Amylin + GLP-1 Combinations for Obesity
Amylin Analogs
20.4% weight loss
CagriSema achieved 20.4% body weight reduction at 68 weeks in the REDEFINE 1 trial, outperforming semaglutide alone by roughly 5 percentage points.
Garvey et al., NEJM, 2025
Garvey et al., NEJM, 2025
View as imageSemaglutide changed obesity treatment. But it left a gap. In the largest trials, roughly 14-15% of body weight disappeared over 68 weeks. For millions of people, that is life-changing. For millions more, it is not enough. That gap is where amylin enters the picture. A second gut hormone, working through different brain circuits than GLP-1, amylin amplifies the appetite-suppressing signal when paired with a GLP-1 agonist. The first combination to prove this at scale, CagriSema, produced 20.4% mean weight loss in the REDEFINE 1 phase 3 trial.[1] If you want background on what amylin is and how it works, read the primer first. This article covers why combining amylin and GLP-1 agonists produces results neither can match alone, and what the clinical evidence actually shows.
Key Takeaways
- CagriSema (cagrilintide + semaglutide) produced 20.4% weight loss at 68 weeks in 3,417 adults with obesity, vs 3.0% for placebo (Garvey et al., NEJM, 2025)
- In adults with type 2 diabetes, CagriSema delivered 13.7% weight loss and lowered HbA1c by 2.2 percentage points vs placebo (Davies et al., NEJM, 2025)
- Amycretin, a single molecule targeting both GLP-1 and amylin receptors, achieved 24.3% weight loss at 36 weeks in early-phase testing (Dahl et al., Lancet, 2025)
- The combination surpassed semaglutide monotherapy: a 2026 meta-analysis found CagriSema produced 11 kg more weight loss than comparators (Gadelmawla et al., 2026)
- CagriSema reduced systolic blood pressure by 10.9 mmHg vs 2.8 mmHg for placebo over 68 weeks (Verma et al., 2026)
- Gastrointestinal side effects were common (79.6% vs 39.9% placebo) but mostly mild to moderate and transient
Why one hormone is not enough
GLP-1 agonists like semaglutide reduce appetite primarily by activating GLP-1 receptors in the hypothalamus and brainstem. Amylin works through a separate set of neurons in the area postrema and nucleus of the solitary tract, two regions in the dorsal vagal complex that process satiety signals from the gut.[2] Because these two hormones act on different neuronal populations, combining them produces additive or synergistic weight loss rather than redundant signaling.
Boyle and colleagues described amylin's dual role in 2018: it reduces eating through both homeostatic pathways (the hunger-regulation system) and hedonic pathways (the reward-driven system that makes food pleasurable).[3] GLP-1 agonists are strong on the homeostatic side but have less influence on reward-driven eating. That is why some patients on semaglutide still experience food cravings despite reduced hunger. Amylin fills that gap.
The preclinical case for combining them was established by Liberini and colleagues in 2019. In diet-induced obese rats, amylin alone reduced body weight by 7%, the GLP-1 analog liraglutide alone reduced it by 15%, but the combination produced 21% weight loss, a greater-than-additive effect. The combination also sustained weight loss longer after treatment stopped than either drug alone.[4]
How cagrilintide was built to fix amylin's problems
Native human amylin has two critical flaws: it forms amyloid fibrils (the same clumping behavior seen in type 2 diabetes pancreatic deposits) and it has a half-life of only 13 minutes. Pramlintide, the only approved amylin analog, solved the aggregation problem but still required three daily injections because its half-life remained short. That dosing burden is a major reason pramlintide never achieved commercial success.
Kruse and colleagues at Novo Nordisk engineered cagrilintide by applying a lipidation strategy, attaching a fatty acid chain that allows the peptide to bind albumin in the bloodstream and circulate for days instead of minutes.[5] This extended the half-life to roughly 7 days, enabling once-weekly dosing. The team also introduced amino acid substitutions that eliminated the amyloid-forming tendency. Out of a series of 27 candidate molecules, cagrilintide (compound 23) was selected for clinical development.
This engineering work is what makes the amylin + GLP-1 combination story possible. Without a long-acting amylin analog, patients would need to inject three times daily for the amylin component and once weekly for semaglutide. That regimen would never scale to a mass-market obesity treatment.
The clinical evidence: phase 1 through phase 3
Phase 1b: first proof the combination works in humans
Enebo and colleagues tested cagrilintide 2.4 mg combined with semaglutide 2.4 mg in a 20-week phase 1b trial. The combination produced 17.1% body weight reduction, with an estimated treatment difference of -7.4 percentage points versus semaglutide plus placebo (95% CI: -11.2 to -3.5).[6] No pharmacokinetic interaction was detected between the two drugs, meaning each one behaved the same whether given alone or together. That was a critical finding: it meant the weight loss amplification came from pharmacodynamic synergy, not altered drug exposure.
