Tirzepatide vs Semaglutide: Complete Comparison
A detailed head-to-head analysis of the two most widely prescribed weight loss medications. We compare mechanism, efficacy, side effects, cost, and help you understand which may be more appropriate for different situations.
At a Glance: Side-by-Side Comparison
| Factor | Tirzepatide (Mounjaro/Zepbound) | Semaglutide (Ozempic/Wegovy) |
|---|---|---|
| Mechanism | Dual agonist (GLP-1 + GIP) | Single agonist (GLP-1 only) |
| Developer | Eli Lilly | Novo Nordisk |
| FDA Approval | 2022 (diabetes), 2023 (obesity) | 2017 (diabetes), 2021 (obesity) |
| Max Weight Loss | ~22.5% (SURMOUNT-1, 72 wks) | ~15.2% (STEP 1, 68 wks) |
| Dosing | Once weekly SC injection | Once weekly SC injection (or daily oral) |
| Dose Range | 2.5 - 15 mg weekly | 0.25 - 2.4 mg weekly |
| Escalation Period | ~20 weeks to max dose | ~16 weeks to max dose (Wegovy) |
| GI Side Effects | Nausea 12-31%, Diarrhea 12-23% | Nausea up to 44%, Diarrhea 30% |
| CV Outcome Data | SURPASS-CVOT (ongoing) | SELECT: 20% MACE reduction |
| Oral Option | Not available | Rybelsus (oral tablet) |
| List Price | ~$1,000-1,100/month | ~$1,000-1,350/month |
| Head-to-Head Winner | Won SURPASS-2 at all doses | Lost SURPASS-2 at 1 mg dose |
Mechanism: Why Dual vs Single Matters
The fundamental difference between tirzepatide and semaglutide is their receptor activity. Semaglutide activates only the GLP-1 receptor, while tirzepatide activates both GLP-1 and GIP receptors. This distinction explains most of the clinical differences between them.
What GLP-1 activation does (both drugs): Reduces appetite via brain signaling, slows gastric emptying to promote fullness, improves insulin secretion in response to food, and suppresses glucagon release.
What GIP activation adds (tirzepatide only): Enhances insulin sensitivity particularly in fat tissue, may improve fat metabolism and distribution, works synergistically with GLP-1 to amplify appetite suppression, and potentially contributes to better tolerability (lower relative nausea rates despite greater weight loss).
Think of it this way: semaglutide is like having one powerful engine driving weight loss. Tirzepatide adds a second engine (GIP) that makes the first engine work even better while contributing its own metabolic benefits.
Weight Loss Results: The Numbers
Tirzepatide produces greater average weight loss in clinical trials:
SURMOUNT-1 (tirzepatide, 72 weeks): 5 mg: -16.0%, 10 mg: -21.4%, 15 mg: -22.5%. Over 90% of participants lost at least 5% body weight.
STEP 1 (semaglutide 2.4mg, 68 weeks): -14.9% mean weight loss. 86.4% lost at least 5% body weight.
SURPASS-2 (direct comparison): This is the most informative study because it directly compared the two drugs in the same patient population (Type 2 diabetes). Tirzepatide won at every dose level. Even tirzepatide 5 mg (the lowest dose) produced more weight loss than semaglutide 1 mg.
For a 250 lb person, these averages translate to roughly: tirzepatide 15 mg: ~56 lbs lost; semaglutide 2.4 mg: ~37 lbs lost. Individual results vary significantly.
Side Effects: How They Compare
Both drugs cause primarily gastrointestinal side effects, which is inherent to how GLP-1 agonists work. However, there are noteworthy differences:
Nausea: Semaglutide causes more nausea on a per-unit-of-weight-loss basis. In STEP 1, up to 44% of participants experienced nausea vs 12-31% in SURMOUNT-1 — despite tirzepatide producing more weight loss. This suggests that GIP co-activation may have a protective effect against nausea.
Diarrhea: Both cause diarrhea at similar rates, though some analyses suggest slightly higher rates with tirzepatide at higher doses.
Discontinuation rates: Both have similar overall discontinuation rates due to side effects (approximately 4-7% in pivotal trials).
Muscle mass loss: Both drugs cause loss of lean mass alongside fat mass. The ratio appears similar (approximately 70-80% fat, 20-30% lean). Resistance training and adequate protein intake are recommended with both medications.
Cardiovascular safety: Semaglutide currently has the stronger cardiovascular evidence, with the SELECT trial showing a 20% reduction in major cardiovascular events. Tirzepatide's dedicated cardiovascular outcome trial (SURPASS-CVOT) is ongoing, with results expected in 2027.
Who Should Choose What?
Tirzepatide may be better if: Maximum weight loss is the primary goal, you have tried semaglutide with insufficient results, you experience significant nausea on GLP-1-only drugs, you have insulin resistance or metabolic syndrome (GIP may provide additional metabolic benefits), or you prefer a newer mechanism with potentially better efficacy.
Semaglutide may be better if: You want a medication with longer track record and more safety data, cardiovascular risk reduction is a priority (proven SELECT trial data), you prefer the option of oral administration (Rybelsus), your insurance covers one but not the other, or you want a drug with the most extensive real-world evidence.
Either drug is appropriate if: You have a BMI of 30+ (or 27+ with weight-related conditions), you are looking for significant, sustained weight loss, you are willing to commit to weekly injections, and you understand these are long-term medications (weight tends to return after stopping).
What Comes Next: Retatrutide
While tirzepatide and semaglutide dominate the current landscape, the next generation is already in development. Retatrutide, also from Eli Lilly, adds a third receptor (glucagon) to tirzepatide's dual mechanism, creating a triple agonist that has shown up to 24.2% weight loss in Phase 2 trials — potentially surpassing even tirzepatide. It is currently in Phase 3 trials with results expected in 2026-2027.
Frequently Asked Questions
Clinical trial data suggests tirzepatide produces greater average weight loss (22.5% vs 15.2%). The SURPASS-2 trial directly compared them and found tirzepatide superior at all doses. However, individual responses vary, and semaglutide is effective for many patients. Both are significant improvements over older weight loss medications.
Both have similar safety profiles with primarily gastrointestinal side effects (nausea, diarrhea, vomiting). Semaglutide has more long-term safety data given its earlier approval. The SELECT trial proved semaglutide's cardiovascular safety and benefit. Tirzepatide's long-term cardiovascular data is still being collected (SURPASS-CVOT trial).
Yes, switching between GLP-1 agonists is common and can be done under medical supervision. Typically, you would transition to the starting dose of the new medication. Your doctor will advise on the appropriate timing and dosing protocol for the switch.
Tirzepatide activates two receptors (GLP-1 and GIP) while semaglutide only activates one (GLP-1). The additional GIP receptor activation enhances insulin sensitivity, may improve fat metabolism, and amplifies the appetite-suppressing effects of GLP-1 activation, leading to greater overall weight loss.
Side effect profiles are similar, but the pattern differs slightly. Semaglutide tends to cause more nausea at equivalent weight loss levels. Tirzepatide may cause slightly more diarrhea. Both see side effects improve significantly after the dose escalation period. Individual tolerance varies.
Both have similar list prices (~$1,000-1,300/month without insurance). Insurance coverage varies significantly by plan and indication. Compounded versions have been available at lower cost during drug shortage periods, but regulatory status of compounding changes frequently. Check with your insurance provider for specific coverage details.
Disclaimer: This comparison is for informational purposes only. Both tirzepatide and semaglutide are prescription medications that should only be used under medical supervision. Individual results vary significantly. Consult your healthcare provider to determine which medication, if any, is appropriate for your specific situation.