Key Takeaways
- Tirzepatide wins on weight loss: ~21% vs ~15% average in obesity trials
- Both excellent for diabetes: Similar HbA1c reductions (~2%)
- Different mechanisms: Tirzepatide targets two receptors (GLP-1 + GIP); semaglutide targets one (GLP-1)
- Similar side effects: GI symptoms comparable, tirzepatide may be slightly better tolerated
- Semaglutide has more CV data: SELECT trial completed; tirzepatide CV trial ongoing
- Availability/cost similar: Both face shortages and high prices
The Quick Comparison
| Feature | Semaglutide | Tirzepatide |
|---|---|---|
| Brand names | Ozempic, Wegovy, Rybelsus | Mounjaro, Zepbound |
| Manufacturer | Novo Nordisk | Eli Lilly |
| Mechanism | GLP-1 agonist | GLP-1 + GIP dual agonist |
| Max weight loss (trials) | 15-17% | 21-22% |
| HbA1c reduction | ~2.0% | ~2.0% |
| Dosing frequency | Weekly (or daily oral) | Weekly |
| Max dose (obesity) | 2.4 mg | 15 mg |
| Oral option | Yes (Rybelsus) | No (in development) |
| CV outcomes trial | SELECT: 20% reduction ✓ | SURPASS-CVOT: ongoing |
| FDA obesity approval | 2021 (Wegovy) | 2023 (Zepbound) |
Weight Loss: The Numbers
15-17%
Semaglutide 2.4mg (STEP trials)
21-22%
Tirzepatide 15mg (SURMOUNT trials)
~5%
Additional weight loss with tirzepatide
STEP Trials (Semaglutide)
| Trial | Population | Duration | Weight Loss |
|---|---|---|---|
| STEP 1 | Obesity, no diabetes | 68 weeks | -14.9% |
| STEP 2 | Obesity + type 2 diabetes | 68 weeks | -9.6% |
| STEP 3 | Obesity + intensive lifestyle | 68 weeks | -16.0% |
| STEP 4 | Maintenance after run-in | 68 weeks | -17.4% (continued) |
| STEP 5 | Obesity, 2-year duration | 104 weeks | -15.2% |
SURMOUNT Trials (Tirzepatide)
| Trial | Population | Duration | Weight Loss (15mg) |
|---|---|---|---|
| SURMOUNT-1 | Obesity, no diabetes | 72 weeks | -20.9% |
| SURMOUNT-2 | Obesity + type 2 diabetes | 72 weeks | -14.7% |
| SURMOUNT-3 | After intensive lifestyle | 72 weeks | -18.4% |
| SURMOUNT-4 | Maintenance | 88 weeks | -21.4% (continued) |
Direct Comparison
SURPASS-2: Head-to-Head in Diabetes
The only head-to-head trial compared tirzepatide vs. semaglutide 1mg (diabetes dose, not the 2.4mg obesity dose) in type 2 diabetes:
HbA1c reduction: Tirzepatide 15mg: -2.30% vs. Semaglutide 1mg: -1.86%
Weight loss: Tirzepatide 15mg: -11.2 kg vs. Semaglutide 1mg: -5.7 kg
Note: This compared max tirzepatide dose to mid-range semaglutide dose. A trial comparing 2.4mg semaglutide to 15mg tirzepatide has not been conducted.
HbA1c reduction: Tirzepatide 15mg: -2.30% vs. Semaglutide 1mg: -1.86%
Weight loss: Tirzepatide 15mg: -11.2 kg vs. Semaglutide 1mg: -5.7 kg
Note: This compared max tirzepatide dose to mid-range semaglutide dose. A trial comparing 2.4mg semaglutide to 15mg tirzepatide has not been conducted.
