GLP-1 + Amylin Combinations 2026: CagriSema, Petrelintide, Amycretin

The amylin pathway is the most consequential addition to obesity drug development since GIP entered the conversation with tirzepatide. Three pipeline candidates have produced Phase 2 or Phase 3 data in the last 18 months that establish amylin agonism as a real lever: CagriSema delivered 22.7% weight loss in REDEFINE-1, petrelintide hit 10.7% as a pure amylin monotherapy in ZUPREME-1, and amycretin produced 14.5% as a single-molecule GLP-1 + amylin co-agonist.

This article covers what the amylin pathway actually does, the three pipeline candidates that lead the field, the dose and trial design distinctions between them, and how the amylin class fits the broader 2026 obesity pipeline alongside the established GLP-1 mono- and multi-agonists.

Why amylin matters

Amylin is a 37-amino-acid peptide co-secreted with insulin from pancreatic beta cells in response to meals. It suppresses postprandial glucagon, slows gastric emptying, and acts on the area postrema in the brainstem to drive satiety. Importantly, amylin's satiety mechanism is distinct from GLP-1's hindbrain mechanism: amylin receptors are upstream of the same effector pathways but engage them through a different ligand-receptor circuit.

The functional implication for obesity therapy: adding amylin agonism to GLP-1 agonism produces additive weight loss because two satiety pathways are engaged in parallel. This is the structural reason CagriSema beats semaglutide alone, and the reason petrelintide produces meaningful weight loss as a standalone agent.

Three mechanistic facts that shape the class:

1. Amylin restores leptin sensitivity. Long-acting amylin analogs in preclinical work appear to restore central leptin signaling that is blunted in chronic obesity. This is a different pharmacology from short-term satiety and may underlie the durable response observed in petrelintide trials.

2. Amylin tolerability is reportedly better than GLP-1 monotherapy. Across the published Phase 2 work on petrelintide and amycretin, the GI side effect rate has been lower than expected based on GLP-1 monotherapy comparisons. The mechanism is not fully characterized but the clinical observation is consistent.

3. Pramlintide (the legacy amylin analog) was a short-half-life daily injection. All three new pipeline candidates are long-acting (weekly subcutaneous). The pharmacokinetic profile is the main practical advance over older amylin work.

The original cagrilintide characterization came from Lau et al., Lancet Diabetes Endocrinol, 2021, which established the dose-response curve for long-acting amylin agonism in obesity, and Enebo et al., Lancet, 2021, which combined cagrilintide and semaglutide for the first time.

CagriSema: the combination that opened the class

CagriSema is the fixed-dose combination of cagrilintide (long-acting amylin analog) and semaglutide, developed by Novo Nordisk. The REDEFINE-1 Phase 3 trial produced the highest published weight loss for any fixed-dose obesity combination.

The 22.7% result at 68 weeks placed CagriSema above injectable semaglutide monotherapy (2.4 mg → 14.9% in STEP 1) and approached tirzepatide 15 mg (22.5% in SURMOUNT-1). The combination produced more weight loss than 2.4 mg semaglutide or 2.4 mg cagrilintide as monotherapy, demonstrating the additive effect of the two pathways.

REDEFINE-4 directly compared CagriSema to tirzepatide 15 mg in approximately 800 adults with obesity. Tirzepatide held a small numerical edge (around 24-25% versus 22-23%), but the gap was narrow enough to make the choice between them more about access and tolerance than headline efficacy.

Bottom line: CagriSema 2.4/2.4 mg produces approximately 8 additional percentage points of weight loss over semaglutide 2.4 mg alone (22.7% vs 14.9%). Adding amylin to GLP-1 is a real lever, mechanistically distinct from raising the GLP-1 dose. Combination therapy and high-dose monotherapy are different strategies, not interchangeable.

The dose ladder for CagriSema mirrors standard semaglutide titration, with cagrilintide scaling in lockstep: 0.25/0.25, 0.5/0.5, 1.0/1.0, 1.7/1.7, 2.4/2.4 mg weekly, each step held for 4 weeks. Full titration is 17 weeks to reach the target maintenance dose.

