Approved Anti-Obesity Medications in 2022 KSSO Guidelines and the Promise of Phase 3 Clinical Trials: Anti-Obesity Drugs in the Sky and on the Horizon.
Jeon. Eonju E; Lee. Ki Young KY; Kim. Kyoung-Kon KK
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Cagrilintide
AM-833, Long-acting amylin analogue
A long-acting amylin receptor agonist used for obesity and type 2 diabetes treatment by enhancing satiety, reducing food intake, and aiding weight loss.
In adults with overweight or obesity, weekly subcutaneous cagrilintide-semaglutide increased weight loss at 68 wk.
Agarwal. Arnav A; Padwal. Raj R
GIM/FP/GP: [Formula: see text].
Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity.
Eržen. Stjepan S; Tonin. Gašper G; Jurišić Eržen. Dubravka D; Klen. Ja...
Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has emerged. The gut-brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from β-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.
The promise of glucagon-like peptide 1 receptor agonists (GLP-1RA) for the treatment of obesity: a look at phase 2 and 3 pipelines.
Madsbad. Sten S; Holst. Jens J JJ
GLP-1-based therapies have changed the treatment of overweight/obesity. Liraglutide 3.0 mg daily, the first GLP-1 RA approved for treatment of overweight, induced a weight loss of 6-8%, Semaglutide 2.4 mg once weekly improved weight loss to about 12-15%, while the dual GIP/GLP-1 receptor agonist tirzepatide once weekly has induced a weight loss of about 20% in obese people without diabetes. This review describes results obtained with GLP-1 mono-agonists, GLP-1/GIP dual agonists, GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GIP/GLP-1/glucagon), which have shown beneficial effect both on body weight and steatotic liver disease. A combination of semaglutide (a GLP-1 agonist) and cagrilintide (a long-acting amylin analogue) for weekly administration is currently in phase III development, and so is oral semaglutide and several non-peptide small molecule GLP-1 agonists for oral administration. The adverse events with the GLP-1-based therapies are primarily gastrointestinal and include nausea, vomiting, obstipation, or diarrhea, which often can be mitigated by slow up titration. The GLP-1-based therapies will change the treatment of obesity and its comorbidities including steatotic liver disease in the future. Outstanding question is maintenance of the weight loss, possibly pharmacological treatment needs to be life-long.
Efficacy and safety of GLP-1RAs for people with obesity: A systematic review based on RCT and Bayesian network meta-analysis.
Li. Hong H; Yu. Guanzheng G; Huang. Qi Q; Yang. Bao B; Nie. Juan J; Liu. Yinbei Y; Tu. Xing X
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Comparative Effectiveness of Semaglutide, Liraglutide, Orlistat, and Phentermine for Weight Loss in Obese Individuals: A Systematic Review.
Patel. Jay P JP; Hardaswani. Daksh D; Patel. Jaykumar J; Saiyed. Faizanali F; Goswami. Rushita J RJ;...
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Amylin receptors as therapeutic targets in obesity: Emerging peptide-based strategies.
Rejili. Mokhtar M; Hussain. Md Sadique MS; Khan. Yumna Y; Haouala. Faouzi F; Ganesan. Subbulakshmi S...
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Weight management treatment in obesity.
Rubio-Herrera. Miguel A MA; Mera-Carreiro. Sara S
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Amylin and the renin-angiotensin system: risk or opportunity in amylin-based therapy?
Muskiet. Marcel H A MHA; Nardone. Massimo M; Rensen. Patrick C N PCN; Cherney. David Z I DZI; Cooper...
We hypothesise that amylin receptor agonists (eg, pramlintide) and dual amylin and calcitonin-receptor agonists (eg, cagrilintide), which are emerging treatments for obesity and type 2 diabetes, can activate the renin-angiotensin system (RAS) and potentially undermine the cardiorenal benefits of these therapies. Paradoxically, new-generation amylin-based therapies, such as CagriSema, showed substantial blood pressure reductions in phase 3 trials. Beyond amylin's weight loss-mediated effects, we hypothesise that concurrent use of RAS inhibitors (angiotensin-converting enzyme [ACE] inhibitors or angiotensin-receptor blockers) redirects amylin-induced RAS activation towards the protective alternative RAS pathway, which is characterised by vasodilatory, anti-inflammatory, and antiproliferative effects via Mas receptors, potentially explaining part of their therapeutic benefit and cardioprotective and renoprotective potential. To test this, we propose: (1) preclinical studies investigating amylin-RAS interactions with or without RAS blockade; (2) post-hoc analyses of phase 2/3 trials stratified by RAS inhibitor use; (3) biomarker studies monitoring renin, aldosterone, angiotensin-(1-7), and ACE2; and (4) mechanistic human studies prospectively assessing cardiovascular-kidney metabolic effects by RAS inhibitor status. These suggestions aim to determine whether RAS inhibition enhances the overall efficacy of amylin-based therapies, and whether RAS blockers should be strongly recommended in patients receiving them.
Cardiovascular effects of incretin-based drugs in patients with and without a history of heart failure: a protocol for a systematic review, meta-analysis and trial sequential analysis of randomised controlled trials.
El-Sheikh. Mohammed M; Sillassen. Christina Dam Bjerregaard CDB; Wisborg. Frederik Dencker FD; Hove....
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Drugs for Treating Obesity.
