Amylin Agonists Compared: Petrelintide vs Eloralintide vs Cagrilintide
Amylin agonists are the next major non-incretin lever in obesity pharmacotherapy, and three programs are racing to define the class: Zealand/Roche's petrelintide, Lilly's eloralintide, and Novo's cagrilintide. All three engage amylin-receptor biology and all three were engineered for once-weekly dosing — but they differ on receptor selectivity, weight-loss magnitude, tolerability, regulatory maturity, and which incretin partner each pharma plans to stack them with. This comparison is the honest mechanistic and clinical split among the three, with the trade-offs that actually distinguish them.
All three are once-weekly amylin agonists, but they make different trade-offs. Petrelintide (Zealand/Roche) is the tolerability play — only ~10.7% weight loss as monotherapy, but with placebo-like GI side effects and trial dropout lower than placebo. Eloralintide (Lilly) is the magnitude play — up to 20% weight loss at 9 mg, rivaling tirzepatide, but with dose-dependent fatigue and meaningful nausea at top doses. Cagrilintide (Novo) is the regulatory-mature option — modest as monotherapy (~10%) but the only one with Phase 3 readouts (REDEFINE), used almost exclusively in the CagriSema combination with semaglutide where it delivers ~20–23% weight loss. Each pharma is engineering its amylin agonist as a combination partner for an in-house incretin: petrelintide + CT-388, eloralintide + macupatide (the Phase 1 tirzepatide combination has completed and the larger Phase 2/2b program has pivoted to macupatide), cagrilintide + semaglutide (the only one already in Phase 3). None is FDA-approved as of mid-2026.
Petrelintide
Zealand Pharma's long-acting amylin analog, partnered with Roche in a $5.3B deal. Phase 2b ZUPREME-1 showed 10.7% weight loss at 42 weeks with placebo-like tolerability — the 'tolerability play' in the amylin class.
Eloralintide
Eli Lilly's once-weekly selective amylin receptor agonist. Phase 2 trials showed up to 20% weight loss at 48 weeks with favorable tolerability. Phase 3 enrollment began late 2025.
Cagrilintide
A long-acting amylin analogue being developed in combination with semaglutide (CagriSema) for enhanced weight loss.
| Category | Petrelintide | Eloralintide | Cagrilintide |
|---|---|---|---|
| Sponsor / Partner | Zealand Pharma + Roche ($5.3B deal, March 2025) | Eli Lilly | Novo Nordisk |
| Receptor Profile | Balanced AMYR + CTR dual agonist | Selective AMY1 receptor (~12× over CTR) | Dual AMYR + CTR (CTR/RAMP1, CTR/RAMP3) |
| Engineering Twist | Acylated 36-aa human amylin, re-engineered for neutral-pH stability — enables co-formulation with other peptides | Selectivity-engineered analog with ~2-week half-life — minimizes calcitonin-receptor side effects | Acylated, C18 fatty-diacid albumin binder — the original once-weekly amylin |
| Half-Life | ~33.8 hours (once-weekly) | ~2 weeks (once-weekly) | ~7–8 days (once-weekly) |
| Monotherapy Weight Loss | 10.7% at 42 wk (ZUPREME-1 Phase 2b, 9 mg) | Up to 20% at 48 wk (Phase 2, 9 mg) | ~10% at 26 wk (Phase 2, 2.4 mg) |
| Combination Weight Loss | Phase 2 with CT-388 (Roche dual GLP-1/GIP) starting H1 2026 — no data yet | Phase 1 combination with tirzepatide completed Jan 2026 (NCT06916065); Phase 2/2b combination program now with macupatide (Lilly's GIPR/GLP-1RA) — NCT07215559, NCT07589608 | CagriSema (+ semaglutide): ~20–23% at 68 wk (REDEFINE 1/2 Phase 3) |
| GI Tolerability | Placebo-like — single-digit diarrhea/constipation; mild nausea resolving after titration; 98% reached maintenance dose | Better than GLP-1s on some axes, but dose-dependent fatigue (up to 46%) and nausea still common at 6–9 mg | Class-typical — nausea, vomiting, constipation generally more common than semaglutide alone in the combination |
