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The Peptide Effect
Comparison

Retatrutide vs Semaglutide

Retatrutide and semaglutide represent two different generations of incretin-based obesity treatments. Semaglutide (Ozempic/Wegovy) is a single GLP-1 receptor agonist that pioneered the modern obesity pharmacotherapy era with ~15% weight loss. Retatrutide (LY3437943) is a triple GLP-1/GIP/glucagon receptor agonist in Phase 3 development that achieved ~24% weight loss in Phase 2 — a roughly 60% improvement over semaglutide. The gap is driven by retatrutide's additional GIP and glucagon receptor activation, which enhance satiety and increase energy expenditure respectively.

Side-by-side comparison diagram of Retatrutide and Semaglutide mechanisms of action
Conceptual comparison — not to scale

Head-to-Head Comparison

CriteriaRetatrutideSemaglutide
Primary mechanismTriple agonist: GLP-1 + GIP + glucagon receptorsSingle GLP-1 receptor agonist
Best forMaximum weight loss, fatty liver disease, metabolic syndrome (once approved)Weight loss, type 2 diabetes, cardiovascular risk reduction
Route of administrationOnce-weekly subcutaneous injectionOnce-weekly subcutaneous injection (or daily oral tablet for T2D)
Typical dosage1 mg escalating to 8–12 mg weekly (Phase 2)0.25 mg escalating to 2.4 mg weekly (Wegovy)
Average weight loss~24.2% at 48 weeks (12 mg, Phase 2)~15.3% at 68 weeks (2.4 mg, STEP 1)
Half-life~6 days~7 days
FDA statusNot approved — Phase 3 trials underwayFDA-approved: Wegovy (obesity, 2021), Ozempic (T2D, 2017)
Cardiovascular dataNo outcomes data yetSELECT trial: 20% reduction in major adverse cardiovascular events
Effect on liver fatDramatic reduction via glucagon-driven hepatic fat oxidation (~86% MASLD resolution)Moderate reduction in liver fat as secondary benefit of weight loss
Side effectsNausea (26%), diarrhea (22%), vomiting (14%) — Phase 2Nausea (44%), vomiting (24%), diarrhea (30%) — STEP 1
Oral formulationNone in developmentAvailable (Rybelsus 7–14 mg daily for T2D)
Approximate monthly costNot commercially available$1,350–$1,430/month (brand)

When to Choose Each

Choose Retatrutide

Future patients seeking maximum weight loss efficacy, individuals with MASLD/fatty liver disease who need hepatic fat reduction, or those who want enhanced metabolic benefits from triple receptor agonism — pending FDA approval

Choose Semaglutide

Patients who need treatment now, those with established cardiovascular disease, patients who prefer oral dosing, or anyone wanting the most-studied GLP-1 agonist with extensive long-term safety data

Verdict

Semaglutide is the proven, FDA-approved standard of care with the longest track record, cardiovascular outcomes data, and an oral option. Retatrutide has the potential to be a significant upgrade, with Phase 2 data showing nearly 60% greater weight loss than semaglutide and notably lower reported GI side effect rates. However, retatrutide is still investigational — Phase 3 results are needed to confirm these findings, and FDA approval is at least a year away. For patients today, semaglutide is the evidence-based choice; retatrutide is the most promising next-generation option on the horizon.

References

  1. Triple-hormone-receptor agonist retatrutide for obesity — a Phase 2 trial (2023) — PubMed
  2. Once-weekly semaglutide in adults with overweight or obesity (STEP 1) (2021) — PubMed
  3. Semaglutide and cardiovascular outcomes in patients with overweight or obesity (SELECT) (2023) — PubMed
  4. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-comparator-controlled, parallel-group, phase 2 trial (2023) — PubMed

Frequently Asked Questions

How much more weight loss does retatrutide produce compared to semaglutide?
In Phase 2 trials, retatrutide at the 12 mg dose produced approximately 24.2% body weight loss at 48 weeks, compared to semaglutide's 15.3% at 68 weeks in STEP 1. That represents roughly 60% greater weight loss in a shorter timeframe. However, these numbers come from separate trials with different patient populations, so a direct head-to-head comparison would be needed for definitive conclusions.
Why does retatrutide appear to have fewer side effects despite stronger weight loss?
The lower reported GI side effect rates in retatrutide Phase 2 trials may be partially due to the GIP receptor component, which has anti-emetic properties that counterbalance GLP-1's nausea-inducing effects. The glucagon component also contributes to weight loss through increased energy expenditure rather than purely through appetite suppression, potentially reducing the GI burden. However, Phase 2 trial populations are smaller and side effect profiles can change in larger Phase 3 studies.
Should I wait for retatrutide instead of starting semaglutide?
For most patients, waiting is not recommended. Obesity is a chronic disease with compounding health risks, and delaying treatment has real consequences. Semaglutide offers proven 15% weight loss and cardiovascular risk reduction available today. If retatrutide is eventually approved and shows clear superiority, switching at that time is straightforward. Starting semaglutide now and potentially transitioning later is a reasonable strategy.
Are semaglutide and retatrutide made by the same company?
No. Semaglutide is manufactured by Novo Nordisk (Denmark), while retatrutide is being developed by Eli Lilly (USA). Lilly also makes tirzepatide (Mounjaro/Zepbound), the dual GIP/GLP-1 agonist. The two companies are the dominant players in the incretin-based obesity treatment market.
Will retatrutide preserve more muscle mass during weight loss than semaglutide?
Preliminary research suggests retatrutide may offer better lean mass preservation compared to semaglutide. The glucagon receptor component is thought to shift the body toward fat oxidation rather than overall caloric restriction alone, potentially favoring fat loss over muscle loss. However, this has not been definitively confirmed in large-scale trials. GLP-1 agonists like semaglutide are associated with approximately 25 to 40 percent of total weight loss coming from lean mass, which remains a concern across the drug class. Resistance training and adequate protein intake are commonly recommended alongside any incretin-based therapy to help preserve muscle. Consulting a healthcare provider about strategies for lean mass preservation is advisable.

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