For deeper coverage including the head-to-head against tirzepatide, see the CagriSema REDEFINE Phase 3 guide.

Petrelintide: amylin monotherapy as a real option

Petrelintide is the Zealand Pharma long-acting amylin analog now being developed with Roche. The ZUPREME-1 Phase 2 results published in March 2026 made petrelintide the first amylin monotherapy with credible standalone weight-loss data.

The 10.7% result is meaningful for monotherapy in this duration. For context, semaglutide 2.4 mg at 42 weeks in STEP 1 was approximately -10.0%, putting petrelintide at parity with mono-GLP-1 monotherapy in a head-to-head duration window despite using an entirely different receptor system.

What sets petrelintide apart from the GLP-1 class is the tolerability profile. In ZUPREME-1, 98% of trial participants in the top-dose cohort reached the maintenance dose, indicating GI side effects were not severely limiting titration. The most frequently reported adverse events were GI-related and mild. This is a notably cleaner tolerability profile than the GLP-1 class typically produces.

Phase 3 was announced by Roche and Zealand on April 29, 2026. The trial program will test whether the Phase 2 efficacy and tolerability profile holds at scale and over longer durations. Roche's commercial weight in the obesity space makes petrelintide the first amylin-pathway candidate with a major-pharma development engine behind it.

The implication for the field: amylin monotherapy is a structurally simpler option than GLP-1 + amylin combinations. The petrelintide approach trades the higher weight loss of combination therapy (22.7% at CagriSema) for better tolerability and a cleaner mechanism (10.7% with reportedly placebo-like safety profile).

Amycretin: unimolecular GLP-1 + amylin

Amycretin is Novo Nordisk's single-molecule GLP-1 and amylin co-agonist. Unlike CagriSema (two separate molecules in a fixed combination), amycretin is one peptide molecule with binding activity at both GLP-1 and amylin receptors.

Subcutaneous amycretin Phase 2 results:

Amycretin also has an oral formulation in Phase 1 development, with reportedly strong early weight-loss signal at the higher doses tested. The oral amycretin program is the most active Novo Nordisk effort at the oral GLP-1 expansion. If the oral formulation reaches Phase 3 with the Phase 1 efficacy holding up, it would be the most active oral obesity drug in development by a meaningful margin.

The mechanistic distinction between amycretin and CagriSema:

CagriSema is two separate peptides delivered in one injection. The cagrilintide-to-semaglutide ratio is fixed at 2.4/2.4 mg, but they are pharmacokinetically and structurally distinct molecules.

Amycretin is one peptide molecule with co-agonist activity at GLP-1 and amylin receptors. The two pathways are engaged from the same ligand, which simplifies pharmacology but trades the flexibility of independent dose ratios.

Both approaches produce additive weight loss from the dual-pathway mechanism. The choice between them in pipeline strategy is a manufacturability and commercial question more than a biological one. Novo Nordisk is running both bets in parallel.

For more context on Novo Nordisk's GLP-1 pipeline beyond CagriSema and amycretin, see the CagriSema REDEFINE Phase 3 guide and orforglipron Phase 3 evidence.

Direct comparison: the three amylin candidates

CagriSema is the highest-weight-loss option but has the highest GI side effect burden (because of the GLP-1 component) and requires the longest titration. Amycretin is roughly midpoint. Petrelintide has the most favorable tolerability profile in published data but the lowest weight loss number, because it does not engage the GLP-1 pathway at all.

Bottom line: Amylin combinations (CagriSema) deliver the highest weight loss but inherit GLP-1 tolerability. Amylin monotherapy (petrelintide) trades weight loss for tolerability and is the right option for patients who cannot run GLP-1. Unimolecular co-agonists (amycretin) sit in the middle structurally and may dominate the oral route if Phase 3 holds.

How to think about this for different goals:

Maximum weight loss in patients tolerating GLP-1: CagriSema or tirzepatide are the front-runners. Both produce 22+% at 68-72 weeks. The choice depends on tolerance history with semaglutide versus tirzepatide and what is on formulary.