| Trial Discontinuation | 8.4% on drug vs 13.6% on placebo (ZUPREME-1) — lower than placebo | Improved with slower titration; not at petrelintide's level | Higher than semaglutide monotherapy arms in REDEFINE |
| Furthest Trial Phase | Phase 2b complete; Phase 3 monotherapy starts H2 2026 (triggers $575M Roche milestone) | Phase 3 ENLIGHTEN-3 started Feb 2026 (NCT07369011, 800 pts, obesity + OSA endpoints, primary completion Mar 2028) | Phase 3 complete (REDEFINE 1, 2, 5); regulatory filings planned for CagriSema |
| Earliest Realistic Approval | 2029–2030 | 2028–2029 | Likely first to market (CagriSema); cagrilintide monotherapy not pursued |
| Defining Differentiator | Tolerability — lowest GI burden in the class, with neutral-pH stability enabling future co-formulations | Magnitude — peak weight loss rivals tirzepatide via amylin pathway alone | Regulatory maturity — first with Phase 3 outcomes data, anchoring the combination paradigm |
| Cardiovascular Outcomes Data | None yet — no CVOT planned at this stage | None yet | None yet — REDEFINE 1 secondary CV data is supportive but not a CVOT |
| Lean Mass Preservation | Preclinical fat-selective loss vs liraglutide; no published human body-composition data | Preclinical and mechanistic rationale; no published human body-composition data | Class-level preclinical signal; no dedicated published cagrilintide body-composition trial |
| Commercial Availability | Investigational — trial-only; not legally compoundable | Investigational — trial-only; not legally compoundable | Investigational — appearing in some compounding channels but outside FDA-authorized use |
In depth
Why the amylin class is suddenly crowded
For twenty years amylin agonism meant pramlintide — a short-acting analog approved in 2005 for diabetes that never broke into the obesity space because of its multiple-daily-injection burden. The modern amylin class is built on solving that problem: each of petrelintide, eloralintide, and cagrilintide is an engineered once-weekly analog, and each comes from a major pharma trying to add a non-incretin mechanism to its obesity portfolio. The strategic logic is identical across the three sponsors — pair an amylin agonist with an in-house GLP-1 or dual/triple incretin to push weight loss past what either does alone, and grab the patients GLP-1 monotherapy can't tolerate. What differs is the engineering choice each program made and the trade-off that choice locks in.
Petrelintide: the tolerability play
Zealand engineered petrelintide for neutral-pH stability, which avoids the amyloid fibrillation problem that has historically plagued amylin analogs and — more strategically — enables co-formulation in a single injection with other peptides. Receptor pharmacology is balanced dual agonism at AMYR and CTR, similar in shape to cagrilintide but with a structurally distinct molecule. The ZUPREME-1 Phase 2b readout (March 2026, 493 patients, 42 weeks) delivered 10.7% weight loss at the 9 mg dose — well below eloralintide's peak — but the tolerability profile is the story: GI side-effect rates similar to placebo, nausea mostly mild and resolving after titration, and trial discontinuation lower on drug (8.4%) than on placebo (13.6%). That is an unusual finding in obesity pharmacology and it positions petrelintide as the answer for the substantial subgroup of patients who can't stay on GLP-1 agonists because of nausea, vomiting, or GI intolerance. The strategic upside is combinatorial: paired with Roche's CT-388 dual GLP-1/GIP in a single neutral-pH co-formulation, petrelintide could match or exceed CagriSema-class outcomes with better tolerability. That Phase 2 combination trial starts H1 2026.
