The Bottom Line
Semaglutide (commonly called “sema”), tirzepatide (“tirz”), and retatrutide (“reta”) represent three generations of GLP-1 weight loss medications - single, dual, and triple receptor agonists respectively. Semaglutide (Ozempic/Wegovy) targets GLP-1 only and produces ~15% weight loss. Tirzepatide (Mounjaro/Zepbound) targets GLP-1 + GIP and produces ~20.9% mean weight loss (up to 22.5% in trial completers). Retatrutide targets GLP-1 + GIP + glucagon and produces ~28.3% weight loss at 80 weeks - the highest of any obesity medication ever studied. Semaglutide and tirzepatide are FDA-approved. Retatrutide is in Phase 3 trials with expected approval in 2027. This guide compares all three across every dimension that matters: weight loss, mechanism, side effects, cost, availability, and who each one is best for. Calculate doses for all three compounds with our free GLP-1 dose calculator.
Regimen is a GLP-1 tracker app that logs your GLP-1 and shows your estimated level between shots.
This guide is for informational purposes only. Retatrutide is an investigational compound not yet FDA-approved. Semaglutide and tirzepatide require prescriptions. Work with a licensed healthcare provider for any medication decisions.
In this guide:
- The Quick Answer: Which One Loses the Most Weight?
- Master Comparison Table
- How Each One Works (Mechanism of Action)
- Weight Loss Results: The Data
- Side Effects Compared
- Cost and Availability
- The Upgrade Path: Sema to Tirz to Reta
- Which One Is Right for You?
- Tracking Any GLP-1 Protocol
- Frequently Asked Questions
On Ozempic? Regimen’s Ozempic app logs the shot in one tap, reminds you before the next one, and ties your side effects and weight to each dose step.
Wondering what is normal? Ozempic side effects by dose has every rate from Novo’s label, including the three warnings most articles skip.
The Quick Answer: Which One Loses the Most Weight?
Retatrutide. In Phase 3 trials, participants on 12mg retatrutide lost an average of 28.3% of their body weight (71.2 lbs / 32.3 kg) over 80 weeks (TRIUMPH-1). Tirzepatide at 15mg produced ~20.9% mean weight loss (up to 22.5% in trial completers) over 72 weeks in SURMOUNT-1. Semaglutide at 2.4mg produced approximately 15% weight loss over 68 weeks.
But weight loss isn’t the only factor. Semaglutide has the most real-world safety data and is the most accessible. Tirzepatide has the best balance of efficacy and availability. Retatrutide has the highest efficacy but isn’t FDA-approved. Each has a different risk-benefit profile depending on your situation.
Master Comparison Table
| Factor | Semaglutide (Ozempic/Wegovy) | Tirzepatide (Mounjaro/Zepbound) | Retatrutide (LY3437943) |
|---|---|---|---|
| Developer | Novo Nordisk | Eli Lilly | Eli Lilly |
| Receptor targets | GLP-1 only | GLP-1 + GIP (dual) | GLP-1 + GIP + Glucagon (triple) |
| Generation | 1st gen GLP-1 RA | 2nd gen (dual agonist) | 3rd gen (triple agonist) |
| Max studied dose | 2.4 mg/week | 15 mg/week | 12 mg/week |
| Average weight loss | ~15% body weight | ~20.9% mean (up to 22.5% in trial completers) | ~28.3% body weight |
| Average lbs lost | ~34 lbs | ~48 lbs (up to ~52 in completers) | ~71 lbs |
| Key trial | STEP 1 | SURMOUNT-1 | TRIUMPH-1 |
| FDA status | Approved (2021) | Approved (2022) | Phase 3 (expected 2027) |
| Brand names | Ozempic, Wegovy, Rybelsus | Mounjaro, Zepbound | None yet |
| Half-life | ~7 days | ~5 days | ~6 days |
| Injection frequency | Once weekly | Once weekly | Once weekly |
| Compounded cost | $100-250/month | $150-350/month | $200-450/month |
| Insurance coverage | Possible | Possible | No |
| Unique advantage | Most safety data, longest track record | Best efficacy/tolerability balance | Highest weight loss, energy expenditure |
How Each One Works (Mechanism of Action)
| Receptor | What It Does | Sema | Tirz | Reta |
|---|---|---|---|---|
| GLP-1 | Reduces appetite, slows stomach emptying, improves insulin | Yes | Yes | Yes |
| GIP | Enhances fat metabolism, synergizes with GLP-1 | No | Yes | Yes |
| Glucagon | Increases energy expenditure, burns liver fat, raises metabolic rate | No | No | Yes |
Think of it as a volume dial:
- Semaglutide turns down your hunger (1 lever)
- Tirzepatide turns down hunger AND improves fat processing (2 levers)
- Retatrutide turns down hunger, improves fat processing, AND turns up your body’s calorie burn (3 levers)
Each additional receptor doesn’t just add to the effect - it compounds it. The glucagon receptor in retatrutide is particularly significant because it’s the first weight loss compound that actively increases energy expenditure rather than just reducing energy intake.
