How Weight-Loss Peptides Compare

1. The four-tier framework

The current weight-loss peptide landscape can be organised into four tiers by receptor coverage. Higher-tier agents engage more receptors with one molecule and have generally produced larger placebo-adjusted weight loss in their pivotal trials, although direct head-to-head comparisons remain limited.

1. Tier 1 — GLP-1 mono-agonists. Liraglutide 3.0 mg (Saxenda); semaglutide 2.4 mg (Wegovy). FDA-approved for chronic weight management.
2. Tier 2 — GLP-1 / GIP dual agonists. Tirzepatide (Zepbound). FDA-approved for chronic weight management.
3. Tier 3 — GLP-1 / GIP / glucagon triple agonists. Retatrutide (LY3437943) — investigational; survodutide (BI 456906, GLP-1/glucagon dual) — investigational.
4. Tier 4 — Combinations and adjacent classes. CagriSema (cagrilintide + semaglutide); amylin mono-agonists.

This framework is a useful organising lens; it is not a clinical recommendation. Selection in real practice depends on regulatory status, patient comorbidities, contraindications, access, and tolerability — not magnitude alone.

2. GLP-1 mono-agonists

Liraglutide 3.0 mg (Saxenda)

Once-daily subcutaneous injection. First GLP-1 RA approved by the FDA for chronic weight management (under the SCALE program). (see FDA Saxenda approval history (December 2014)) Pivotal trial: SCALE Obesity (Pi-Sunyer et al.) reported placebo-adjusted weight loss in the mid-single-digit percent range at 56 weeks. (Pi-Sunyer et al., 2015, NEJM — PMID 26132939)

Semaglutide 2.4 mg (Wegovy)

Once-weekly subcutaneous injection. Approved under the STEP program. (see FDA Wegovy approval announcement, June 2021) Pivotal trial: STEP 1 (Wilding et al.) reported substantially greater placebo-adjusted weight loss than liraglutide and established the modern reference for GLP-1 mono-agonist efficacy in obesity. (Wilding et al., 2021, NEJM — PMID 33567185) SELECT extended this efficacy story with cardiovascular outcome data. (Lincoff et al., 2023, NEJM — PMID 37952131)

Strengths: large evidence base, weekly dosing, cardiovascular and now renal outcome data. Limitations: GI tolerability profile typical of the class; weight regain after discontinuation reported in extension data.

3. GLP-1 / GIP dual agonists

Tirzepatide (Mounjaro / Zepbound)

Once-weekly subcutaneous injection. Marketed as Mounjaro for type 2 diabetes and Zepbound for chronic weight management. (see FDA Zepbound approval announcement, November 2023) Pivotal weight-loss program: SURMOUNT. SURMOUNT-1 reported placebo-adjusted weight loss exceeding semaglutide 2.4 mg at the highest dose, although the trials were not directly head-to-head. (Jastreboff et al., 2022, NEJM — PMID 35658024)

The first head-to-head, SURMOUNT-5, compared tirzepatide vs semaglutide 2.4 mg directly. (Aronne et al., 2025, NEJM — PMID 40353578) The mechanistic rationale for adding GIP-receptor agonism remains an active research question; some authors emphasise GIP-driven attenuation of GLP-1 nausea, others emphasise direct effects on adipose tissue.

Strengths: strongest approved single-agent efficacy at the time of writing; weekly dosing; expanding cardiovascular and sleep-apnoea data. Limitations: same GI tolerability pattern; cost and access remain practical barriers.

4. GLP-1 / GIP / glucagon triple agonists

Retatrutide (LY3437943)

Investigational. Once-weekly subcutaneous injection. The phase 2 obesity trial reported the largest placebo-adjusted weight-loss magnitudes seen for any single-agent injectable to date at the highest dose at 48 weeks. (Jastreboff et al., 2023, NEJM — PMID 37366315) Phase 3 development is ongoing under the TRIUMPH program. (see ClinicalTrials.gov for TRIUMPH programme entries) See the dedicated retatrutide pillar guide for full mechanism and trial detail.

Survodutide (BI 456906)

Investigational GLP-1 / glucagon dual agonist (note: dual, not triple — it does not engage GIP). Once-weekly subcutaneous injection. Phase 2 obesity data have been published; phase 3 is in progress. (le Roux et al., 2024, Lancet Diabetes Endocrinol — PMID 38330987)

Both compounds are at investigational stage and access outside trials is not consistent with current FDA guidance; the relevant warning is at /glp3-retatrutide-black-market-warning/.

5. Combinations and adjacent classes

CagriSema (cagrilintide + semaglutide)

Investigational combination of the long-acting amylin analogue cagrilintide with semaglutide 2.4 mg. The REDEFINE phase 3 program is underway. (Garvey et al., 2025, NEJM — PMID 40544433) The therapeutic rationale combines GLP-1 receptor agonism with amylin-receptor agonism, which independently slows gastric emptying and reduces food intake.

