🔍 Description:

Cagrilintide is a novel peptide analog that acts as a dual amylin and calcitonin receptor agonist (DACRA). It plays a crucial role in appetite suppression, slowing gastric emptying, and inhibiting glucagon secretion outside of hypoglycemic states. This peptide has emerged as a promising candidate in the treatment of obesity and metabolic disorders. It is currently being studied for its potential in weight loss, type 2 diabetes management, and metabolic improvement.

💡 What is it?

Cagrilintide, also known as AM833, NNC0174-0833, and GLXC-26801, is a synthetic peptide based on human amylin. Amylin is a hormone co-secreted with insulin from the pancreas, and it plays a key role in reducing glucagon levels after meals, slowing gastric emptying, and increasing satiety. Cagrilintide is designed to mimic these effects by interacting with both amylin and calcitonin receptors, thereby enhancing blood sugar regulation, digestive motility, and appetite control.

Development: Cagrilintide was developed by Novo Nordisk with specific amino acid substitutions to enhance receptor activity compared to naturally occurring amylin. The peptide also features a C-20 fatty diacid attachment that prolongs its half-life to up to 7.3 days, allowing for once-weekly subcutaneous injections.

🎯 Do you need it?

Cagrilintide is ideal for individuals seeking effective weight management strategies, particularly those struggling with obesity or metabolic disorders. It is especially useful when combined with other treatments, such as GLP-1 receptor agonists, to provide a comprehensive approach to metabolic health.

📝 How to use it:

– Dosage: Typically, Cagrilintide is administered via subcutaneous injection. Initial doses range from 0.1 mg to 0.3 mg per week, with gradual escalation based on tolerance and response. In clinical trials, a maximum weekly dose of 4.5 mg has been identified as safe.

 – Cycling: Continuous use is common, with regular assessment of ongoing needs and response. Cycling off every few months may be beneficial.

 – Administration: Administered once weekly via subcutaneous injection, usually in the abdomen or thigh. When combined with semaglutide, the dosing strategy might be adjusted for optimal results.

⚠️ Reasons not to use:

– Caution: Individuals with severe gastrointestinal disease or a history of gastroparesis should avoid Cagrilintide due to its effects on gastric emptying. Pregnant or breastfeeding individuals should consult a healthcare provider before use.

📊 Expected outcomes:

Users can expect a significant reduction in appetite, leading to decreased caloric intake and weight loss. Additionally, Cagrilintide may improve metabolic markers such as insulin sensitivity and blood glucose levels. When combined with GLP-1 receptor agonists like semaglutide, the peptide can produce enhanced weight loss and glycemic control.

🔍 What about GLP-1 agonists?

The combination of Cagrilintide with GLP-1 receptor agonists, such as semaglutide, creates a synergistic effect that further enhances weight loss and metabolic health. This combination addresses multiple pathways involved in appetite regulation and energy balance, making it a powerful therapeutic strategy.

🤝 Stacking with other peptides:

Cagrilintide pairs well with GLP-1 receptor agonists for synergistic effects on weight loss and metabolic control. It can also be stacked with other metabolic enhancers or appetite suppressants, but careful monitoring is required to avoid excessive appetite suppression and nutrient deficiency.

📚 References:

1. Dehestani B, Stratford NR, le Roux CW. “Amylin as a Future Obesity Treatment.” J Obes Metab Syndr. 2021.

2. Larsen AT, Sonne N, Andreassen KV, Karsdal MA, Henriksen K. “The Calcitonin Receptor’s Role in Glucose Regulation.” J Pharmacol Exp Ther. 2020.

3. Eržen S, Tonin G, Jurišić Eržen D, Klen J. “Amylin, Another Important Neuroendocrine Hormone for Diabesity Treatment.” Int J Mol Sci. 2024.

4. Melson E, Miras AD, Papamargaritis D. “Future Therapies for Obesity.” Clin Med (Lond).

2023.

5. Aroda VR, Blonde L, Pratley RE. “A New Era for Oral Peptides: SNAC and Semaglutide for Type 2 Diabetes.” Rev Endocr Metab Disord. 2022.

6. D’Ascanio AM, Mullally JA, Frishman WH. “Cagrilintide: A Long-Acting Amylin Analog for Obesity Treatment.” Cardiol Rev. 2024.

7. Züger D, Forster K, Lutz TA, Riediger T. “Amylin and GLP-1 Target Different Populations of Area Postrema Neurons.” Physiol Behav. 2013.

8. Boyle CN, Zheng Y, Lutz TA. “Mediators of Amylin Action in Metabolic Control.” J Clin Med. 2022.

9. Enebo LB, Berthelsen KK, Kankam M, Lund MT, Rubino DM, Satylganova A, Lau DCW. “Safety and Pharmacodynamics of Cagrilintide with Semaglutide.” Lancet. 2021.

10. Lau DCW, Erichsen L, Francisco AM, Satylganova A, le Roux CW, McGowan B, et al. “Once-Weekly Cagrilintide for Weight Management.” Lancet. 2021.