Phase 2: dose-finding for cagrilintide alone
Before the combination could advance, cagrilintide needed standalone dose-finding data. Lau and colleagues randomized 706 adults with overweight or obesity to cagrilintide (0.3 mg to 4.5 mg weekly) or placebo for 26 weeks. The highest dose produced 10.8% weight loss from baseline.[7] For a single-agent amylin analog given once weekly, that was a strong result and provided the dosing rationale for the combination program.
Phase 2 combination in type 2 diabetes
Frias and colleagues tested cagrilintide 2.4 mg plus semaglutide 2.4 mg against semaglutide 2.4 mg alone in 92 adults with type 2 diabetes over 32 weeks. The combination achieved 15.6% weight loss compared to 5.1% with semaglutide alone, a difference of roughly 10 percentage points.[8] HbA1c improvements were also greater with the combination.
Phase 3 REDEFINE 1: the landmark obesity trial
The REDEFINE 1 trial enrolled 3,417 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity, none of whom had type 2 diabetes. Participants were randomized 3:1 to once-weekly CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) or placebo for 68 weeks.[1]
The results:
- Mean weight loss: 20.4% with CagriSema vs 3.0% with placebo (estimated difference: -17.3 percentage points; 95% CI: -18.1 to -16.6; P<0.001)
- 60% of CagriSema patients lost ≥20% of their body weight
- 23% lost ≥30% of their body weight
- Mean absolute weight loss from a baseline of 236 lbs: approximately 48 lbs
These numbers represent a meaningful step beyond semaglutide monotherapy, which in the STEP 1 trial produced roughly 14.9% weight loss at 68 weeks. The roughly 5 percentage point improvement translates to approximately 10-12 additional pounds of weight loss.
Phase 3 REDEFINE 2: obesity with type 2 diabetes
Davies and colleagues tested CagriSema in adults who had both obesity/overweight and type 2 diabetes. Over 68 weeks, CagriSema produced 13.7% weight loss versus 3.4% for placebo.[9] The smaller magnitude compared to REDEFINE 1 is expected: people with type 2 diabetes consistently lose less weight on GLP-1 agonists than those without diabetes. HbA1c dropped by 2.2 percentage points more with CagriSema than with placebo, with 73.5% of CagriSema patients achieving an HbA1c of 6.5% or below.
Beyond weight: blood pressure, cardiometabolic, and alcohol effects
CagriSema's effects extend beyond the scale. A secondary analysis of REDEFINE 1 by Verma and colleagues focused specifically on blood pressure outcomes. CagriSema reduced systolic blood pressure by 10.9 mmHg compared to 2.8 mmHg with placebo over 68 weeks. Among participants with resistant hypertension, 42% on CagriSema achieved blood pressure targets versus 29.3% on placebo.[10]
A 2026 systematic review and meta-analysis by Gadelmawla and colleagues pooled data from 4 randomized controlled trials (n=4,419). Compared to semaglutide monotherapy or placebo, CagriSema produced an additional 11 kg of weight loss, 9.41 cm of waist circumference reduction, and 7.06 mmHg lower systolic blood pressure. The effect size for weight loss was large (Cohen's d = -1.38).[11]
One unexpected finding: the amylin + GLP-1 combination may influence alcohol consumption. Aranäs and colleagues demonstrated synergistic-like decreases in alcohol intake in male rats treated with combined GLP-1 and amylin agonists.[12] This parallels reports of reduced alcohol interest in patients on GLP-1 agonists alone, and suggests the combination may produce even stronger effects on reward-driven behaviors beyond eating.
Side effects: what the trials show
Gastrointestinal side effects are the dominant issue with CagriSema, following the same pattern seen with GLP-1 agonists but at somewhat higher rates. In REDEFINE 1:[1]
- Nausea: 55% CagriSema vs 12.6% placebo
- Constipation: 30.7% vs 11.6%
- Vomiting: 26.1% vs 4.1%
- Overall GI adverse events: 79.6% vs 39.9%
Most events were mild to moderate in severity and occurred during dose escalation. A QTc safety study by Gabe and colleagues confirmed that cagrilintide does not prolong the QT interval, an important cardiovascular safety marker.[13]
The Dutta meta-analysis of early trials noted that GI adverse events and vomiting were markedly higher with CagriSema than with semaglutide alone.[14] Whether this difference persists in larger datasets and whether it leads to higher discontinuation rates are open questions. The REDEFINE trials reported that most patients stayed on treatment, but real-world adherence often differs from trial settings.
