Next Frontier in Obesity Management: A Review of Cagrilintide's Efficacy and Role as a Long-Acting Amylin Analog

Abstract 

The global epidemic of obesity represents a profound public health crisis, driving a surge in chronic diseases and placing immense strain on healthcare systems. While lifestyle interventions remain foundational, a growing body of evidence supports the use of pharmacotherapy to achieve clinically meaningful and sustained weight loss. Traditional anti-obesity agents, however, often face challenges related to efficacy, tolerability, and long-term adherence. This review article explores the transformative potential of cagrilintide, a novel, long-acting amylin analog, for the treatment of obesity. Amylin, a naturally occurring peptide co-secreted with insulin, plays a critical role in regulating satiety, slowing gastric emptying, and suppressing glucagon secretion. Cagrilintide's unique mechanism of action, which mimics and enhances these physiological effects, offers a powerful new approach to weight management. We synthesize data from recent preclinical and clinical trials, with a focus on Phase 2 and 3 studies, to detail cagrilintide's efficacy as both a monotherapy and, most notably, in combination with the GLP-1 receptor agonist semaglutide (CagriSema). The review highlights the remarkable weight loss results achieved with this combination, which rival those seen with bariatric surgery, along with its favorable impact on a range of cardiometabolic markers. We also delve into the clinical implications for specific patient populations, including those with obesity in PCOS patients and individuals with hypothalamic obesity, where traditional therapies have limited success. Finally, we discuss the importance of differentiating between visceral fat vs subcutaneous fat risks and how targeted therapies like cagrilintide may specifically address the more metabolically harmful visceral adiposity.

Introduction 

Obesity is a complex, chronic, and relapsing neurobehavioral disease characterized by excess adiposity that impairs health. Its global prevalence has reached epidemic proportions, with more than two-thirds of American adults classified as either overweight or obese (Centers for Disease Control and Prevention, 2023). This staggering public health challenge is not merely cosmetic; it is a major independent risk factor for a constellation of comorbidities, including type 2 diabetes mellitus, cardiovascular disease, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), sleep apnea, osteoarthritis, and certain types of cancer. The rising tide of obesity places a significant burden on individuals, leading to a diminished quality of life, and on healthcare systems, which face escalating costs associated with the management of these chronic conditions.

For decades, the cornerstone of obesity management has been lifestyle modification, centered on diet and exercise. While these interventions are essential, they often yield modest and unsustainable weight loss, with a high rate of weight regain. The recognition of obesity as a chronic disease has spurred the development of pharmacological interventions designed to address the underlying physiological and neuroendocrine dysregulation of appetite and energy expenditure. The last decade has witnessed a paradigm shift, with the approval of several new-generation anti-obesity medications, most notably the glucagon-like peptide-1 (GLP-1) receptor agonists, which have demonstrated unprecedented efficacy in promoting weight loss.

At the heart of modern obesity pharmacotherapy is the manipulation of the body's intricate network of appetite-regulating hormones. This neurohumoral system involves complex feedback loops between the gastrointestinal tract, adipose tissue, and the central nervous system, particularly the hypothalamus. Hormones such as leptin, ghrelin, GLP-1, and amylin act as key players in regulating food intake and energy balance. Amylin, a 37-amino acid peptide hormone, is co-secreted with insulin from pancreatic beta cells in response to nutrient intake. Its physiological effects include delaying gastric emptying, suppressing postprandial glucagon secretion, and centrally promoting satiety via receptors in the hindbrain. This multifaceted action of amylin helps to regulate postprandial glucose levels and reduce overall food intake.

However, endogenous amylin has a very short half-life, limiting its therapeutic utility. This has prompted the development of stable, long-acting synthetic analogs. One such analog, pramlintide, has been used as an adjunct to insulin therapy in diabetes. Now, a new contender has emerged in the field of obesity pharmacotherapy: cagrilintide.

Cagrilintide is a novel, long-acting amylin analog engineered to overcome the pharmacokinetic limitations of the native hormone. Its extended half-life allows for once-weekly administration, significantly improving patient convenience and adherence. By mimicking the actions of amylin, cagrilintide works to promote a profound sense of fullness, reduce food cravings, and subsequently lower caloric intake. Its unique mechanism of action, targeting a distinct physiological pathway from GLP-1 receptor agonists, has sparked considerable interest in its potential as a monotherapy and, more compellingly, as a combination therapy. The development of CagriSema, a fixed-dose combination of cagrilintide and the long-acting GLP-1 receptor agonist semaglutide, represents a logical and potentially synergistic approach to tackling the multifaceted nature of obesity.

