Amylin — the forgotten second pancreatic hormone and its late return
In 1987 Garth Cooper in Oxford discovered that the pancreatic β-cell secretes not only insulin but a second peptide in parallel: amylin. 18 years later, pramlintide became the first amylin analog on the market — and never emerged from insulin's shadow. Today, in 2024-2026, the amylin line is gaining new attention via cagrilintide: as a combination partner with semaglutide in the CagriSema combination.
A second peptide in the same cell
In the mid-1980s the function of the pancreatic β-cell seemed well understood: it produces insulin, secretes it on elevated blood glucose, done. Garth Cooper, a New Zealand biochemist at the University of Oxford, found in the late 1980s in insulinoma tumour tissue and in the amyloid deposits of β-cells in type-2 diabetics a 37-amino-acid peptide he and his co-authors named amylin (today also designated islet amyloid polypeptide / IAPP). They published the characterisation in 1987.
It turned out: amylin is co-secreted with insulin from the same β-cell at roughly a 1:100 ratio. Functionally it contributes to three mechanisms: slowing gastric emptying, modulating postprandial glucagon secretion, and central satiety modulation via the area postrema. In type-1 diabetes — when the β-cell is destroyed — not only insulin but also amylin is missing. That observation suggested an immediate therapeutic path.
Pramlintide: the first iteration, with obstacles
Native human amylin has a practical problem: it is amyloidogenic — at higher concentrations it forms insoluble fibrils, similar to amyloid plaques in Alzheimer's. This physical instability makes it clinically unusable. The Canadian/American firm Amylin Pharmaceuticals (San Diego, later acquired by Bristol-Myers Squibb) developed a modified analog in the 1990s: pramlintide (substituted at three positions: proline instead of alanine/serine) is not amyloidogenic and stable in aqueous solution.
In 2005 pramlintide received FDA approval under the name Symlin — as add-on therapy for type-1 and insulin-treated type-2 diabetes. Clinical effects: small HbA1c reduction (0.3-0.5%), moderate weight reduction (1-3 kg), reduced postprandial glucose excursions. All of that was undeniably real — but compared with insulin optimisation alone, the additional benefit was small. Pramlintide required a separate subcutaneous injection before each meal in addition to insulin. This complexity, combined with the moderate effect, meant the substance never achieved broad use. Pramlintide remains on the market today, but as a niche therapy.
Cagrilintide: same hormone, new context
In the mid-2010s Novo Nordisk picked up the amylin line again — with two decisive changes. First: a new substance, cagrilintide, with extended half-life for weekly administration (vs. pramlintide's multi-daily injections). Second: cagrilintide was not primarily developed as monotherapy but as a combination partner with semaglutide — the combination is called CagriSema and has been in phase 3 since 2024 for obesity and diabetes.
The pharmacological logic is transparent: semaglutide acts via the GLP-1 receptor (central satiety plus glucagon suppression plus insulin stimulation), cagrilintide acts via the amylin receptor (gastric-emptying suppression plus glucagon modulation plus area-postrema satiety). The combination addresses two mechanistically distinct but complementary pathways — with the hypothesis of an additive or slightly synergistic effect on body weight.
„Amylin was for 30 years a hormone with clear biology and unclear clinical path. The combination with GLP-1 has resolved exactly this problem — not because amylin changed, but because the pharmacological context changed."
The first clinical signals
The REDEFINE trial series for CagriSema in obesity and type-2 diabetes has been completed or is still running in phase 3 since 2024. Early data points suggest weight reductions in the range of 20-25% over about 68 weeks — a magnitude comparable to tirzepatide monotherapy (SURMOUNT-1: 22.5%) and substantially exceeding semaglutide monotherapy (STEP-1: 14.9%). These data are preliminary and will be fully published in the coming quarters.
If the final endpoints confirm the early signals, CagriSema will become one of the most serious competitors for tirzepatide — and amylin will, almost 40 years after Cooper's first discovery, make a principal contribution in obesity pharmacology.
What the amylin story shows
Three methodological observations from this long line. First: a hormone that becomes productive in combination with another mechanism was not 'wrongly discovered' — it was tested in the wrong clinical context. Pramlintide as monotherapy add-on to insulin was a sensible idea but met an unfavourable market (complex application profile, small additional benefit). The same substance family in combination with GLP-1 meets a different market logic (one weekly injection, large effect size).
Second: pharmacological iteration happens not only at molecular level but also at indication and context level. The same hormone can move over 30 years from a clinically marginally useful therapeutic to a central component of a highly effective combination — without much change to the substance itself. Third: the iteration of the GLP-1 line is not complete with tirzepatide and retatrutide. CagriSema represents an alternative iteration line — not multiple receptors in one molecule, but multiple substances in a combination — and is methodologically a different lever.
Open questions
- Do the phase 3 data on CagriSema confirm early signals of tirzepatide-comparable or -exceeding efficacy?
- How does the safety profile of the combination compare with monotherapies — do gastrointestinal side effects add up?
- Will the 'combine multiple peptides' iteration line eventually be superior to the 'multiple receptors in one molecule' line (tirzepatide, retatrutide)?
- Which other co-secreted pancreatic peptides (pancreatic polypeptide, ghrelin) are under-explored as combinatorial therapeutics?