PwPepwise

Cagrilintide

Weight Loss

a.k.a. AM833

Long-acting amylin analog

Cagrilintide is a long-acting synthetic analogue of amylin, a hormone naturally released by the pancreas alongside insulin to help regulate appetite.

§Dosing at a glance

3 protocols · from the research
What it's forDoseHow oftenHowFor how long
Cagrilintide Monotherapy (Weight Management)0.3 mgWeeklySubcutaneousInjected just under the skin, into the fat layer.6 wks
CagriSema Fixed Combination (Obesity, with or without Type 2 Diabetes)2.4 mgWeeklySubcutaneousInjected just under the skin, into the fat layer.16 wks
East Asian populations2.4 mgWeeklySubcutaneousInjected just under the skin, into the fat layer.—

Approximate values pulled from the research — double-check before dosing.

§01Summary

Cagrilintide is a long-acting synthetic analogue of amylin, a hormone naturally released by the pancreas alongside insulin to help regulate appetite, food intake, and body weight. By activating amylin receptors in the brain, cagrilintide promotes feelings of fullness and reduces calorie consumption. While it demonstrates meaningful weight loss as a monotherapy, its most compelling application is as part of CagriSema — a fixed weekly combination with the GLP-1 receptor agonist semaglutide that targets two distinct appetite-regulating pathways simultaneously.

In large randomized trials, CagriSema reduces body weight by an average of approximately 20% in adults with obesity over 68 weeks1, and by approximately 14% in people who also have type 2 diabetes2 — outcomes that exceed what semaglutide alone typically achieves. The combination also produces significant improvements in blood pressure3 and, in people with type 2 diabetes, drives HbA1c levels to near-normal ranges in nearly three-quarters of treated patients2. The most commonly reported side effects are gastrointestinal — including nausea, vomiting, and diarrhea — which are generally mild to moderate and tend to resolve over time1,2,4. CagriSema is being investigated in cardiovascular outcome trials and in populations ranging from pediatric patients to individuals with treatment-resistant hypertension17,20.

This is the layperson summary. Mechanism, dosing, the evidence base, and the published literature are in the sections below — every claim links to its source.

§02In depth

Cagrilintide is a fatty-acid acylated, long-acting analogue of human amylin (islet amyloid polypeptide, IAPP), engineered for once-weekly subcutaneous administration. Amylin is a 37-amino acid peptide hormone co-secreted with insulin by pancreatic beta cells in response to nutrient ingestion. Endogenous amylin exerts its effects primarily through the amylin receptor, a heterodimeric complex composed of the calcitonin receptor (CTR) paired with one of three receptor activity-modifying proteins (RAMP1, RAMP2, or RAMP3), with RAMP1-containing complexes (AMY1 receptors) being predominantly implicated in metabolic regulation. Amylin receptors are highly expressed in the area postrema and nucleus tractus solitarius of the brainstem, regions critical for integrating satiety signals, as well as in the hypothalamus. Activation of these receptors by cagrilintide suppresses appetite, slows gastric emptying, and reduces caloric intake, leading to negative energy balance and progressive weight reduction4.

The pharmacokinetic engineering of cagrilintide involves C-terminal fatty-acid acylation and amino acid substitutions that confer protease resistance and albumin binding, yielding a plasma half-life of 159–195 hours and enabling once-weekly dosing8. Importantly, co-administration of cagrilintide with semaglutide 2.4 mg does not alter the pharmacokinetics of either compound, confirming non-overlapping metabolic clearance pathways and supporting safe co-formulation8.

The scientific rationale for combining cagrilintide with semaglutide (a GLP-1 receptor agonist) rests on the complementary and non-redundant nature of amylin and GLP-1 receptor signaling. GLP-1 receptors are expressed in the vagal afferents, dorsal vagal complex, and hypothalamus; their activation reduces appetite, slows gastric emptying, stimulates glucose-dependent insulin secretion, and suppresses glucagon. Amylin receptors activate overlapping but distinct downstream neural circuits, particularly in the area postrema. The dual engagement of these parallel satiety pathways by CagriSema produces additive weight loss beyond what either agent achieves alone, with combination therapy yielding approximately 6–7 percentage points greater weight reduction than semaglutide monotherapy in controlled trials6,8. In people with type 2 diabetes, the dual mechanism drives HbA1c to ≤6.5% in nearly three-quarters of treated patients, suggesting both improved insulin sensitivity and enhanced beta-cell support through complementary hormonal pathways2.

Beyond weight and glycemic effects, CagriSema reduces systolic blood pressure by approximately 10.9 mmHg versus placebo, an effect that may extend beyond weight-loss-mediated mechanisms given the known vasoregulatory role of amylin receptor signaling and the established cardiovascular benefits of GLP-1 receptor agonism3. Cardiac ion channel safety has been formally assessed: cagrilintide at 4.5 mg does not prolong the QTcF interval beyond the 10 ms regulatory threshold at any pre-specified time point, meeting ICH E14 criteria for a negative thorough QT study5.