Pro Tip
The glucagon receptor is why reta users report feeling “warmer” - their metabolism is literally running hotter. This also explains why retatrutide may preserve lean muscle mass better than the other two during weight loss: when the body is burning more fat for energy through glucagon activation, it’s less likely to break down muscle tissue.
Weight Loss Results: The Data
Semaglutide (STEP 1 Trial)
- Dose: 2.4mg/week
- Duration: 68 weeks
- Average weight loss: 14.9% body weight
- Patients reaching 10%+ loss: ~70%
- Patients reaching 20%+ loss: ~32%
Tirzepatide (SURMOUNT-1 Trial)
- Dose: 15mg/week
- Duration: 72 weeks
- Average weight loss: ~20.9% body weight (treatment-regimen estimand); up to 22.5% in trial completers (efficacy estimand)
- Patients reaching 10%+ loss: ~91%
- Patients reaching 20%+ loss: ~55%
Retatrutide (TRIUMPH-1 Trial)
- Dose: 12mg/week
- Duration: 80 weeks
- Average weight loss: 28.3% body weight (71.2 lbs / 32.3 kg)
- Patients reaching 15%+ loss: ~80%
- Patients reaching 20%+ loss: ~70%
Additional retatrutide findings from TRIUMPH-1:
- Also produced significant improvements in knee osteoarthritis pain
- Reduced cardiovascular risk markers (non-HDL cholesterol, systolic blood pressure)
- 9mg group achieved 25.9% weight loss - nearly as effective as 12mg with fewer side effects
Community Insight
In community discussions, the practical comparison often comes down to: “sema got me 30 lbs, tirz got me another 20, and reta is where people go when they’ve plateaued on tirz.” The triple agonist seems to break through plateaus that the dual agonist can’t, likely because the glucagon component introduces a completely new metabolic pathway. This upgrade path (sema to tirz to reta) is becoming the standard progression in the peptide community.
Side Effects Compared
| Side Effect | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Nausea | Common | Common | Common (more intense at 8mg+) |
| Decreased appetite | Very common | Very common | Very common (strongest of the three) |
| Diarrhea | Common | Common | Common |
| Constipation | Common | Common | Common |
| Injection site reactions | Occasional | Occasional | More frequent |
| Vomiting | Occasional | Occasional | Occasional (more common at higher doses) |
| Heart rate increase | Rare | Rare | Common (5-12 bpm, unique to reta) |
| Fatigue | Occasional | Occasional | Occasional |
| Body heat / thermogenesis | Not reported | Not reported | Common at 6mg+ (unique to reta) |
Key differences:
- Semaglutide has the mildest side effect profile overall but also the least weight loss
- Tirzepatide has a similar side effect profile to semaglutide with modestly higher efficacy
- Retatrutide has the most intense side effects - particularly the glucagon-driven nausea at higher doses and the heart rate elevation - but also the most weight loss
For detailed side effect management at each retatrutide dose tier, see our Retatrutide Side Effects Guide.
Cost and Availability
| Factor | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Brand-name retail | $900-1,350/month | $550-1,100/month | Not available |
| With insurance | $0-300/month (varies) | $0-300/month (varies) | Not covered |
| Compounded | $100-250/month | $150-350/month | $200-450/month |
| Availability | Widely available, some shortages | Widely available | Research/compounding only |
| Prescription required | Yes (FDA-approved) | Yes (FDA-approved) | N/A (not approved) |
The practical reality for most people:
- If you have insurance that covers GLP-1s, tirzepatide (Zepbound) is the best value - better results than semaglutide at similar out-of-pocket cost
- If you’re paying out of pocket through compounding, tirzepatide offers the best bang for your buck
- Retatrutide is the most expensive option AND carries the risk of using an unapproved compound - it makes sense primarily for people who’ve genuinely plateaued on tirzepatide
Warning
Retatrutide is not FDA-approved and is only available through research sources or compounding pharmacies. The quality, purity, and dosing accuracy of compounded retatrutide varies by source. If you choose to use compounded retatrutide, obtain it only from a licensed 503A or 503B compounding pharmacy and work with a healthcare provider who can monitor your progress.