Patient struggling with GLP-1 tolerance: Petrelintide is the most interesting option once Phase 3 data confirms the Phase 2 tolerability. The trade-off is less weight loss, but the difference between not tolerating treatment and tolerating treatment is the relevant comparison.

Pipeline researchers tracking combinations: Amycretin's oral formulation may be the most consequential development in 2026-2027. If oral amycretin produces injectable-class weight loss with the convenience of the oral route, the entire route-of-administration conversation shifts.

For our complete dose-response coverage across the GLP-1 class plus amylin combinations, see the GLP-1 dosing comparison 2026 and the Wegovy HD 7.2 mg STEP UP trial guide.

How amylin combinations compare to GIP and glucagon multi-agonists

The other major multi-receptor approach in obesity therapy is GIP + GLP-1 (tirzepatide) and GIP + GLP-1 + glucagon (retatrutide). The amylin class is structurally different from these.

What is notable: each added pathway produces additional weight loss above GLP-1 monotherapy, but the magnitude of the additive effect varies. Adding amylin to GLP-1 (CagriSema) produces about +8 percentage points over semaglutide alone. Adding GIP to GLP-1 (tirzepatide) produces a similar +8 percentage point gain over semaglutide. Adding both GIP and glucagon (retatrutide) appears to produce more.

The amylin pathway slots cleanly into this framework. It is a real mechanism for additive weight loss, on par mechanistically with GIP, with the additional benefit of reportedly cleaner GI tolerability in monotherapy and combination work.

For the broader pipeline coverage, see the survodutide Phase 2 evidence, mazdutide IBI362 Phase 3 evidence, and MariTide Phase 2 evidence.

Cagrilintide on its own: what is already known

Cagrilintide as a standalone amylin analog was characterized in detail by Lau et al., Lancet Diabetes Endocrinol, 2021. The Phase 1b dose-finding work showed cagrilintide 2.4 mg as the dose level driving the maximum sustainable weight loss as monotherapy, approximately 10% over 26 weeks. This is roughly equivalent to what petrelintide produced over 42 weeks in ZUPREME-1, suggesting the amylin class has a converging dose-response profile.

Enebo et al., Lancet, 2021 demonstrated the combination of cagrilintide with semaglutide produces additive weight loss in healthy adult volunteers. This was the trial design proof-of-concept that led to the full CagriSema Phase 3 program.

What is still unknown

Three open questions for the amylin class through 2026:

1. Does the better-tolerability claim hold at scale? Both petrelintide and amycretin Phase 2 work reported favorable GI profiles. Phase 3 with thousands of patients will determine whether the tolerability advantage survives population-scale variability. If yes, this is a defining advantage of the class.

2. Does long-term durability hold? Amylin's claimed restoration of leptin sensitivity should produce durable weight loss with less rebound on discontinuation than GLP-1 monotherapy. This is mechanism-level theory; clinical trials of discontinuation have not been published yet. The stopping GLP-1 weight regain research covers what happens with GLP-1 discontinuation, and the amylin discontinuation question is the next test.

3. Where does amycretin oral fit? If the Phase 1 oral amycretin efficacy holds in Phase 2-3, the oral route gains a meaningful candidate. The current oral GLP-1 options (Rybelsus, orforglipron) are mono-receptor. Oral amycretin would be the first multi-receptor oral.

Sourcing notes

For research-grade injectable cagrilintide vials, Ascension Peptides ships with public per-batch COAs and 50% off using code ENHANCED. The cagrilintide compound guide covers the published research on the parent amylin analog.

Petrelintide and amycretin are not available as research-grade compounds as of May 2026, since they are in active Phase 2/3 development with sponsor exclusivity. For our broader sourcing analysis, see the best legit peptide vendors 2026 ranking.

FAQ

What is the difference between CagriSema and amycretin?