The Mechanism: Why Tirzepatide May Work Better
Semaglutide: Single Target
Semaglutide activates only the GLP-1 receptor:
- Reduces appetite via brain signaling
- Slows gastric emptying
- Increases insulin secretion (glucose-dependent)
- Reduces glucagon secretion
Tirzepatide: Dual Target
Tirzepatide activates both GLP-1 and GIP receptors:
- GLP-1 effects: Same as semaglutide
- GIP effects: Enhances insulin secretion, may improve fat tissue metabolism, amplifies GLP-1 effects
- Synergy: The combination appears to produce greater weight loss than either alone
The GIP Paradox
GIP (glucose-dependent insulinotropic polypeptide) was long thought to promote fat storage. So why does adding a GIP agonist increase weight loss?
- GIP receptors exist in the brain—may have central appetite effects
- GIP may improve insulin sensitivity in fat tissue
- The combination may enhance satiety more than GLP-1 alone
- GIP may reduce some GLP-1 side effects (less nausea)
Side Effects Comparison
| Side Effect | Semaglutide 2.4mg | Tirzepatide 15mg |
|---|---|---|
| Nausea | 44% | 31% |
| Diarrhea | 30% | 23% |
| Vomiting | 24% | 12% |
| Constipation | 24% | 12% |
| Abdominal pain | 20% | 14% |
| Discontinuation (GI) | 4.5% | 4.3% |
Key observation: Tirzepatide appears to cause less GI side effects despite producing more weight loss. The GIP component may buffer some GLP-1 effects on gastric emptying.
Cardiovascular Outcomes
Completed Trial
SELECT Trial (Semaglutide)
Population: 17,604 adults with obesity and established cardiovascular disease (no diabetes)
Result: 20% reduction in major adverse cardiovascular events (heart attack, stroke, CV death)
Significance: First evidence that weight loss from GLP-1s translates to hard CV outcomes in people without diabetes
Result: 20% reduction in major adverse cardiovascular events (heart attack, stroke, CV death)
Significance: First evidence that weight loss from GLP-1s translates to hard CV outcomes in people without diabetes
Tirzepatide CV data: The SURPASS-CVOT trial is ongoing and expected to report around 2025-2026. Until then, tirzepatide does not have proven cardiovascular benefit for labeling purposes.
Diabetes Control
Both are excellent for type 2 diabetes:
| Metric | Semaglutide | Tirzepatide |
|---|---|---|
| HbA1c reduction | ~1.5-2.0% | ~2.0-2.3% |
| Patients reaching <7% | ~70-80% | ~80-90% |
| Patients reaching <5.7% | ~30-40% | ~50-60% |
| Fasting glucose reduction | ~25-30 mg/dL | ~35-40 mg/dL |
Tirzepatide appears slightly more effective for glycemic control, particularly in achieving "normal" HbA1c levels below 5.7%.
Other Conditions
| Condition | Semaglutide | Tirzepatide |
|---|---|---|
| Sleep apnea | STEP-OSA: Significant improvement | SURMOUNT-OSA: Greater improvement |
| Heart failure (HFpEF) | STEP-HFpEF: Improved symptoms | SUMMIT: Improved symptoms + outcomes |
| MASH/fatty liver | Significant improvement | Significant improvement (may be greater) |
| Kidney protection | FLOW trial: Proven benefit | Not yet studied |
Dosing and Titration
| Aspect | Semaglutide (Wegovy) | Tirzepatide (Zepbound) |
|---|---|---|
| Starting dose | 0.25 mg weekly | 2.5 mg weekly |
| Titration steps | 0.25 → 0.5 → 1 → 1.7 → 2.4 mg | 2.5 → 5 → 7.5 → 10 → 12.5 → 15 mg |
| Time to max dose | ~16-20 weeks | ~20-24 weeks |
| Injection volume | 0.25-1.0 mL | 0.5 mL (all doses) |
Practical Considerations
Availability
- Both face intermittent shortages
- Semaglutide: Longer track record, more prescribers familiar
- Tirzepatide: Newer, growing availability
Cost
- Both: ~$1,000-1,300/month list price without insurance
- Both: Manufacturer savings programs available
- Both: Insurance coverage varies widely
Oral Option
- Semaglutide: Rybelsus (oral) available for diabetes; higher oral doses in development for obesity
- Tirzepatide: Oral formulation in Phase 3 trials
Who Might Choose Which?