The Upgrade Path: Sema to Tirz to Reta
A growing number of people follow a progression through all three compounds. Here’s how it typically works:
Stage 1: Semaglutide (months 1-6+)
- Start here if you’re new to GLP-1 medications
- Most accessible, most safety data, insurance-friendly
- Expect 10-15% body weight loss
- Move to Stage 2 if: weight loss stalls after 3+ months at max dose, or you want faster results
Stage 2: Tirzepatide (months 6-12+)
- Upgrade when semaglutide plateau hits
- Dual mechanism often restarts weight loss
- Expect additional 7-10% body weight loss
- Move to Stage 3 if: plateau on max tirz dose after 2+ months AND you’ve optimized diet/exercise
Stage 3: Retatrutide (when available or via compounding)
- The “final level” for maximum weight loss
- Triple mechanism breaks through dual-agonist plateaus
- Expect additional 5-10% body weight loss beyond tirzepatide
- Not everyone needs this stage - many people reach their goal weight on tirzepatide
Make sure you’ve optimized diet, training, and sleep before stepping up to retatrutide, and confirm you’re working with a provider who can monitor the transition.
Community Insight
Not everyone follows this path linearly. Some people start directly on tirzepatide (especially with insurance coverage for Zepbound). Others jump from sema to reta, skipping tirz entirely. The “right” path depends on your starting point, insurance situation, risk tolerance, and weight loss goals. There’s no wrong order - there’s only what works for your situation.
Which One Is Right for You?
Start with semaglutide if:
- You’re new to GLP-1 medications and want the safest entry point
- Your insurance covers Ozempic or Wegovy
- You have 30-50 lbs to lose
- You prefer the compound with the most published long-term safety data
Choose tirzepatide if:
- You’ve plateaued on semaglutide or want stronger initial results
- Your insurance covers Mounjaro or Zepbound
- You have 50-80+ lbs to lose
- You want the best balance of efficacy, safety, and accessibility
Consider retatrutide if:
- You’ve genuinely plateaued on tirzepatide at max dose
- You have a BMI of 40+ and need maximum weight loss
- You’re comfortable with an investigational compound
- You train regularly and prioritize muscle preservation during fat loss
- You’re working with a provider who can monitor your labs and progress
Tracking Any GLP-1 Protocol
Whether you’re on your first week of semaglutide or switching from tirzepatide to retatrutide, tracking makes every protocol more effective. The Regimen app supports all three compounds with dose logging, PK curve modeling, weight trends, side effect logging, and progress photos.
Semaglutide Tracker · Tirzepatide Tracker · Retatrutide Tracker · GLP-1 Dose Calculator · Tirzepatide Reconstitution Calculator
Frequently Asked Questions
Which GLP-1 medication causes the most weight loss?
Retatrutide produces the most weight loss in clinical trials - about 28.3% average body weight at 12mg over 80 weeks (Phase 3 TRIUMPH-1). Tirzepatide is second at ~20.9% mean, up to 22.5% in trial completers (SURMOUNT-1). Semaglutide is third at approximately 15% (STEP 1). However, retatrutide is not yet FDA-approved, so tirzepatide is currently the most effective approved option.
Can I switch from semaglutide to tirzepatide?
Yes, this is a common transition. Most providers recommend finishing your current semaglutide dose, waiting one week (a gap week), then starting tirzepatide at 2.5mg and titrating up. The GLP-1 receptor effects will feel familiar, and many people tolerate the switch well.
Can I switch from tirzepatide to retatrutide?
Yes, but start retatrutide at 2mg regardless of your tirzepatide dose. The glucagon receptor is new to your body and requires its own tolerance-building period. Allow a 1-week gap between your last tirzepatide dose and first retatrutide dose.
Is retatrutide safe?
Retatrutide has shown acceptable safety in Phase 2 and Phase 3 clinical trials, with side effects similar to (but somewhat more intense than) tirzepatide. However, it does not have FDA approval and lacks the years of real-world safety data that semaglutide and tirzepatide have.
When will retatrutide be FDA approved?
The TRIUMPH Phase 3 trial program is expected to complete throughout 2026. If results are positive, Eli Lilly would submit for FDA approval in late 2026 or early 2027, with potential approval in 2027.
What is the best GLP-1 for someone just starting?
For most people starting their first GLP-1 medication, semaglutide or tirzepatide are the recommended options since both are FDA-approved with established safety profiles. Tirzepatide generally produces more weight loss than semaglutide (~20.9% vs ~15%), but semaglutide has a longer track record.
Do I need all three, or can I just start with retatrutide?
You don’t need to progress through all three compounds. Some people start on tirzepatide and never need anything else. Others reach their goal on semaglutide alone. The upgrade path exists for people who plateau and need a stronger mechanism, but it’s not a required sequence.
