GLP1 Sema vs GLP2 Tirz vs GLP3 Reta: A Comparison Guide

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The Short Version

Three injectable peptides. Three different mechanisms. Three different levels of evidence. If you’re trying to figure out which one fits your research goals, this guide breaks down what actually matters: how they work, what the clinical data shows, how to dose them, and who each one is best suited for.

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1. What Each One Targets (And Why It Matters)

The names GLP-1, GIP, and glucagon refer to hormones your body already makes. These peptides work by mimicking or amplifying those signals. The more receptors a compound hits, the more metabolic levers it pulls.

GLP1 Sema (Semaglutide): Single Agonist

• Targets GLP-1 receptors only
• GLP-1 is the hormone released after eating. It signals your brain that you’re full, slows how fast food leaves your stomach, and reduces appetite
• In practice: subjects eat less because hunger signals are quieted and satiety kicks in faster
• The oldest and most studied of the three

GLP2 Tirz (Tirzepatide): Dual Agonist

• Targets GLP-1 and GIP receptors simultaneously
• GIP (glucose-dependent insulinotropic polypeptide) works alongside GLP-1 to regulate insulin, and research suggests it enhances the appetite-suppressing effects when paired with GLP-1 activation
• In practice: stronger appetite reduction and improved metabolic effects compared to GLP-1 alone
• Notably, the two receptors appear to work synergistically, not just additively

GLP3 Reta (Retatrutide): Triple Agonist

• Targets GLP-1, GIP, and glucagon receptors
• The glucagon component adds a third layer: it increases energy expenditure (the body burns more calories at rest) and mobilizes stored fat more aggressively
• In practice: combines appetite suppression from GLP-1/GIP with a metabolic acceleration effect from glucagon activation
• This is why the weight loss numbers are higher, the body is being pushed to both eat less and burn more

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2. Weight Loss Effectiveness: What the Trials Show

GLP1 Sema: STEP Trials

• Trial name: STEP 1 (2021, published in NEJM)
• Dose: 2.4 mg once weekly
• Duration: 68 weeks
• Average weight loss: 14.9% of body weight
• 86% of participants lost at least 5% of body weight
• 69% lost at least 10%
• This is the benchmark. Significant, well-replicated, with the longest follow-up data of the three

GLP2 Tirz: SURMOUNT Trials

• Trial name: SURMOUNT-1 (2022, published in NEJM)
• Duration: 72 weeks
• Dose-dependent results:
  • 5 mg/week: average -16.0%
  • 10 mg/week: average -21.4%
  • 15 mg/week: average -22.5%
• Over a third of participants on the 15mg dose lost 25% or more of their body weight
• Consistently outperformed semaglutide across all dose levels in head-to-head and comparative analyses

GLP3 Reta: Phase 2 NEJM Trial

• Trial name: Phase 2 Retatrutide trial (2023, published in NEJM, ClinicalTrials.gov NCT04881760)
• Duration: 48 weeks (shorter than the STEP or SURMOUNT trials)
• Dose-dependent results:
  • 1 mg/week: average -8.7%
  • 4 mg/week: average -17.1%
  • 8 mg/week: average -22.8%
  • 12 mg/week: average -24.2% (approximately 57.8 lbs lost on average)
• At 24 weeks, the 12mg group had already achieved -17.5% average weight loss
• 100% of participants on 8mg or 12mg lost at least 5% body weight

Important caveat on reta: These results are from a single Phase 2 trial with 48 weeks of data. The STEP and SURMOUNT trials ran longer and involved thousands of subjects across multiple trials. Reta’s numbers are the most impressive on paper, but the evidence base is significantly thinner. Phase 3 trials are ongoing as of 2025.

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3. Dosing Protocols

GLP1 Sema: Titration Schedule

Standard titration ramps up every 4 weeks to allow the body to adjust and minimize GI side effects.

• Weeks 1-4: 0.25 mg/week
• Weeks 5-8: 0.5 mg/week
• Weeks 9-12: 1.0 mg/week
• Weeks 13-16: 1.7 mg/week
• Week 17+: 2.4 mg/week (maintenance)

Total ramp-up time: approximately 16 weeks to reach full dose. Some research protocols hold at 1.7 mg if tolerance is a concern. Maintenance is typically 2.4 mg/week indefinitely.

