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What Is Cagrilintide?
Cagrilintide is a long-lasting synthetic version of amylin, a natural peptide released alongside insulin by the pancreas. Studies in animals suggest it could help treat obesity and type 2 diabetes. It has also been explored for its potential to address liver damage, alcohol-related liver disease, and heart or blood vessel conditions. While there’s some interest in its possible role in Alzheimer’s disease, no studies have been published on this topic yet. Many trials have focused on combining cagrilintide with semaglutide to treat obesity and type 2 diabetes, showing that the two peptides work together to produce stronger, longer-lasting weight loss effects.
Sequence: XKCNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP
Molecular Formula: C194H312N54O59S2.xC2H4O2
Molecular Weight: 4409.01 g/mol
PubChem SID: 171397054
CAS Number: 1415456-99-3
Synonyms: AT42613, AM833[1]
Cagrilintide Origin: What Is Amylin?
Amylin, also known as islet amyloid polypeptide (IAPP), is a natural peptide released with insulin from the pancreas's beta cells. It plays a key role in the brain by creating feelings of fullness. Amylin starts as a larger 89-amino-acid propeptide and is processed into a smaller 37-amino-acid active form, released at about a 100:1 ratio with insulin.
Amylin has several effects: it slows digestion, promotes a sense of fullness in the brain, and helps prevent sharp rises in blood sugar after eating. This allows the body to use sugar for energy rather than storing it as fat. Amylin also affects bone health by encouraging calcium storage in bones, which may help protect them from breaking down. It shares similarities with calcitonin and CGRP, other peptides that lower blood calcium by promoting its uptake in bones. Its impact on calcium loss through the kidneys is still unclear.
In animal studies where the amylin gene was turned off, animals ate less and consumed fewer calories. Amylin is broken down by the same enzymes that degrade insulin. Unlike natural amylin, cagrilintide is designed to resist these enzymes, giving it a longer duration of action and stronger effects.
There's also a possible link between amylin and Alzheimer's disease. Too much amylin, often seen in insulin resistance and diabetes, can lead to the formation of fibrils (protein clumps). These may interact with amyloid beta in the brain, potentially contributing to Alzheimer's-related plaques, though a direct connection hasn't been proven.
What Is Cagrilintide?
Cagrilintide is a synthetic version of amylin designed to resist breakdown by enzymes in the blood, giving it a longer-lasting effect. It's not the first amylin-based drug—pramlintide, developed in the early 2000s, was used alongside insulin to reduce blood sugar spikes in diabetes, allowing for lower insulin doses. Cagrilintide stands out due to its much longer half-life.
Beyond lasting longer, cagrilintide avoids a problem with natural amylin: protein clumping. When amylin levels are too high, it can form clumps that make it ineffective and may harm pancreatic beta cells, potentially worsening type 2 diabetes. This clumping is similar to the amyloid beta plaques seen in Alzheimer's disease. Scientists modified amylin to create cagrilintide by adding proline residues to prevent clumping, an amide residue to improve receptor binding, and a fatty acid to help it reach the brain more effectively. These changes allow cagrilintide to bind better to RAMP-1 and RAMP-3 receptors, which work with other receptors to influence functions related to heart disease, diabetes, and possibly cancer, though the exact roles are still being studied.
How Does Cagrilintide Work?
Cagrilintide works in several ways. In the stomach and intestines, it slows food movement, signaling fullness to the brain and reducing hunger, which leads to less food intake. Slower digestion also reduces blood sugar spikes, allowing the body to process sugar more efficiently and store less as fat.
In the brain, cagrilintide binds to amylin receptors in the arcuate nucleus, which connects to the brainstem and pituitary gland to promote feelings of fullness and reduce the urge to eat. In the pancreas, it acts like amylin by reducing glucagon release, which helps prevent sugar from being converted into fat.
The Research on Obesity
Two major trials highlight cagrilintide's effects. In one, weekly doses led to 6-11% body weight loss over six weeks compared to a placebo, outperforming liraglutide, another weight-loss drug, with similar side effects. In another trial, combining cagrilintide with semaglutide resulted in even greater weight loss—up to 17.1% over 20 weeks. This is more than the sum of their individual effects, suggesting they work together synergistically. For a 200-pound person, that's 34 pounds lost in just five months.
Diabetes
Cagrilintide and similar drugs like pramlintide can significantly reduce insulin resistance and lower hemoglobin A1C levels by blocking glucagon release. Studies show a 2.2% drop in A1C levels in a short time. Cagrilintide's weekly dosing makes it more convenient and effective, providing steady blood sugar control and sustained appetite reduction for weight loss.
Alzheimer's Disease
High blood sugar is linked to memory and attention problems, even in younger people with diabetes. It can damage brain cells, increase inflammation, and cause oxidative stress, contributing to cognitive decline, heart disease, and kidney issues. Studies, like one over four years with elderly women, show that consistently high blood sugar raises the risk of mild cognitive impairment and dementia. High blood sugar may also lead to lower glucose levels in the brain, which relies on glucose for energy, and insulin resistance in the brain is a key factor in cognitive issues tied to diabetes.
Amylin levels also affect brain function. Both very high and very low levels are linked to cognitive problems and a higher risk of Alzheimer's disease, according to data from the Framingham Heart Study. Amylin shares traits with amyloid beta, the main component of Alzheimer's plaques, as both cross the blood-brain barrier, have similar structures, bind to the same receptors, and are broken down by the same enzyme. Research shows a strong link between blood amylin levels and amyloid plaque precursors in the brain, even when accounting for factors like age, gender, and diabetes severity. In mouse studies, synthetic amylin cleared amyloid plaques from the brain, increasing blood levels of amyloid. Too much amylin may form clumps that block its ability to enter the brain, potentially allowing amyloid beta to build up.
While more research is needed, cagrilintide and similar peptides may hold promise for preventing or treating Alzheimer's disease and other forms of dementia, but no studies have yet explored cagrilintide's specific role in this area.
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