Eloralintide: the magnitude play
Lilly took the opposite engineering bet — selectivity over balance. Eloralintide preferentially activates the AMY1 receptor (~12× over the calcitonin receptor), and the design hypothesis is that selectivity reduces the calcitonin-related side-effect overhead while preserving the satiety signal. The Phase 2 readout (263 patients, 48 weeks, published in The Lancet) delivered dose-dependent weight loss from 9% at 1 mg up to 20% at 9 mg, with cardiometabolic improvements across all doses. That 20% number is the headline that put eloralintide on the map: it rivals tirzepatide and exceeds semaglutide as monotherapy, using a completely different pathway. The cost is real — dose-dependent fatigue is the prominent side effect at top doses (up to ~46% at 9 mg), and nausea remains meaningful at 6 mg and 9 mg arms despite the receptor-selectivity rationale. Lilly's Phase 3 program — ENLIGHTEN-3 — began February 2026 (NCT07369011, 800 patients) with a distinctive dual obesity-plus-OSA endpoint structure, primary completion targeted March 2028. The combination strategy has evolved: the Phase 1 eloralintide-plus-tirzepatide trial (NCT06916065) completed in January 2026, and Lilly has since pivoted its larger Phase 2/2b combination program to pair eloralintide with macupatide, the in-house GIPR/GLP-1RA — keeping the dual-mechanism stack but moving both halves inside Lilly's pipeline.
Cagrilintide: the regulatory-mature one
Cagrilintide is the longest-developed of the three, and it's the only one that's already cleared Phase 3 — but as a combination component, not as monotherapy. Novo's REDEFINE program (REDEFINE 1 in obesity without diabetes, REDEFINE 2 in T2D, REDEFINE 5 in East Asia) delivered ~20–23% weight loss with CagriSema versus ~15% with semaglutide alone over 68 weeks, positioning the combination as a direct competitor to tirzepatide. Standalone cagrilintide showed ~10% weight loss in Phase 2 dose-finding but Novo never pursued monotherapy regulatorily — the entire strategic value of cagrilintide is as semaglutide's partner. The trade-off cagrilintide makes is closer to classical amylin pharmacology: it's a balanced AMYR/CTR dual agonist without neutral-pH stability or AMY1 selectivity, and its GI side-effect profile in CagriSema runs higher than semaglutide alone — patients are paying tolerability cost for the magnitude gain. The advantage is that all of this is known: cagrilintide has the deepest dataset, the highest near-term regulatory probability, and the only published Phase 3 outcomes among the three.
How to think about choosing among them
None of these is available to prescribe today, so the choice is really for clinicians and patients thinking about what's coming. Petrelintide makes sense for the GLP-1-intolerant patient who couldn't stay on semaglutide or tirzepatide — assuming its tolerability advantage holds in Phase 3 — or for anyone where the future petrelintide + CT-388 co-formulation hits the market. Eloralintide makes sense where weight-loss magnitude is the dominant goal and the patient tolerates dose escalation reasonably well; the Lilly-internal combination with macupatide (Lilly's GIPR/GLP-1RA) is the practical end-state of the Phase 2/2b combination strategy. Cagrilintide is essentially CagriSema for clinical purposes — it's the option that will actually exist commercially first, in a single weekly injection with semaglutide, and it's the safest bet for patients and clinicians waiting on regulatory approval rather than betting on the longer-horizon programs.
Bottom line
Three once-weekly amylin agonists, three engineering trade-offs, three different strategic stories. Petrelintide trades peak magnitude for placebo-like tolerability and co-formulation flexibility. Eloralintide trades GI tolerability for GLP-1-class weight loss through a non-GLP-1 pathway. Cagrilintide trades novelty for regulatory maturity — it's the one already in Phase 3 and almost certain to reach market first as part of CagriSema. The class as a whole reflects a real shift in obesity pharmacology: combining amylin-based satiety with incretin-based metabolic effects is going to be the standard architecture of next-generation weight-loss therapy, and these three programs are the leading bets on how to assemble it.
These peptides are often used together. See our stack profiles for combination details.