GLP2 Tirz: Titration Schedule

Similar 4-week step approach, but starting dose is higher and the dose range is wider.

• Weeks 1-4: 2.5 mg/week
• Weeks 5-8: 5 mg/week
• Weeks 9-12: 7.5 mg/week
• Weeks 13-16: 10 mg/week
• Weeks 17-20: 12.5 mg/week
• Week 21+: 15 mg/week (maximum dose)

Many research subjects find effective maintenance between 10 and 15 mg/week. Clinical trial data shows meaningful weight loss at all three dose levels, so not everyone needs to push to maximum.

GLP3 Reta: Titration Schedule

Retatrutide is still investigational and does not have an FDA-approved dosing schedule. Based on the Phase 2 trial protocol, the general framework used in research was:

• Starting dose: 1 mg/week for the initial period
• Step-ups: Gradual escalation through 2 mg, 4 mg, and 8 mg
• Maximum dose studied: 12 mg/week

Because the glucagon component adds additional metabolic activity (and additional GI sensitivity), conservative titration is especially important with reta. Clinical trial protocols used slow, multi-week steps before advancing to the next tier. Research suggests rushing the ramp-up significantly increases side effect burden.

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4. Side Effects: What to Expect

All three share the same core GI side effect profile. This is a direct consequence of slowing gastric emptying and altering GI hormone signaling.

Common to all three:

• Nausea (most common, especially during dose escalation)
• Vomiting
• Diarrhea or constipation
• Reduced appetite (this is partly the point, but can be uncomfortable)
• Fatigue during the first few weeks at each new dose level

GI side effects typically peak during dose escalation and settle down once the body adapts. Going too fast through the titration schedule is the most common reason for dropping out or reducing doses.

Notable differences:

• GLP1 Sema: Generally the mildest GI profile of the three. The simplest mechanism means fewer variables. Side effects are well-characterized from years of real-world data
• GLP2 Tirz: GI side effects are comparable to sema in most research subjects, though some users report slightly more noticeable nausea during escalation. Overall tolerability is still considered good
• GLP3 Reta: The glucagon component adds complexity. Glucagon activation can increase heart rate, and some subjects in the Phase 2 trial reported elevated pulse (average heart rate increased about 4-5 bpm). Nausea and GI symptoms were more pronounced at higher doses. The triple mechanism makes side effect prediction less straightforward compared to the other two

Across all three: Staying well hydrated, eating smaller meals, and not rushing titration are the primary tools for managing GI effects.

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5. Timeline: When to Expect Results

GLP1 Sema

• Weeks 1-4: Appetite suppression starts. Most subjects notice reduced hunger within the first 1-2 weeks, though the effect intensifies with each dose increase
• Weeks 4-12: First measurable weight loss. Most people are down 5-8% by week 12
• Weeks 16-32: Consistent, steady loss. This is where the bulk of the weight reduction happens
• Weeks 48-68: Weight loss slows and begins to plateau. The 14.9% average in STEP 1 was measured at 68 weeks

GLP2 Tirz

• Weeks 1-4: Similar early appetite suppression, often described as more pronounced than sema even at the lower starting dose
• Weeks 8-16: Stronger early weight loss trajectory than sema at equivalent timepoints
• Weeks 16-40: The dose escalation window where most of the loss occurs
• Weeks 40-72: Continued loss with a later, higher plateau than sema. The 22.5% average at 15mg was measured at 72 weeks

GLP3 Reta

• Weeks 1-8: Appetite suppression tends to be aggressive early, though GI side effects during ramp-up can be more disruptive
• Weeks 12-24: Rapid weight loss phase. The 12mg group averaged -17.5% by week 24, which is faster than either sema or tirz at the same timepoint
• Weeks 24-48: Weight loss continues with no clear plateau visible in the 48-week trial data, which is notable. Most agonists show slowing by this point
• Peak timing: The Phase 2 data did not capture a plateau, suggesting weight loss may continue beyond 48 weeks at higher doses. Phase 3 trials will clarify this

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6. Maturity and Data Confidence

This matters. More data means more confidence in both the efficacy numbers and the long-term safety profile.