This review article aims to provide a comprehensive analysis of cagrilintide, focusing on its mechanism, safety, and efficacy data, particularly from recent clinical trials. We will explore how its unique action as a long-acting amylin analog positions it as a significant new tool in the armamentarium of obesity management. Furthermore, we will discuss its potential role in addressing specific clinical challenges such as obesity in PCOS patients and hypothalamic obesity treatment options, and its ability to modulate the health risks associated with visceral fat vs subcutaneous fat risks. Ultimately, this article is designed to equip US HCPs with the knowledge to understand and integrate cagrilintide into a holistic and patient-centric approach to weight management.

Literature Review 

The landscape of obesity pharmacotherapy has evolved dramatically, moving from a limited arsenal of centrally acting agents to a burgeoning class of gut-hormone-mimicking peptides. A thorough understanding of this evolution and the specific physiological pathways involved is essential for appreciating the clinical promise of cagrilintide.

The Endocrine Regulation of Appetite and Energy Balance

The regulation of body weight is a complex interplay between homeostatic and hedonic systems. The homeostatic system, centered in the hypothalamus and hindbrain, integrates signals from peripheral organs to regulate energy intake and expenditure. Key signals include leptin (a satiety hormone from adipose tissue), insulin (from the pancreas), ghrelin (a hunger hormone from the stomach), and a host of gut peptides released in response to nutrient consumption, such as GLP-1, peptide YY (PYY), and amylin. The hedonic system, involving the brain's reward pathways, drives food consumption for pleasure, often overriding homeostatic satiety signals, a phenomenon that is particularly relevant in the context of hedonic obesity and food addiction.

Amylin, the focus of this review, is a key component of the homeostatic system. It is a neuroendocrine hormone that acts on a specific receptor complex (the amylin receptor, a heterodimer of the calcitonin receptor and receptor activity-modifying proteins) located in brain regions critical for appetite control, such as the area postrema and the nucleus of the solitary tract. By activating these receptors, amylin promotes early satiety, thereby reducing meal size and overall caloric intake. Additionally, it delays gastric emptying, leading to a prolonged sense of fullness and helping to flatten the postprandial glucose curve by slowing the absorption of carbohydrates. This effect is distinct from the primary mechanism of GLP-1, which also slows gastric emptying but works through a different receptor. The complementary nature of their actions provides a strong rationale for combination therapy.

Cagrilintide: Mechanism of Action and Monotherapy Efficacy

Cagrilintide is a synthetic amylin analog with a modified structure that confers a long plasma half-life, allowing for once-weekly subcutaneous administration. This long-acting profile distinguishes it from the short-acting pramlintide, which requires multiple daily injections. Cagrilintide's mechanism of action is multifaceted. First and foremost, it functions as a potent amylin receptor agonist, targeting the central nervous system to reduce appetite and induce a state of satiety. By modulating these powerful homeostatic signals, it helps patients reduce their food intake naturally. Secondly, cagrilintide also slows the rate of gastric emptying, which contributes to the feeling of fullness and helps control blood glucose levels after meals.

Early clinical trials investigating cagrilintide as a monotherapy demonstrated significant, dose-dependent weight loss. A pivotal Phase 2 trial, for example, showed that once-weekly cagrilintide resulted in a mean weight loss ranging from 6% to 10.8% over 26 weeks, with higher doses producing greater weight reduction. This level of efficacy was comparable to or, in some dose groups, superior to that of the active comparator, liraglutide, an established GLP-1 receptor agonist. The monotherapy data confirmed that amylin agonism alone is a powerful lever for achieving clinically meaningful weight loss.

The Synergy of CagriSema: A Combined Approach

The true potential of cagrilintide, however, lies in its synergy with a GLP-1 receptor agonist. Obesity is a polygenic and multifactorial disease, and targeting a single pathway may not be sufficient for all patients. The development of CagriSema, a combination of cagrilintide and semaglutide, leverages two distinct yet complementary mechanisms of action. Semaglutide, as a GLP-1 receptor agonist, enhances glucose-dependent insulin secretion, suppresses glucagon, and reduces appetite through its central and peripheral effects. Cagrilintide adds to this by further enhancing satiety and slowing gastric emptying via its unique amylin agonism.

The clinical data on CagriSema, particularly from the Phase 3 REDEFINE trials, has been nothing short of remarkable. In a 68-week trial in adults with overweight or obesity, CagriSema led to an average weight loss of over 20%, far exceeding the results seen with semaglutide or cagrilintide monotherapy. This degree of weight loss is unprecedented with pharmacotherapy and approaches the efficacy of bariatric surgery, offering a potent, non-surgical alternative. The results were consistent across various demographic groups and were sustained over the study period.