Semaglutide May Be Preferred If:
- You have established cardiovascular disease (proven CV benefit)
- You have diabetic kidney disease (FLOW trial data)
- You want an oral option (Rybelsus)
- Your insurance covers it but not tirzepatide
- You're needle-phobic but can take daily pills
Tirzepatide May Be Preferred If:
- Maximum weight loss is the priority
- You've plateaued on semaglutide
- You had significant GI side effects on semaglutide
- You have HFpEF (SUMMIT trial data)
- You have severe sleep apnea
- Your insurance covers it
Switching Between Them
If considering a switch:
- Semaglutide → Tirzepatide: Common for plateaus or GI intolerance; typically start tirzepatide at 2.5mg, may titrate faster than naive patients
- Tirzepatide → Semaglutide: Less common; may occur for insurance/availability reasons
- No washout needed: Can switch directly due to long half-lives
- Discuss with prescriber: Individual circumstances matter
The Bottom Line
Tirzepatide produces approximately 5 percentage points more weight loss than semaglutide in clinical trials (21% vs. 15-17%), likely due to its dual GLP-1/GIP mechanism. It also appears to cause somewhat fewer GI side effects. However, semaglutide has proven cardiovascular benefits from the SELECT trial and kidney protection from FLOW—data tirzepatide doesn't yet have. Both are excellent medications that produce unprecedented weight loss for pharmaceuticals. The "better" choice depends on individual factors: CV disease history, insurance coverage, tolerance of GI symptoms, and weight loss goals. Many patients who don't respond adequately to one may benefit from switching to the other. The good news is we now have two highly effective options where we previously had none.
Sources
- Wilding JPH, et al. STEP 1: Semaglutide in Obesity. N Engl J Med. 2021.
- Davies M, et al. STEP 2: Semaglutide in Obesity with Diabetes. Lancet. 2021.
- Wadden TA, et al. STEP 3: Semaglutide + Intensive Behavioral Therapy. JAMA. 2021.
- Rubino D, et al. STEP 4: Continued Semaglutide Treatment. JAMA. 2021.
- Garvey WT, et al. STEP 5: Two-Year Semaglutide Treatment. Nat Med. 2022.
- Jastreboff AM, et al. SURMOUNT-1: Tirzepatide in Obesity. N Engl J Med. 2022.
- Garvey WT, et al. SURMOUNT-2: Tirzepatide in Obesity with Diabetes. Lancet. 2023.
- Wadden TA, et al. SURMOUNT-3: Tirzepatide After Lifestyle Intervention. Nat Med. 2023.
- Aronne LJ, et al. SURMOUNT-4: Tirzepatide Maintenance. JAMA. 2024.
- Frías JP, et al. SURPASS-2: Tirzepatide vs Semaglutide in Diabetes. N Engl J Med. 2021.
- Lincoff AM, et al. SELECT Trial: Semaglutide CV Outcomes. N Engl J Med. 2023.
- Perkovic V, et al. FLOW Trial: Semaglutide in CKD. N Engl J Med. 2024.
- Kosiborod MN, et al. SUMMIT: Tirzepatide in HFpEF. N Engl J Med. 2024.
- FDA. Wegovy Prescribing Information. 2021, updated 2024.
- FDA. Zepbound Prescribing Information. 2023.
- FDA. Ozempic Prescribing Information. 2017, updated 2024.
- FDA. Mounjaro Prescribing Information. 2022, updated 2024.
- Coskun T, et al. Tirzepatide Mechanism. Mol Metab. 2022.