11. Frias JP, Deenadayalan S, Erichsen L, Knop FK, Lingvay I, et al. “Efficacy and Safety of Cagrilintide with Semaglutide in Type 2 Diabetes.” Lancet. 2023.

12. Chetty AK, Ra E, Bellini NJ, Buchholz N, Isaacs D. “A Review of Incretin Therapies for Obesity Management.” Endocr Pract. 2024.

13. ClinicalTrials.gov: REIMAGINE 1 https://clinicaltrials.gov/study/NCT06323174

14. ClinicalTrials.gov: REIMAGINE 3 https://clinicaltrials.gov/study/NCT06323161

15. ClinicalTrials.gov: REIMAGINE 2 https://clinicaltrials.gov/study/NCT06065540

Cagrilintide, a long-acting amylin analogue, is making waves in the world of weight management and type 2 diabetes treatment. While still under development, its promising results in clinical trials have sparked excitement. However, it’s essential to remember that I cannot provide medical advice and this information should not be taken as such. Always consult with your healthcare professional for diagnosis and treatment.

Understanding Cagrilintide:

Mimics natural amylin, a hormone regulating blood sugar and appetite.

Investigated for its potential to treat obesity and type 2 diabetes.

Exploring the Trials:

Obesity:

Phase 2: Evaluated different Cagrilintide doses for weight management in overweight/obese individuals.

Link: https://pubmed.ncbi.nlm.nih.gov/34798060/

Key findings: Significant weight loss compared to placebo, similar efficacy to other obesity drugs like tirzepatide.

Type 2 Diabetes:

Phase 2: Assessed Cagrilintide’s impact on blood sugar control and weight in individuals with type 2 diabetes.

Link: https://pubmed.ncbi.nlm.nih.gov/34798060/

Key findings: Improved blood sugar control, modest weight loss compared to obesity trials.

Combination Therapy:

CagriSema: Combines Cagrilintide with semaglutide (GLP-1 agonist).

Link: https://pubmed.ncbi.nlm.nih.gov/37364590/

Key findings: Greater weight loss compared to individual medications, improved blood sugar control compared to Cagrilintide alone.

Looking Ahead:

Phase 3 trials: Larger, longer-term studies are crucial for regulatory approval.

Combination therapy: Further exploration of CagriSema and other combinations is likely.

Specific patient populations: Identifying groups who benefit most from Cagrilintide is a potential area of focus.

Cagrilintide is not yet approved for any medical use.

Novo Nordisk Cagrilintide information: https://www.evaluate.com/vantage/articles/news/corporate-strategy/novo-fights-back

ClinicalTrials.gov: https://clinicaltrials.gov/ (Search for “Cagrilintide”)

Once-weekly cagrilintide for weight management in people with overw…

Novo Nordisk A/S.

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Efficacy and safety of co-administered once-weekly cagrilintide 2·4…

Novo Nordisk.

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Novo fights back

A day after Lilly’s strong clinical showing in obesity, Novo comes out swinging.

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ClinicalTrials.gov

👍

22

Wiki says the CagriSema is as effective as Tirz.   https://en.wikipedia.org/wiki/Cagrilintide/semaglutide

Cagrilintide/semaglutide

Cagrilintide/semaglutide, marketed as CagriSema, is a combination of cagrilintide, a dual amylin and calcitonin receptor agonist, and semaglutide, a GLP-1 agonist. It is injected once weekly and is being tested in type 2 diabetes and obesity. Preliminary trial results found a greater weight loss compared to either medication alone. HbA1c was sig…

5:22 PM

Here is the Phase II announcement. The CagriTirz, which is mentioned by a vendor, would be a unique formulation combining products from Novo and Lily. The idea would be that the benefits from CargriSema will also apply to combining cargrilintide with tirz, providing even more rapid weight loss. https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=131155

Candy benefits (or lack of side effects) compared to taking just Tirz or Reta?

There have been no studies with Tirz or Reta, just Sema. Here is one https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01163-7/abstract

Here is more detailed information, at least a bit:  https://www.medscape.com/viewarticle/951424

Semaglutide New Drug Combo Well-Tolerated, Leads to Weight Loss

A combination of cagrilintide with semaglutide in people with a BMI over 27 was well-tolerated, had a good safety profile, and led to more weight loss than semaglutide alone.

“Treatment with cagrilintide at all tested doses in combination with semaglutide 2.4 mg was generally well-tolerated with an acceptable safety profile,” say Enebo and coauthors, adding that no apparent difference was seen in the number of adverse events across treatment groups.

