24th October 2024, A/Prof Chee L Khoo
We all know about how effective and potent the GLP1 agonists are in improving metabolic control in patients with T2D and obesity. We also know about how even more potent the new dual GIP/GLP1 agonist is in improving glycaemic control and losing body weight. There are further studies demonstrating their efficacy in reducing heart failure mortality, sleep quality in patients with obstructive sleep apnoea and liver fibrosis in patients with metabolic dysfunction associated fatty liver disease (MAFLD) (albeit in combination with other agents). There are other agents which combine GLP1 with glucagon agonist or GIP antagonists or both (so-called triple G agonists). The landscape is getting even more crowded with those agonists combining with an amylin receptor agonists. Cagrilintide in combination with semaglutide is undergoing Phase 3 trials in patients with T2D. We need to know what cagrilintide is.
Amylin has a strange bipolar existence in the body. You will remember amylin as the evil amyloid deposits in Alzheimer’s dementia. Yes, the same guy. It can aggregate into amyloid fibrils in the pancreatic beta-cells and cause damage leading to type 2 diabetes (T2D). The first description of amylin-derived deposits in pancreatic islets dates back to 1900 when “hyaline appearance” was reported within islets from diabetic patients (1). It was originally called insulinoma amyloid peptide (IAP), and was renamed later as islet amyloid polypeptide (IAPP) (2).
Amylin also plays a good guy role. It is actually a beta-cell product, just as insulin, and is in fact co-packed and co-released with insulin. It activates amylin receptors in the brain to produce effects on glucose metabolism and nutrient intake. Specifically, it can inhibit glucagon secretion, reduce gastric emptying and induce satiety, just like our incretins! It is here that it lends itself to be useful in weight and glucose lowering.
Amylin receptors
Amylin’s metabolic actions on the brain are mediated by direct activation of the central nervous system, in particular the area postrema (AP). The amylin receptors (AMY) in the brain consist of the calcitonin receptor core (CTR) which heterodimerizes with receptor-activity modifying proteins (RAMP) 1, 2 or 3 to form the AMY 1–3 receptors. The CTR core receptor changes its specificity and affinity for amylin depending on the co-expression of one of the three RAMPs in the same cell.
Amylin as an anti-obesity target
Many amylin analogues tested are dual agonists at the calcitonin and the amylin receptors because their in vitro characteristics imply the potential to activate both receptors. Human and rat calcitonin seems to have minor effect on eating while salmon calcitonin inhibit eating and strongly activate amylin receptors. The only approved amylin-based drug is the amylin analogue pramlintide which has similar characteristics and a similar pharmacodynamic and pharmacokinetic profile than (rat) amylin. Early studies had indicated a weight lowering profile of pramlintide but the absolute effect was modest. Pramlintide was approved for use in type 1 diabetes back in the 1990s but its use is limited because of its short half-life.
Cagrilintide is a nonspecific calcitonin and amylin agonist has been shown to produced sustained and marked weight loss. The effect on weight loss is even more potent when combined with semaglutide (CagriSema).
In a multicentre, double blind Phase 2 trial, 92 adults with T2D were randomly assigned to CagriSema 2.4mg/2.4mg, semaglutide 2.4mg, or cagrilintide 2.4mg (3). Adults with T2D were eligible for participation if they had a BMI of ≥27·0 kg/m2 and HbA1c between 7·5% – 10·0%, despite being treated with a stable daily dose of metformin with or without an SGLT2 inhibitor for at least 90 days before screening. After 32 weeks:
- The mean change in HbA1c from baseline to week 32 was -2.2% with CagriSema; -1.8% with semaglutide and -0.9% with cagrilintide.
- The mean change in bodyweight from baseline to week 32 was CagriSema: -15·6%; semaglutide: -5·1%; cagrilintide: -8·1%.
- The mean change in fasting plasma glucose from baseline to week 32 (CagriSema: -3·3 mmol/L; semaglutide: -2·5 mmol/L; cagrilintide: -1·7 mmol/L
- CGM Time in range (3·9-10·0 mmol/L) was 45·9%, 32·6%, and 56·9% at baseline and 88·9%, 76·2%, and 71·7% at week 32 with CagriSema, semaglutide, and cagrilintide, respectively.
Adverse events were reported by 21 (68%) participants in the CagriSema group, 22 (71%) in the semaglutide group, and 24 (80%) in the cagrilintide group. Mild or moderate gastrointestinal adverse events were most common; no level 2 or 3 hypoglycaemia was reported. No fatal adverse events were reported.
It would appear that the combination of Cagrilintide 2.4mg and semaglutide 2.4mg is more potent in losing weight, reducing glucose matrix and improving time in range in patients with T2D compared with semaglutide or cagrilintide on their own. This is a small Phase 2 trial. A large randomised controlled, Phase 3 trial is planned and will complete and report in early 2026.
Exciting times ahead.
References:
1. E.L. Opie, The relation oe diabetes mellitus to lesions OF the pancreas.
Hyaline degeneration OF the islands oe Langerhans. Journal of Experimental
Medicine, 5 (1901), pp. 527-540
2. P. Westermark, C. Wernstedt, E. Wilander, K. Sletten A novel peptide in the calcitonin gene related peptide family as an amyloid fibril protein in the endocrine pancreas Biochemical and Biophysical Research Communications, 140 (1986), pp. 827-831
3. Juan P Frias, Srikanth Deenadayalan, Lars Erichsen, Filip K Knop, Ildiko Lingvay, Stanislava Macura, Chantal Mathieu, Sue D Pedersen, Melanie Davies, Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial, The Lancet, Volume 402, Issue 10403, 2023,