-1/GIP receptor agonist and may provide superior glycemic control for diabetes patients. Semaglutide is a GLP-1-only agonist and is also highly effective for diabetes. For weight loss in non-diabetic patients, tirzepatide's superior weight loss efficacy makes it the stronger choice.
Without insurance, tirzepatide (Zepbound) and semaglutide (Wegovy) cost similarly, approximately $900-1,400 per month at retail pricing. Insurance coverage varies by plan; both are increasingly covered for weight loss. Generic options are not yet available for either medication.
Most patients begin noticing weight loss within 2-4 weeks of starting, with significant loss occurring over 3-6 months. Maximum weight loss typically occurs around 12-16 weeks on maintenance dosing. Both medications show similar timelines for weight loss progression.
Summary and Recommendations
Tirzepatide is clinically superior for weight loss, achieving 5 percentage points more weight loss than semaglutide (22.5% vs 17.4%) in head-to-head trials. However, semaglutide remains a highly effective option with slightly better tolerability for GI side effects during titration.
For most patients seeking maximum weight loss, tirzepatide is the preferred first-line choice. For patients with diabetes, the glycemic benefits of tirzepatide\'s dual mechanism make it especially valuable. For patients who cannot tolerate tirzepatide or require slower titration, semaglutide offers robust efficacy with established long-term safety data.
See also: Semaglutide vs Tirzepatide detailed comparison, Tirzepatide dosage and titration schedule, and Semaglutide dosing for weight loss.