§04Evidence & efficacy

Evidence base
174Studies
85Human
8Animal

CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) reduces mean body weight by 20.4% over 68 weeks compared to 3.0% with placebo in adults with overweight or obesity without type 2 diabetes, representing an estimated treatment difference of −17.3 percentage points (95% CI −18.1 to −16.6, P<0.001)1. Significantly greater proportions of CagriSema-treated participants achieve weight-loss thresholds of ≥5%, ≥20%, ≥25%, and ≥30% compared to placebo1. In adults with overweight or obesity and type 2 diabetes, CagriSema reduces body weight by 13.7% versus 3.4% with placebo, and 73.5% of CagriSema patients achieve HbA1c ≤6.5% compared to 15.9% with placebo2.

Cagrilintide monotherapy reduces body weight in a dose-dependent manner ranging from 6.0% to 10.8% at doses of 0.3–4.5 mg versus 3.0% for placebo, with the 4.5 mg dose demonstrating superiority over liraglutide 3.0 mg (10.8% vs 9.0%, P=0.03)4. In combination with semaglutide 2.4 mg, cagrilintide at doses of 1.2–4.5 mg reduces body weight by 15–17% over 20 weeks, versus ~9.8% for the semaglutide-alone arm8.

In an east Asian population, CagriSema reduces body weight by 18.4% versus 11.9% with semaglutide alone, representing an estimated treatment difference of −6.5 percentage points (P<0.0001)6. CagriSema also reduces systolic blood pressure by 10.9 mmHg versus 2.8 mmHg with placebo, and nearly doubles the proportion of participants reaching blood pressure targets (63.0% vs 32.0%)3. Pooled meta-analyses confirm CagriSema produces approximately 11 kg greater absolute weight loss than comparators, with waist circumference reductions of approximately 10–11 cm versus placebo9,10.

§05Safety

Cagrilintide and CagriSema are associated with a well-characterized gastrointestinal adverse event profile consistent with the amylin analogue and GLP-1 receptor agonist classes. In the phase 3 REDEFINE 1 trial, gastrointestinal adverse events occurred in 79.6% of CagriSema-treated participants versus 39.9% in the placebo group, encompassing nausea, vomiting, diarrhea, constipation, and abdominal pain, with events described as predominantly transient and mild-to-moderate in severity1. In the type 2 diabetes REDEFINE 2 trial, gastrointestinal adverse events were reported in 72.5% of CagriSema patients versus 34.4% with placebo2. In the phase 2 monotherapy dose-finding trial, gastrointestinal adverse events occurred in 41–63% of cagrilintide-treated participants, with nausea being the most common individual event (20–47%)4. Permanent treatment discontinuation attributable to adverse events was approximately 4% in phase 24, and the combination showed modestly higher discontinuation rates compared to semaglutide monotherapy in the east Asian REDEFINE 5 trial (10% vs 6%)6.

A dedicated thorough QT study demonstrated that cagrilintide 4.5 mg does not produce clinically relevant QTcF prolongation, with all 90% confidence interval upper limits remaining below the 10 ms regulatory threshold, indicating no increased risk of ventricular tachyarrhythmias5. In the phase 1b combination study, adverse events were reported in over 96% of participants across both active and placebo groups, though events were predominantly mild to moderate and the high rate was substantially attributable to background semaglutide8. A meta-analysis confirmed that gastrointestinal adverse events are significantly more frequent with CagriSema compared to monotherapy or placebo, with a relative risk of 1.3210.

No novel or unexpected safety signals beyond the established GI profile have been described in published trials1,2. Cardiovascular safety in high-risk populations with established cardiovascular disease is being evaluated in an ongoing outcome trial17.

§06History

Cagrilintide was developed by Novo Nordisk as a next-generation, long-acting amylin analogue, building on the scientific foundation established by pramlintide, the first synthetic amylin analogue approved by the FDA in 2005 for type 1 and type 2 diabetes. Pramlintide required multiple daily injections due to a short half-life; cagrilintide was engineered with fatty-acid acylation and structural modifications to achieve a half-life of 159–195 hours, enabling the once-weekly dosing schedule that is central to its clinical utility8.

Early clinical development advanced through a phase 1b pharmacokinetic and pharmacodynamic study published in 2021, which demonstrated that cagrilintide co-administered with semaglutide 2.4 mg was well tolerated, showed dose-proportional exposure, and produced body weight reductions of 15–17% over 20 weeks — establishing the combination's safety and early efficacy signal8. The pivotal phase 2 monotherapy dose-finding trial, also published in 2021, confirmed a clear dose-response relationship from 0.3 to 4.5 mg once-weekly and demonstrated superiority over liraglutide 3.0 mg at the highest dose, representing the first head-to-head comparison between an amylin analogue and an approved obesity pharmacotherapy4.

The combination product CagriSema then entered the REDEFINE phase 3 program. Results from REDEFINE 1 (obesity without diabetes)1 and REDEFINE 2 (obesity with type 2 diabetes)2 were published in June 2025, demonstrating mean weight reductions of 20.4% and 13.7% respectively. REDEFINE 5, targeting east Asian populations, reported results in April 20266. A dedicated cardiovascular outcomes trial and long-term extension studies are currently ongoing17,16, and a head-to-head comparison against tirzepatide is registered15, positioning CagriSema at the frontier of obesity pharmacotherapy.

§07References