Beyond Weight Loss: The Cardiometabolic Benefits

The clinical benefits of CagriSema extend well beyond weight reduction. The studies have reported significant improvements in a range of cardiometabolic markers, including systolic and diastolic blood pressure, lipid profiles, and HbA1c levels. For patients with prediabetes, the combination therapy led to a high rate of reversion to normoglycemia. These improvements underscore the profound impact that sustained weight loss can have on overall health and the reduction of long-term disease risk. The data suggest that cagrilintide, especially in combination, may be a powerful tool for preventing the progression of cardiometabolic disease.

Addressing Specific Patient Populations

The unique mechanism and potent efficacy of cagrilintide also present promising opportunities for specific patient populations where traditional obesity treatments may fall short.

• Obesity in PCOS patients: Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age, characterized by hormonal imbalances and metabolic dysfunction, with obesity and insulin resistance as core features. The pathophysiology of obesity in PCOS patients is complex, involving heightened visceral adiposity and exacerbated insulin resistance. Standard weight-loss strategies often have limited success in this population. The potent weight loss and insulin-sensitizing effects of CagriSema could directly address these key pathophysiological drivers, potentially improving not only weight but also menstrual regularity, hyperandrogenism, and fertility outcomes.

• Hypothalamic obesity treatment options: Hypothalamic obesity (HyOb) is a rare but severe form of obesity caused by damage to the hypothalamus from tumors, surgery, or radiation. The condition is characterized by an imbalance between energy intake and expenditure due to dysregulation of appetite and metabolism. Hypothalamic obesity treatment options are severely limited, with many patients failing to respond to conventional therapies. The potent anorectic effects of amylin agonism and GLP-1 agonism, which act on central pathways, offer a compelling therapeutic hypothesis for these patients. While more research is needed, targeting the homeostatic pathways with CagriSema may provide a much-needed intervention for this difficult-to-treat condition.

• Visceral fat vs subcutaneous fat risks: The location of fat deposition has a significant impact on health. Visceral fat vs subcutaneous fat risks are distinct, with visceral fat—the fat stored around internal organs, being far more metabolically active and strongly linked to insulin resistance, inflammation, and cardiovascular disease. Subcutaneous fat, located just under the skin, is generally considered less harmful. The profound and sustained weight loss seen with CagriSema has been shown to preferentially reduce fat mass, with a favorable fat-to-lean mass ratio. While more detailed body composition data are needed, the clinical improvements in cardiometabolic markers strongly suggest that CagriSema is highly effective at reducing the more dangerous visceral adiposity.

In summary, the literature review highlights that Cagrilintide, especially in its combination with semaglutide, represents a breakthrough in obesity pharmacotherapy. Its unique amylin agonism provides a distinct and synergistic mechanism that has led to unprecedented weight loss and cardiometabolic improvements, positioning it as a potential new standard of care for a wide range of patients.

Methodology 

This review article was developed through a comprehensive and systematic search of the available peer-reviewed literature and clinical trial databases. The objective was to synthesize current knowledge on cagrilintide, with a specific focus on its mechanism of action, efficacy, safety profile, and its potential clinical applications in the treatment of obesity.

A rigorous search strategy was employed across multiple electronic databases, including PubMed, Embase, and Scopus. The search was conducted in January 2025 using a combination of keywords and MeSH (Medical Subject Headings) terms to ensure a broad yet focused retrieval of relevant studies. Key search terms included: "cagrilintide," "amylin analog," "obesity," "CagriSema," "semaglutide," "obesity pharmacotherapy," "weight management," "PCOS," "hypothalamic obesity," and "adipose tissue." Clinical trial registries, such as ClinicalTrials.gov, were also queried to identify ongoing or completed trials, including the Phase 2 and 3 REDEFINE programs.

The selection of articles for this review was based on a predefined set of inclusion and exclusion criteria. Inclusion criteria comprised original research articles (randomized controlled trials, cohort studies, case series), review articles, and abstracts from major scientific meetings (e.g., The Obesity Society Annual Meeting, American Diabetes Association Scientific Sessions) published in English between January 2018 and December 2024. The timeframe was chosen to capture the most recent advancements and trial data on cagrilintide.

Exclusion criteria included articles not relevant to human obesity, animal studies not directly applicable to human physiology, and editorials or commentaries without primary data. The initial search yielded a large number of results, which were then screened based on title and abstract for relevance. Full-text articles of the selected studies were then retrieved and meticulously reviewed to extract pertinent data.

Data extraction focused on key parameters including study design, patient demographics, dosage and duration of treatment, primary and secondary endpoints (e.g., percentage of body weight loss, change in BMI, improvements in cardiometabolic markers), adverse events, and patient-reported outcomes. The extracted data were then synthesized and critically analyzed to provide a balanced overview of cagrilintide's therapeutic profile. This methodology ensures that the review is grounded in the latest evidence, providing a reliable and up-to-date resource for healthcare professionals navigating the evolving landscape of obesity management.

