Cagrilintide

Cagrilintide mimics and extends the activity of native human amylin through several mechanisms:

Amylin Receptor Agonism: Cagrilintide binds to amylin receptors (AMY1, AMY2, AMY3), which are composed of calcitonin receptor paired with receptor activity-modifying proteins (RAMPs). These receptors are concentrated in the area postrema and nucleus of the solitary tract in the brainstem, regions critical for appetite regulation and nausea signaling.

Gastric Emptying Reduction: Like native amylin, cagrilintide slows the rate at which food moves from the stomach into the small intestine. This prolongs the feeling of fullness after meals and reduces postprandial glucose spikes. The effect is dose-dependent and contributes significantly to caloric intake reduction.

Central Appetite Suppression: Cagrilintide acts on brainstem satiety centers to reduce hunger independently of the GLP-1 pathway. This is the key insight behind CagriSema: stacking two distinct central appetite suppression mechanisms produces greater-than-additive effects on food intake and body weight.

Glucagon Suppression: Amylin signaling suppresses postprandial glucagon release from pancreatic alpha cells. This complements insulin's glucose-lowering effect and helps stabilize blood sugar after meals, which reduces the reactive hunger that comes from glucose fluctuations.

Synergy with GLP-1: When combined with semaglutide, cagrilintide engages complementary but non-overlapping pathways. GLP-1 acts primarily on the hypothalamus and pancreatic beta cells. Amylin acts on the area postrema and alpha cells. The result is deeper appetite suppression and metabolic improvement than either pathway alone can deliver.

Superior Weight Loss in Combination: The REDEFINE trials showed CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) producing mean weight loss of approximately 25% of body weight. This exceeds semaglutide alone (~15-17%), tirzepatide (~20-22%), and approaches the results seen with bariatric surgery, but without the surgical risks.

Distinct Satiety Mechanism: Cagrilintide targets the amylin pathway, which operates independently of GLP-1. Users who have hit a weight loss plateau on semaglutide or tirzepatide may find that adding an amylin agonist restarts progress by engaging a pathway that was not previously activated.

Improved Glycemic Control: Through gastric emptying reduction and glucagon suppression, cagrilintide meaningfully improves post-meal blood sugar stability. For individuals with type 2 diabetes or insulin resistance, this translates to better HbA1c levels and reduced glucose variability.

Reduced Food Noise: Users in clinical trials consistently report a reduction in intrusive thoughts about food. This goes beyond simple appetite suppression: the combination of GLP-1 and amylin agonism appears to reduce the psychological preoccupation with eating that drives overeating behavior.

Long Half-Life: Cagrilintide's ~8-day half-life allows once-weekly dosing, matching the convenience of semaglutide. A single injection per week manages appetite for the full 7 days, with steady plasma levels that avoid the peaks and troughs of shorter-acting compounds.

Potential for Metabolic Syndrome Improvement: Early data suggests benefits beyond weight: improved lipid profiles, reduced liver fat content, and better cardiovascular risk markers. These effects are consistent with substantial weight loss combined with direct metabolic actions of amylin signaling.

Common (dose-dependent, usually transient): - Nausea (the most frequent side effect, often resolves after 2-4 weeks) - Vomiting, particularly during dose escalation - Diarrhea or constipation - Injection site reactions (redness, swelling) - Decreased appetite (intended effect but can become excessive)

Less Common: - Abdominal pain or bloating - Headache - Fatigue during initial weeks - Dyspepsia - Dizziness

Contraindications: - Personal or family history of medullary thyroid carcinoma (applies to the semaglutide component of CagriSema) - Multiple endocrine neoplasia syndrome type 2 - Severe gastroparesis (slowed gastric emptying can worsen this condition) - Pregnancy and breastfeeding - History of pancreatitis (use with caution; GLP-1 class concern)

The GI side effects follow the typical pattern seen with incretin-based therapies: they are worst during dose escalation and tend to resolve as the body adjusts. Slow titration is the standard mitigation strategy. In clinical trials, discontinuation rates due to adverse events were modest and comparable to semaglutide monotherapy.