Amycretin: the single-molecule approach
CagriSema combines two separate peptides administered as a single injection. Amycretin takes a different approach: one engineered molecule that activates both GLP-1 and amylin receptors. Novo Nordisk developed it as both a subcutaneous injection and an oral formulation.
In a phase 1b/2a trial, Dahl and colleagues tested subcutaneous amycretin at escalating doses. The highest dose group (60 mg weekly) achieved 24.3% mean body weight reduction at 36 weeks, compared to 1.1% with placebo. A 20 mg maintenance dose achieved 22.0% weight loss, and even the 5 mg dose produced 16.2% at 28 weeks.[15]
These are early-phase numbers with small sample sizes, and they cannot be directly compared to CagriSema's phase 3 data. The 36-week timeframe is shorter than CagriSema's 68 weeks, and smaller studies tend to produce more variable results. But the trajectory is notable: if these results hold in phase 3 (expected to begin in 2026), amycretin could represent the next generation of amylin + GLP-1 therapy, simplifying treatment from two co-administered peptides to a single molecule.
The oral formulation of amycretin is particularly significant for patient convenience. Early data showed a 13.1% weight reduction at 12 weeks with the highest oral dose, though this program is behind the subcutaneous formulation in development.[15]
Where the evidence has gaps
The amylin + GLP-1 combination story is compelling, but several questions remain unanswered.
Long-term durability. The longest trial data covers 68 weeks. Whether the additional weight loss from amylin persists at 2, 3, or 5 years is unknown. Weight loss drugs typically show some regain after the first year, and it is unclear whether amylin's contribution to reward-pathway suppression changes this pattern.
Comparison to tirzepatide. Tirzepatide, a dual GIP/GLP-1 agonist, produced up to 22.5% weight loss in the SURMOUNT-1 trial. No head-to-head trial has compared CagriSema to tirzepatide. The mechanisms differ (GIP vs amylin), and the patient populations that respond best to each approach may also differ.
Muscle preservation. Rapid weight loss on GLP-1 agonists often includes significant lean mass loss. Jacobsen and colleagues showed in a 2025 rat study that CagriSema drives weight loss primarily by reducing energy intake while preserving energy expenditure.[16] Whether that translates to better muscle preservation in humans is unconfirmed.
Cost and access. CagriSema will likely cost at least as much as Wegovy (semaglutide 2.4 mg), which runs approximately $1,300/month before insurance. As a premium combination product, the price could be higher. Insurance coverage for obesity medications remains inconsistent.
Real-world GI tolerability. The 55% nausea rate in REDEFINE 1 is higher than typical rates with semaglutide alone. In clinical practice, where patients have less structured support than in trials, higher side effect burden could lead to more treatment discontinuation.
The regulatory and development timeline
Novo Nordisk filed the CagriSema NDA with the FDA in December 2025. The FDA review is expected to complete in 2026. If approved, CagriSema would be the first combination of a GLP-1 receptor agonist and an amylin analog for weight management.
Meanwhile, the broader amylin pipeline continues to expand. A 2025 review by Lee identified multiple amylin receptor agonists in preclinical and early clinical development.[17] Bailey and colleagues described the second generation of long-acting amylin analogs in a 2026 review, noting that improved peptide engineering has overcome the limitations that held back pramlintide.[18] Cagrilintide's specific design innovations represent just one branch of a rapidly growing field.
The trajectory points toward multi-hormone obesity treatment as the standard of care. GLP-1 alone was the first wave. GLP-1 + GIP (tirzepatide) was the second. GLP-1 + amylin is emerging as the third. And triple agonists targeting GLP-1, GIP, and glucagon are in clinical development. Each additional mechanism captures a different part of the appetite-regulation circuit, incrementally moving average weight loss closer to what bariatric surgery achieves.
The Bottom Line
Combining amylin and GLP-1 agonists produces greater weight loss than either hormone alone. CagriSema has demonstrated this in phase 3 trials with 20.4% mean weight loss in adults with obesity and 13.7% in those with type 2 diabetes, along with blood pressure and metabolic improvements. Amycretin, a single-molecule dual agonist, has shown even larger reductions in early testing. Gastrointestinal side effects are common but manageable, and questions about long-term durability, muscle preservation, and comparative effectiveness against tirzepatide remain open. With the CagriSema NDA under FDA review in 2026, the amylin + GLP-1 approach is positioned to become the next major advance in pharmaceutical obesity treatment.