Semaglutide and tirzepatide reset expectations for obesity treatment, but both Novo Nordisk and Eli Lilly are already developing candidates intended to improve on them. Amycretin and retatrutide are two of the most closely watched, and they take meaningfully different approaches to the same goal.

Amycretin: A GLP-1/Amylin Dual Agonist

Amycretin, developed by Novo Nordisk, is a unimolecular dual agonist that activates both the GLP-1 receptor and the amylin receptor in a single molecule. Amylin is a separate appetite-regulating hormone normally co-released with insulin by the pancreas; drugs that activate its receptor are thought to increase satiety and slow gastric emptying through a partially different pathway than GLP-1 alone, which is the rationale for combining the two mechanisms. Notably, Novo Nordisk is developing amycretin in both a once-weekly subcutaneous injectable form and a once-daily oral form — testing both delivery routes for the same molecule.

In a Phase 2 trial in adults with type 2 diabetes, with results reported in November 2025, amycretin produced weight loss of up to 14.5% with the subcutaneous version and up to 10.1% with the oral version over 36 weeks, compared with roughly 2.5-2.6% in the placebo groups. HbA1c reductions in the same trial were also substantial, with the majority of participants reaching HbA1c targets below 7%. Novo Nordisk has said it plans to start a Phase 3 program for amycretin in type 2 diabetes in 2026, and has separately moved the subcutaneous and oral versions of amycretin into Phase 3 development for weight management specifically.

Retatrutide: A GLP-1/GIP/Glucagon Triple Agonist

Retatrutide, developed by Eli Lilly, takes a different route: it activates three separate receptors — GLP-1, GIP (the same second incretin hormone targeted by tirzepatide), and glucagon. Adding glucagon receptor activity is the key mechanistic difference from tirzepatide's dual-agonist design; glucagon signaling is associated with increased energy expenditure in addition to appetite suppression, which is the proposed reason retatrutide has shown larger weight-loss figures in trials reported so far.

Retatrutide is further along in development than amycretin. Eli Lilly announced in July 2026 that two additional Phase 3 trials in its TRIUMPH program met their primary weight-loss and blood-sugar endpoints, and the company has said it plans to file for FDA approval in 2027. Reported weight-loss figures across retatrutide's various trials, doses, and follow-up periods have varied — different sources have cited numbers from roughly the low-20s up to about 30% depending on which trial, dose, and duration is being described — so it's worth checking the specific trial being referenced rather than treating any single headline number as universal. As PeptideAAA has covered elsewhere, the gap between a trial's "observed" weight-loss number and its placebo-adjusted number can also be substantial, which is a useful check before comparing any two drugs' headline figures directly.

Key Differences at a Glance

The two candidates differ in mechanism (amylin co-agonism for amycretin versus glucagon co-agonism for retatrutide), delivery options (amycretin is being developed in both injectable and oral forms; retatrutide's furthest-along trials have used a weekly injectable), and development stage (retatrutide is in Phase 3 with an FDA filing targeted for 2027; amycretin's weight-management program has also advanced into Phase 3, but with less mature trial data publicly reported so far, and its type 2 diabetes program only began moving to Phase 3 in 2026).

What Hasn't Been Tested

Neither drug has been directly compared with the other in a head-to-head clinical trial, so any comparison between them, including this one, relies on separate trials with different designs, populations, and durations — the same limitation that applies to most cross-trial drug comparisons in this space. Differences in reported weight-loss percentages should be read as suggestive rather than conclusive until, and unless, a trial compares them directly.

Regulatory Status

Neither amycretin nor retatrutide is FDA-approved; both remain investigational. Retatrutide is further along, with an anticipated FDA submission in 2027, while amycretin's weight-management development is at an earlier stage. Anyone considering either drug should understand they are not yet available by prescription for obesity and are not legally available outside of clinical trials.