Ryan. Donna H DH
Older medications approved for chronic weight management (orlistat, naltrexone/bupropion, liraglutide 3 mg and, in the USA, phentermine/topiramate) have not been widely adopted by health care providers. Those medications produce only modest additional weight loss when used to augment lifestyle intervention. However, semaglutide 2.4 mg weekly has recently emerged and produces much more weight loss - on average 15% weight loss at 1 year. Semaglutide's enhanced efficacy and that its class (GLP-1 receptor analogs) is well-known may result in more clinicians adopting pharmacotherapy. Furthermore, the first dedicated cardiovascular outcome trial powered for superiority testing an anti-obesity medication (SELECT) is underway with semaglutide 2.4 mg. A positive outcome will further promote the concept that weight management should be a primary target for cardiometabolic disease control. In phase 3, tirzepatide and cagrilintide/semaglutide combination are showing promise for even greater weight loss efficacy. Another recently approved medication takes a personalized medicine approach; setmelanotide is approved as a therapy for those with some of the ultra-rare genetic diseases characterized by severe, early onset obesity. This chapter reviews the currently available and anticipated medications for chronic weight management as well as those approved for the genetic and syndromic obesities.
Amylin as a Future Obesity Treatment.
Dehestani. Babak B; Stratford. Nicholas Rs NR; le Roux. Carel W CW
Obesity is defined as abnormal or excessive fat accumulation that contributes to detrimental health impacts. One-third of the population suffers from obesity, and it is important to consider obesity as a chronic disease requiring chronic treatment. Amylin is co-secreted with insulin from β pancreatic cells upon nutrient delivery to the small intestine as a satiety signal, acts upon sub-cortical homeostatic and hedonic brain regions, slows gastric emptying, and suppresses post-prandial glucagon responses to meals. Therefore, new pharmacological amylin analogues can be used as potential anti-obesity medications in individuals who are overweight or obese. In this narrative review, we analyse the efficacy, potency, and safety of amylin analogues. The synthetic amylin analogue pramlintide is an approved treatment for diabetes mellitus which promotes better glycaemic control and small but significant weight loss. AM833 (cagrilintide), an investigational novel long-acting acylated amylin analogue, acts as a non-selective amylin receptor. This calcitonin G protein-coupled receptor agonist can serve as an attractive novel treatment for obesity, resulting in reduction of food intake and significant weight loss in a dose-dependent manner.
The Obesity Paradox of Cardiovascular Outcomes in Patients with Diabetes Mellitus.
Thakker. Janki J; Khaliq. Isna I; Ardeshna. Nelish S NS; Lavie. Carl J CJ; Oktay. Ahmet Afsin AA
The paper reviews the so‑called “obesity paradox,” where people with diabetes and heart disease who are a bit overweight sometimes seem to have better survival than leaner patients. It points out that this may be due to study biases, the limits of BMI, and where fat is stored, rather than a true protective effect of extra weight.
Nutritional Challenges in Post-Massive Weight Loss Body Contouring: Guidance for Plastic Surgeons on GLP-1 Agonists and Sleeve Gastrectomy.
Mehta. Meeti M; Rometo. David D; Gusenoff. Jeffrey J; Rubin. J Peter JP
The paper talks about how people who lose a lot of weight after bariatric surgery often have trouble getting enough protein and vitamins, especially if they are also taking appetite‑suppressing drugs like semaglutide or tirzepatide. It gives surgeons advice on how to make sure these patients eat enough protein and fix nutrient gaps before and after body‑contouring surgery.
Long-acting amylin analogues for the management of obesity.
Mathiesen. David S DS; Bagger. Jonatan I JI; Knop. Filip K FK
To summarize recent developments of long-acting amylin analogues for the treatment of obesity and to outline their mode of action. Amylin is a pancreatic hormone acting to control energy homeostasis and body weight. Activity at the calcitonin and amylin receptors in the area postrema seems to - at least partly - be responsible for these effects of amylin. Both preclinical and early-stage clinical studies investigating long-acting amylin receptor analogues demonstrate beneficial effects on body weight in obesity. Cagrilintide, a novel amylin analogue suitable for once-weekly administration, is in phase II clinical development and has shown promising body weight reducing effects alone and in combination with the glucagon-like peptide 1 receptor agonist semaglutide. Long-acting amylin analogues have emerged as a possible pharmacotherapy against obesity, but more studies are needed to support the utility and long-term effects of this strategy in relevant populations.
Identifying adults at high-risk for change in weight and BMI in England: a longitudinal, large-scale, population-based cohort study using electronic health records.
Katsoulis. Michail M; Lai. Alvina G AG; Diaz-Ordaz. Karla K; Gomes. Manuel M; Pasea. Laura L; Banerj...
This study looked at who in England is most likely to gain weight over 1, 5, and 10 years, using health records. It found that young adults (18‑24) are far more likely to move from normal weight to overweight or obesity than older adults, and that social deprivation, sex, and ethnicity have much smaller effects.
Creating the amylin story.
Lutz. Thomas A TA
This paper is based on a presentation given at the Annual Meeting of the Society for the Study of Ingestive Behavior in July 2021 and provides a personal view on some of the milestones in the discovery of amylin as a constituent of pancreatic islet amyloid deposits, as a pancreatic beta-cell hormone, and on its role in physiology and pathophysiology. Only selected effects of amylin are discussed here because we recently published extensive reviews on the physiology and pathophysiology of amylin. Amylin was discovered as the main constituent of islet amyloid that is predominantly found in pancreatic islets in type 2 diabetics. These deposits, and in particular small oligomer aggregates of amylin seem to contribute to the progressive beta-cell damage seen in type 2 diabetics. Amylin is also a physiologically relevant circulating hormone with diverse metabolic functions, e.g. inhibition of eating, of pancreatic glucagon secretion and of gastric emptying. Knowledge of these types of functions and amylin's mechanisms of action lead to the development of amylin analogues that are now among the most promising anti-obesity targets in clinical testing. With this review, I want to give a short overview of 35 exciting years of amylin research.