GLP1 Sema

• FDA approved for weight management (Wegovy, 2021) and type 2 diabetes (Ozempic, 2017)
• Years of data: 8+ years in clinical use across millions of subjects
• Multiple STEP trials (STEP 1 through 5), plus real-world data from Ozempic use since 2017
• Cardiovascular benefit data from the SELECT trial (published 2023): 20% reduction in major cardiovascular events
• Confidence level: highest of the three

GLP2 Tirz

• FDA approved for weight management (Zepbound, 2023) and type 2 diabetes (Mounjaro, 2022)
• Years of data: 3-4 years in clinical use, plus multiple SURMOUNT trials
• SURMOUNT-1 through SURMOUNT-4 trials cover different populations and scenarios
• Cardiovascular outcome trial data (SURMOUNT-MMO) ongoing
• Confidence level: strong, growing rapidly

GLP3 Reta

• Not FDA approved. Still in Phase 3 clinical trials as of 2025
• Years of data: Phase 2 trial only (48-week duration, published August 2023)
• Phase 3 trials are the next step before any approval consideration
• Long-term safety data does not yet exist
• Confidence level: promising but preliminary

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7. Who Should Consider Which

This is a practical framework, not medical advice.

Consider GLP1 Sema first if:

• You’re new to this class of peptides
• You want the most established safety and efficacy record
• Tolerability and predictability are your top priorities
• You want the most real-world usage data available
• Modest, consistent weight loss in the 10-15% range is the goal

Consider GLP2 Tirz if:

• You’ve looked at the sema data and want meaningfully stronger results
• You’re comfortable with a newer but still FDA-approved compound
• Your target is in the 20%+ range and you’re willing to reach max dose
• You want a well-studied dual mechanism with multiple major trials behind it

Consider GLP3 Reta if:

• You’ve researched the current trial landscape and understand the limitations of Phase 2 data
• You’re specifically interested in the frontier of this compound class
• The 24%+ average at 12mg in the Phase 2 trial is compelling to you and you understand that Phase 3 results could look different
• You accept that long-term safety data simply doesn’t exist yet
• You’re focused on the research aspect and want to track the most novel mechanism in this space

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8. Side-by-Side Comparison

GLP1 Sema (Semaglutide)

• Receptors targeted: GLP-1 only
• Key trial: STEP 1 (NEJM, 2021)
• Average weight loss: 14.9% at 68 weeks (2.4mg/week)
• Starting dose: 0.25 mg/week
• Typical maintenance dose: 2.4 mg/week
• FDA status: Approved (Wegovy for obesity, Ozempic for T2D)
• Years of data: 8+ years

GLP2 Tirz (Tirzepatide)

• Receptors targeted: GLP-1 + GIP (dual agonist)
• Key trial: SURMOUNT-1 (NEJM, 2022)
• Average weight loss: 16.0% (5mg), 21.4% (10mg), 22.5% (15mg) at 72 weeks
• Starting dose: 2.5 mg/week
• Typical maintenance dose: 10-15 mg/week
• FDA status: Approved (Zepbound for obesity, Mounjaro for T2D)
• Years of data: 3-4 years

GLP3 Reta (Retatrutide)

• Receptors targeted: GLP-1 + GIP + Glucagon (triple agonist)
• Key trial: Phase 2 Retatrutide Trial (NEJM, 2023, NCT04881760)
• Average weight loss: 17.1% (4mg), 22.8% (8mg), 24.2% (12mg) at 48 weeks
• Starting dose: 1 mg/week (investigational)
• Typical maintenance dose: Up to 12 mg/week (Phase 2 max dose)
• FDA status: Not approved; Phase 3 trials ongoing
• Years of data: Less than 2 years (Phase 2 only)

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Key Takeaways

• All three work through overlapping but distinct mechanisms, and more receptor targets generally means stronger weight loss effects based on current data
• The efficacy ranking based on available trial data is reta > tirz > sema, but that ranking is not straightforward given very different amounts of supporting evidence
• GI side effects are manageable for most research subjects when titration is done slowly and carefully
• The choice between these three is largely a question of how you weigh efficacy potential against data maturity and risk tolerance

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For Research Purposes Only. GLP1 Sema, GLP2 Tirz, and GLP3 Reta are sold by Progression Peptides for research use only. These products are not intended to diagnose, treat, cure, or prevent any disease. They are not approved for human consumption. All information in this guide references published clinical trial data and is provided for educational purposes. Consult a licensed healthcare provider before making any decisions about your health.