Both engage GLP-1 and amylin pathways and produce additive weight loss. CagriSema is two separate molecules (cagrilintide + semaglutide) in one weekly injection. Amycretin is a single peptide molecule with binding activity at both GLP-1 and amylin receptors. CagriSema produces more weight loss in published trials (22.7% vs 14.5%) but amycretin is at an earlier development stage with potentially different trial conditions. The structural difference matters for manufacturability and dose flexibility more than for the underlying biology.

Is petrelintide better than semaglutide?

Petrelintide produced 10.7% weight loss at 42 weeks in ZUPREME-1. Semaglutide 2.4 mg at similar timepoints in STEP 1 produced about 10% weight loss. The two are roughly equivalent on weight loss in matched-duration comparisons. Where petrelintide may have an advantage is GI tolerability, where the Phase 2 data reportedly showed a notably cleaner profile than GLP-1 monotherapy. Phase 3 will confirm or refine this.

Could you combine petrelintide with semaglutide?

Mechanistically, this would replicate the CagriSema mechanism using different molecules. There is no published trial of petrelintide + semaglutide combination, and Roche and Novo Nordisk are separate commercial sponsors, so the combination is unlikely to be pursued by either as a primary development program. If both were approved as monotherapies, off-label or research combinations could theoretically be tested but are not part of the current pipeline.

Why does amylin produce better GI tolerability than GLP-1?

The full mechanism is not characterized, but the leading hypothesis is that amylin's satiety pathway works upstream of the gastric emptying slowdown that drives much of GLP-1's GI side effect profile. GLP-1 slows gastric emptying directly, which produces nausea and constipation as side effects. Amylin works through area postrema circuits that engage satiety without the same gastric-emptying effect. The clinical observation is consistent across petrelintide, cagrilintide monotherapy, and amycretin Phase 2 work.

When will petrelintide and amycretin be available?

Petrelintide entered Phase 3 in April 2026, so commercial availability is likely several years out depending on trial duration and approval timeline. Amycretin is still in Phase 2 for both subcutaneous and oral formulations. CagriSema is the only amylin-pathway candidate filed as of May 2026, with approval expected through 2026-2027.

Is cagrilintide alone worth using?

Cagrilintide monotherapy at 2.4 mg produced about 10% weight loss over 26 weeks in Phase 1b dose-finding work, which is comparable to petrelintide's Phase 2 result. Cagrilintide is not approved as monotherapy; it is being developed primarily in the CagriSema combination context. For research-grade application, Ascension Peptides ships injectable cagrilintide with code ENHANCED, and the cagrilintide compound guide covers the published research.

How does the amylin class compare to retatrutide?

Retatrutide is the triple agonist (GIP + GLP-1 + glucagon) producing 24.2% weight loss at 48 weeks in Phase 2. CagriSema is the strongest amylin-combination option at 22.7% at 68 weeks. Retatrutide is the higher absolute number, but the triple-mechanism approach produces higher GI side effect burden. Petrelintide and amycretin are not directly comparable on weight loss but offer different tolerability profiles. The pipeline runs on at least two parallel tracks: GIP/glucagon-based multi-receptor compounds like retatrutide, and amylin-based combinations like CagriSema, amycretin, and petrelintide-plus.

Further reading

• CagriSema REDEFINE Phase 3 guide
• Cagrilintide compound guide
• GLP-1 dosing comparison 2026
• Wegovy HD 7.2 mg STEP UP trial guide
• Tirzepatide vs Semaglutide 2026 head-to-head
• Retatrutide vs Tirzepatide vs Semaglutide
• Survodutide GCG/GLP-1 dual agonist evidence
• Mazdutide IBI362 Phase 3 evidence
• MariTide Phase 2 evidence
• Stopping GLP-1 and weight regain research

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This article is for educational and research purposes only. CagriSema is filed with the FDA and not yet approved as of May 2026. Petrelintide is in Phase 3 development. Amycretin is in Phase 2 development. None of the content above constitutes medical advice. Cagrilintide as a research-grade compound is sold under research-use disclosures and is not for human consumption. Consult a qualified clinician for individual medical questions about weight management therapy.