Amylin mono-agonists

Cagrilintide and other amylin analogues are also being studied as monotherapy. Magnitude of single-agent weight loss is reported below that of GLP-1 monotherapy but with a distinct tolerability profile. (Enebo et al., 2021, Lancet — PMID 33894838)

Adjacent and emerging

The pipeline includes oral non-peptide GLP-1 receptor agonists (e.g., orforglipron, danuglipron), oral semaglutide at higher obesity-relevant doses, and a range of preclinical multi-receptor candidates. (Frias et al., 2023, Lancet — PMID 37369232) Real-time updates are surfaced via the Research News feed.

6. Decision factors in clinical practice

Magnitude of pivotal-trial weight loss is one of several inputs to therapy selection, and on its own it is rarely the deciding factor in a real encounter. The patient's comorbidity profile, prior tolerability with related agents, payer formulary status, and personal preferences around route and frequency of administration usually carry more weight in the conversation than a 2- to 4-percentage-point difference in pivotal-trial mean weight loss. The four-tier framework is a useful organising lens for the literature, not a prescription for sequential therapy.

A second framing point concerns lean-mass preservation. Greater absolute weight loss raises the absolute amount of lean tissue at risk during the loss phase. Resistance training, adequate dietary protein intake, and, in some protocols, deliberate slowing of the loss trajectory are all strategies under active investigation. The LEAN-PREP protocol and related programmes are aimed precisely at this question. (LEAN-PREP protocol; see PubMed; verification pending) Body-composition outcomes from the dedicated phase 3 sub-studies of the higher-tier agents are awaited.

A third practical point: durability of weight loss after discontinuation. Randomised-withdrawal designs at the GLP-1 mono-agonist level (STEP 4) have demonstrated meaningful regain after stopping; analogous data for dual and triple agonists are still maturing. (Rubino et al., 2021, JAMA — PMID 33755728) The clinical implication is that any of these therapies, in approved indications, is appropriately framed as chronic.

In a clinical encounter, the more decisive factors are typically:

• Approval status. Investigational compounds are not options outside trials.
• Coverage and cost. Practical access varies sharply by payer and by indication (diabetes vs obesity).
• Cardiovascular and renal comorbidity. Outcome trial data may favour one agent over another.
• Contraindications. Personal or family history of MTC, MEN2, prior pancreatitis, severe gastroparesis.
• Tolerability history. Patients who have failed one GLP-1 RA on GI grounds may or may not tolerate another; titration patience is more important than agent switching in many cases.
• Administration preference. Daily vs weekly; injection vs oral.
• Pregnancy plans. All agents in this class are recommended to be discontinued before planned pregnancy.

For pairwise comparisons with current data, see the side-by-side pages at /compare/ and the dedicated retatrutide vs semaglutide vs tirzepatide page.

References

This guide cites primary peer-reviewed and regulatory sources where the underlying claim has been verified. A small number of supporting items remain in active verification and are listed below for transparency.

Verified primary references

1. Pi-Sunyer X et al. Liraglutide 3.0 mg in Weight Management (SCALE Obesity). NEJM 2015. PMID 26132939.
2. Wilding JPH et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). NEJM 2021. PMID 33567185.
3. Lincoff AM et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT). NEJM 2023. PMID 37952131.
4. Jastreboff AM et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). NEJM 2022. PMID 35658024.
5. Aronne LJ et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5). NEJM 2025. PMID 40353578.
6. Jastreboff AM et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — Phase 2. NEJM 2023. PMID 37366315.
7. le Roux CW et al. Survodutide for Obesity — Phase 2. Lancet Diabetes Endocrinol 2024. PMID 38330987.
8. Knop FK et al. Oral Semaglutide 50 mg for Obesity (OASIS 1). Lancet 2023. PMID 37385278.
9. Enebo LB et al. Cagrilintide with Semaglutide 2.4 mg for Weight Management — Phase 1b. Lancet 2021. PMID 33894838.
10. Garvey WT et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE-1). NEJM 2025. PMID 40544433.
11. Frias JP et al. Oral Orforglipron in Type 2 Diabetes — Phase 2. Lancet 2023. PMID 37369232.
12. Rubino D et al. Continued Semaglutide vs Placebo on Weight Loss Maintenance (STEP 4). JAMA 2021. PMID 33755728.

Still seeking primary citation

• FDA Saxenda approval announcement (December 2014)
• FDA Wegovy approval announcement (June 2021)
• FDA Zepbound approval announcement (November 2023)
• TRIUMPH ClinicalTrials.gov NCT identifier
• LEAN-PREP protocol for resistance exercise during incretin therapy — verification pending