Key Differences Between Amylin Agonists and GLP-1 Receptor Agonists

Feature	Amylin Agonists (Amylin Mimetics)	GLP-1 Receptor Agonists (GLP-1RAs)
Natural hormone	Amylin (also called islet amyloid polypeptide, IAPP) – co-secreted with insulin from pancreatic β-cells	GLP-1 (glucagon-like peptide-1) – secreted by intestinal L-cells after meals
Main physiological actions	- Slows gastric emptying - Suppresses post-meal glucagon secretion - Increases satiety (feeling of fullness) via brain centers - Reduces food intake (strong central appetite suppression)	- Stimulates glucose-dependent insulin secretion - Strongly suppresses glucagon - Slows gastric emptying - Increases satiety and reduces appetite (mainly via vagal nerve + some direct brain effects)
Effect on weight loss	Moderate to strong (typically 5–10 % body weight loss as monotherapy; stronger when combined with GLP-1)	Strong (15–20 %+ with current dual/triple agonists like tirzepatide, 8–15 % with pure GLP-1s like semaglutide)
Effect on blood glucose	Modest lowering (mostly postprandial); does not stimulate insulin directly	Strong glucose lowering (both fasting and postprandial) via insulin secretion + glucagon suppression
Side effects	Nausea (dose-dependent), injection-site reactions; historically hypoglycemia risk when combined with insulin (pramlintide era)	Nausea, vomiting, diarrhea, constipation; very low hypoglycemia risk alone
Administration	Currently only injectable (daily or weekly in new candidates)	Injectable (daily or weekly) and oral (semaglutide, orforglipron, etc.)
Approved examples	Pramlintide (Symlin®) – human amylin analog, used as adjunct in type 1 & type 2 diabetes	Semaglutide (Ozempic, Wegovy, Rybelsus), liraglutide (Victoza, Saxenda), tirzepatide (Mounjaro/Zepbound – GLP-1 + GIP), dulaglutide (Trulicity), exenatide (Byetta, Bydureon), etc.
Next-generation pipeline	Long-acting amylins: AZD6234 (AstraZeneca), pemvidutide (Altimmune), survodutide (Boehringer – GLP-1 + glucagon, but some amylin-like effects), cagrilintide (Novo – used in CagriSema combo)	Oral GLP-1s (orforglipron, danuglipron), triple agonists (retatrutide = GLP-1 + GIP + glucagon), amylin + GLP-1 combos

 

Why Companies Are Combining Them (e.g., CagriSema, pemvidutide)

• Amylin and GLP-1 work through completely separate receptors and pathways → additive or synergistic effects.
• Amylin adds extra appetite suppression in the brain (hypothalamus and area postrema) that GLP-1 alone does not fully hit.
• Clinical trials of amylin + GLP-1 combos show 20–25 %+ weight loss (approaching bariatric surgery territory) with better tolerability than very high-dose single agents.

Summary

Aspect	Amylin Agonist	GLP-1 Agonist
Primary strength	Stronger central appetite suppression	Strong insulin secretion + glucose control
Weight-loss ceiling (alone)	~8–12 %	~15–20 % (current best-in-class)
When combined	Can push total weight loss >22–25 %	Same
Current market presence	Very small (only pramlintide)	Dominant ($50 B+ market)
Future role	Mostly as part of dual/triple agonist combos	Remains the backbone of most new obesity drugs

GLP-1 drugs are the current kings of the obesity/diabetes market, but amylin agonists are the rising co-star in the next wave of even more powerful combination therapies.