Last updated: July 30, 2026

Research reference only. Tirzepatide is FDA-approved for its indicated uses; the other compounds discussed here remain investigational. This article summarizes publicly available clinical trial data and is intended for educational purposes. It is not medical advice and should not be interpreted as a recommendation to use any of these compounds.

Four metabolic pathways currently dominate the obesity and metabolic research pipeline: amylin, GLP-1, GIP, and glucagon. Understanding how each compound engages these pathways explains why weight-loss outcomes vary as much as they do across trials — and why combination approaches are becoming the dominant development strategy at both Lilly and Novo Nordisk.

The Four Pathways, Briefly

Amylin is co-released with insulin after meals. It promotes satiety, slows gastric emptying, and suppresses glucagon — with a tolerability profile that researchers have found more favorable than traditional incretin therapies in early trials.
GLP-1 remains the foundation of current obesity pharmacotherapy, improving glucose-dependent insulin secretion and appetite regulation.
GIP appears to amplify GLP-1’s effects when both pathways are activated simultaneously, which is the basis for dual-agonist compounds like tirzepatide.
Glucagon receptor activation increases energy expenditure and has been linked to substantial reductions in liver fat, though it may come with a tradeoff in gastrointestinal tolerability.

Eloralintide (LY3841136)

Eloralintide is a selective, once-weekly amylin receptor agonist and represents a newer class of obesity therapeutics distinct from GLP-1-based approaches.

Phase 1 data showed dose-proportional pharmacokinetics, with weight reductions between roughly 2.6% and 11.3% over 12 weeks. In the Phase 2 obesity trial, extended to 48 weeks, weight loss ranged from approximately 9% to 20% depending on dose — and notably, the weight-loss curve had not clearly plateaued by the end of the study, suggesting further reductions with continued treatment.

Secondary findings included improvements in lipid parameters and high-sensitivity C-reactive protein. Gastrointestinal adverse events were generally mild to moderate, with nausea and vomiting reported less frequently than is typical with GLP-1 receptor agonists. Lilly has since advanced eloralintide into Phase 3 trials and is separately evaluating it in combination with tirzepatide — a signal that the company sees amylin agonism as complementary to, rather than competitive with, incretin-based therapy.

Retatrutide (LY3437943)

Retatrutide is a triple agonist, engaging GIP, GLP-1, and glucagon receptors simultaneously, and currently holds the strongest published weight-loss results among late-stage obesity therapies.
Phase 2 data showed approximately 24% weight loss at 48 weeks, alongside liver fat reductions approaching 86%. In the TRIUMPH-1 trial, average weight loss reached 25.0% at 80 weeks, with an extended-duration subgroup approaching 30%. Additional outcomes included meaningful HbA1c reductions, improvement in metabolic-associated steatotic liver disease, normalization of liver fat in many participants, and improvement in osteoarthritis symptoms.

That efficacy comes with a tradeoff: treatment discontinuation increased with dose, reaching approximately 11.3% at the highest dose studied, reflecting the balance between retatrutide’s exceptional efficacy and its gastrointestinal tolerability profile.

Tirzepatide

Tirzepatide, a dual GIP/GLP-1 receptor agonist, is the current FDA-approved benchmark for obesity pharmacotherapy. SURMOUNT-1 established approximately 22.5% average weight loss over 72 weeks, and it now has the largest body of real-world and cardiovascular outcomes data of any compound in this comparison — which is precisely why it functions as the reference point against which newer, investigational compounds are measured.

Cagrilintide and CagriSema

Cagrilintide is a long-acting amylin/calcitonin receptor agonist. As a standalone compound, it produced approximately 11.5% weight loss in Phase 3 testing — confirming that amylin agonism alone is clinically meaningful, if less potent than dual- or triple-receptor approaches.

Combined with semaglutide as CagriSema, weight loss increased to approximately 22.7%, demonstrating a synergistic interaction between the amylin and GLP-1 pathways. Novo Nordisk’s development strategy reflects this same combination-first logic that Lilly is pursuing with eloralintide and tirzepatide.

Clinical Interpretation

Across all four compounds, a clear pattern emerges: engaging more metabolic pathways simultaneously tends to produce greater average weight loss, generally at the cost of increased gastrointestinal adverse events and higher discontinuation rates. Amylin agonists stand out within this pattern — they contribute meaningful satiety effects while maintaining comparatively favorable tolerability, which is likely why both major manufacturers are now pursuing them as combination partners rather than standalone competitors to GLP-1 therapy.

Frequently Asked Questions

Is eloralintide FDA-approved?

No. Eloralintide is currently investigational and is in Phase 3 clinical trials. Tirzepatide is the only compound in this comparison with FDA approval.

How is eloralintide different from semaglutide or tirzepatide?

Eloralintide is a selective amylin receptor agonist, while semaglutide and tirzepatide work through the GLP-1 and GIP/GLP-1 pathways, respectively. Amylin agonism has shown a comparatively favorable gastrointestinal tolerability profile in early trials, and Lilly is studying eloralintide both alone and in combination with tirzepatide.

Which compound has produced the greatest weight loss in trials?

Among the compounds compared here, retatrutide has shown the largest published weight-loss signal, reaching approximately 25% average weight loss at 80 weeks in the TRIUMPH-1 trial, with some participants approaching 30%.

What is CagriSema?

CagriSema is the combination of cagrilintide (an amylin/calcitonin receptor agonist) and semaglutide (a GLP-1 receptor agonist). Combined, they produced approximately 22.7% weight loss in Phase 3 testing — more than either compound alone.

Why are amylin agonists like eloralintide and cagrilintide gaining attention?

Amylin agonists have shown they can contribute meaningful satiety and weight-loss effects while maintaining relatively favorable tolerability. This is likely why Lilly and Novo Nordisk are both pursuing amylin-based combination strategies rather than treating amylin agonists as standalone competitors to GLP-1 therapy.

References

• New England Journal of Medicine — SURMOUNT, REDEFINE study data
• The Lancet — Eloralintide Phase 2; Cagrilintide Phase 2
• Diabetes, Obesity and Metabolism — Eloralintide Phase 1
• Eli Lilly — TRIUMPH and TRANSCEND trial press materials
• American Diabetes Association — scientific sessions
• ClinicalTrials.gov

This article is provided for informational and research purposes only. It does not constitute medical advice, and none of the investigational compounds discussed are approved for personal use outside of clinical trials. Always consult a licensed healthcare provider before making any decisions related to your health.