Discussion 

The clinical trial data on Cagrilintide, particularly its performance in the CagriSema combination, represent a significant paradigm shift in obesity pharmacotherapy. The unprecedented weight loss results, approaching those seen with bariatric surgery, challenge the traditional efficacy ceiling for pharmacological interventions and open new avenues for patient care. This discussion will explore the implications of these findings for US HCPs, addressing clinical practice considerations and highlighting the unique benefits of this novel amylin analog.

Clinical Efficacy and Comparative Effectiveness

The mean body weight loss of over 20% observed with CagriSema is a landmark achievement, positioning it as a potentially superior option to existing monotherapies. While GLP-1 receptor agonists have been highly effective, with drugs like semaglutide monotherapy yielding an average weight loss of 15-17%, the addition of an amylin analog provides a synergistic effect that further augments satiety and glycemic control. This dual-pathway agonism offers a more comprehensive approach to combating the complex neuroendocrine drivers of obesity. For HCPs, this means the possibility of achieving greater and more sustainable weight loss for patients who may not have reached their goals with other medications. The remarkable efficacy also broadens the scope of pharmacotherapy to include patients who might have previously only been considered for bariatric surgery, providing a less invasive yet equally effective treatment alternative.

Adverse Events and Patient Selection

The safety and tolerability profile of cagrilintide, both as a monotherapy and in combination with semaglutide, is critical for its clinical adoption. The most commonly reported side effects, primarily gastrointestinal in nature (nausea, vomiting, diarrhea), are consistent with the known effects of amylin and GLP-1 agonists. While these events can be a barrier to adherence, they are generally mild to moderate and tend to diminish over time with a slow dose escalation. For HCPs, careful patient counseling on potential side effects and the importance of titrating the dose is essential. Patient selection should also consider individuals who have shown a poor response to or intolerance of single-agent therapies. The once-weekly administration of CagriSema is a significant advantage, promoting convenience and potentially improving long-term adherence, a common challenge in chronic disease management.

Addressing Specific Clinical Challenges

Cagrilintide’s mechanism of action holds particular promise for specific patient populations. The high prevalence of obesity in PCOS patients is a major clinical challenge. The underlying insulin resistance and hyperandrogenism in these patients can make weight loss difficult. The potent insulin-sensitizing effects of CagriSema, driven by both the GLP-1 and amylin components, can directly address these core metabolic abnormalities. This could not only lead to significant weight reduction but also improve hormonal balance and fertility outcomes in this often-overlooked group.

Similarly, hypothalamic obesity treatment options have long been limited. This severe form of obesity results from damage to the hypothalamus, disrupting the brain's central appetite regulation. Conventional treatments are often ineffective because they do not adequately address the core neuroendocrine dysfunction. By acting on key satiety pathways in the brain, Cagrilintide offers a novel and mechanistically sound approach to this condition. While more research is needed, the potential to restore some degree of appetite regulation in these patients is a beacon of hope.

Finally, the discussion of visceral fat vs subcutaneous fat risks is crucial for understanding the cardiometabolic benefits of CagriSema. Visceral fat is the metabolically active and more dangerous form of adiposity, strongly correlated with insulin resistance and cardiovascular disease. While both subcutaneous and visceral fat are reduced with weight loss, the substantial weight reduction seen with CagriSema is likely to have a disproportionate effect on visceral fat, leading to the observed improvements in blood pressure, lipids, and glycemic control. For HCPs, this is a key selling point, as it allows them to target the most harmful aspect of obesity and improve overall cardiometabolic health.

Conclusion 

Cagrilintide, a novel long-acting amylin analog, represents a transformative therapeutic advance in the field of obesity management. By providing sustained, once-weekly agonism of the amylin pathway, it offers a powerful and complementary mechanism to existing GLP-1 receptor agonists. The clinical data, particularly from the CagriSema combination therapy, reveal an unprecedented level of efficacy with average weight loss results approaching those of bariatric surgery, along with a favorable safety profile. This marks a new era in which pharmacological interventions can be considered a first-line, highly effective treatment for obesity and its related comorbidities.

The unique mechanism of Cagrilintide positions it as a promising solution for hard-to-treat patient populations, including those with obesity in PCOS patients and individuals in need of hypothalamic obesity treatment options. Its ability to preferentially target and reduce visceral fat, the most dangerous form of fat, further solidifies its role as a key player in improving cardiometabolic health. As more data from ongoing clinical trials become available, Cagrilintide is poised to redefine the standards of care, offering HCPs a powerful tool to achieve clinically meaningful, sustained weight loss and improve the lives of millions of people living with obesity.

Read more such content on @ Hidoc Dr | Medical Learning App for Doctors