“The data support once-weekly dosing. The combination of cagrilintide 1.2, 2.4, or 4.5 mg plus semaglutide 2.4 mg led to greater weight loss compared with semaglutide 2.4 mg only.”

meph2u }:-)> 3/6/2024 3:34 PM

This makes it clear that 1) the dose was 2.4 Cagri and 2.4 Sema, and 2) that the titration for phase 2 was standard sema for weight loss: .25, .5, 1, 1.7 and 2.4. Thanks to Krysia on Peppys for finding the details.

meph2u }:-)> 3/11/2024 9:14 PM

Stacking Reta and Cagri is not fundamentally problematic. They are synergistic. Stay tuned for more information. (edited)

Primum Non Nocere 3/12/2024 10:25 PM

We are entering the Golden age of weight loss science, and potential compounds after compounds are being tested in the pipelines and there will be many coming in the next several years. Two of the more popular new players are: retatrutide, and most recently cagrilintide. These two are not even launched officially yet, and yet here we are playing research with them already. We are at the cutting edge. Without pun intended, “cutting edge” is a double-edged sword, if it works out then you are leading the pack, but at the same time it comes with a risk of spectacular failure. Without a doubt there will be many who will stack cagrilintide with any of the 3 popular GLP(s), or maybe even all of them. Obviously the only data that we have for cagrilintide is, at best, on phase 2 trial in combination with semaglutide. Even the phase 3 is still ongoing, we don’t have a full data yet. And rest assured that we will not have official data/study for Cagrilintide combined with Tirzepatide or retatrutide, due to pharmaceutical/financial interests, at least not for as long as they’re still under patent protection. So we will be left to our own devices for the foreseeable future. (edited)

Recently it has been brought to our attention that there was some concern about combining Cagrilintide with Retatrutide. The premise of the concern was that Retatrutide causes hepatic gluconeogenesis at the expense of adipose/fat (hence it is effective for fatty liver resolution), while Cagrilintide has inhibitory effect on gluconeogenesis, so on the surface it may seem that these two are working against each other. Since we will not have official clinical study for this combination, for now all we can do is to analyze it using theoretical model and extrapolating previous data of each. So take this analysis with a grain of salt. (edited)

We all know that retatrutide is a triple agonist, on GLP-1, GIP, and glucagon receptors. While Cagrilintide is an amylin mimetic. Most of us are already quite familiar with the mechanisms of action of these receptors so I won’t belabor it too much. Simply said:

GLP-1 pathway includes: increases satiety, decreases hunger, decreases gastric emptying, increases glucose uptake by cardiac and skeletal muscles, increases somatostatin, increases insulin secretion, and lastly, where we will focus our attention: decreases glucagon secretion

GIP pathway includes: a lot of similarities to GLP-1 above, with 1 notable difference, GIP increases glucagon secretion

Glucagon pathway includes: hepatic lipolysis + glycogenolysis leading to gluconeogenesis, skeletal muscle breakdown (at high doses), increases basal metabolic rate and HR

Amylin pathway includes: increases satiety, decreases gastric emptying, decreases postprandial glucagon secretion, but also increases muscle glycogenolysis and basal metabolic rate

So as you can see, there are lots of overlap and a few seemingly contradictory effects of all these receptors. And all these different drugs bind at these receptors with different affinities. And yet, they ultimately have similar results: weight loss, improved fatty liver, improved metabolic parameters (lipids, insulin sensitivity), and for reta and cagrilintide also increases basal metabolic rate. You cannot just focus on one particular aspect and disregard the rest. So the concern that reta is a terrible pair with cagrilintide based on the glucagon effect alone is…. an oversimplification at best, and an unfortunate misunderstanding and misapplication at worst. In fact, if this factor trumps everything else, then why does sema work well with reta for some people? Remember, sema and reta have opposite effects when it comes to glucagon. In fact, reta by itself has contradictory effects since it stimulates glucagon receptor but at the same time decreases glucagon via its GLP-1 mechanism. Perhaps lost in translation is the fact that glucagon and insulin, despite their opposite effects, work together to maintain balance. You don’t want one to excessively dominate the other. (edited)

So when it comes to reta + cagri, specifically on the glucagon-pathway effects, let’s summarize it one more time:

It has been floated out there that stacking Cagri and Reta is a terrible idea because reta works by pushing out fat as glucose while Cagri suppresses glucose release. This may seem true on the surface, because reta, via the glucagon receptor, stimulates gluconeogenesis at the expense of fat (for the most part) and to a small degree increases energy expenditure. While cagri, as an amylin mimic, can inhibit gluconeogenesis. However, this effect is pronounced only in cases of inappropriately high glucagon release after a meal (usually happens in diabetic patients). If you don’t have postprandial glucagon dysregulation, this effect is much less. Cagri also has other effects that are synergistic with reta (more specifically with the GLP component of reta), including slowing gastric emptying, increasing satiety perception (brain), and also increasing energy expenditure (probably by stimulating muscle glycogenolysis, converting muscle glycogen into glucose to be burned off, and also via the so-called “substrate cycling” effect, if you haven’t heard of this term, try looking it up, it’s a very interesting concept).

Please note that this is all theoretical. Cagri has not been tested with Reta (or Tirz), and any research done with these combinations is on the cutting edge.