Introduction
Obesity, characterized by abnormal or excessive fat accumulation, affects a significant portion of the global population. Defined as a chronic disease, obesity requires long-term management strategies. Fundamentally, obesity is caused by dysregulation of appetite control which then results in excess adipose tissue causing deterioration in health. One-third of the population suffers from obesity (body mass index, ≥30 kg/m2).1 Previously, the disease was not fully understood, and this resulted in a stigmatisation of people living with obesity.1 Homeostatic centres in the brain play a key regulatory role in hunger and satiety. The gastrointestinal system releases a plethora of satiety hormones in response to food intake.3 Hormones such as glucagon-like peptide 1 (GLP-1), oxyntomodulin, and islet amyloid polypeptide (amylin) relay signals to hypothalamic nuclei and other areas of the subcortical areas of the brain, resulting in feelings of increased fullness and satisfaction.4 Amylin receptors are located on specific nuclei of the dorsal-vagal-complex located within the hindbrain-the nucleus tractus solitarius (NTS), area postrema (AP), and dorsal motor nucleus of the vagus nerve.4 Amylin and the amylin receptors (AMYRs) have been identified as potential targets for treatment of obesity.
Amylin, a hormone co-secreted with insulin, plays a crucial role in glucose homeostasis and appetite regulation. This article explores the potential of amylin analogues as anti-obesity medications, analyzing their efficacy, potency, and safety, and also discusses the latest research and clinical trials.
Understanding Amylin and Its Role in the Body
Amylin is a 37-amino-acid polypeptide released from β pancreatic cells along with insulin in response to nutrient delivery to the small intestine. It acts as a satiety signal, influencing sub-cortical homeostatic and hedonic brain regions, slowing gastric emptying, and suppressing post-prandial glucagon responses to meals. Released from β pancreatic cells, amylin is a 37-amino-acid polypeptide co-secreted with insulin, playing a primary role in glucose homeostasis by slowing gastric emptying, suppressing glucagon secretion, and initiating an anorectic signal postprandially (Fig. 1).5-11 The synthetic amylin analogue pramlintide is an approved treatment for diabetes mellitus which promotes better glycaemic control and small but significant weight loss. Amylin functions as a satiety hormone. Released into the bloodstream by β pancreatic cells, amylin activates various homeostatic and reward centres in the brain to suppress appetite and reduce food intake. In addition, amylin acts as an inhibitory signal to delay gastric emptying and suppress the release of glucagon from α pancreatic cells. POMC, proopiomelanocortin; ARC, arcuate nucleus; BNST, bed nucleus of the stria terminalis; NTS, nucleus tractus solitarius; LPBN, lateral parabrachial nucleus; AP, area postrema.Therefore, newer pharmacological amylin analogues such as AM833 (cagrilintide), an investigational novel long-acting acylated amylin analogue, acts as a non-selective AMYR.
The Complex Structure of Amylin Receptors
Amylin functions as both a hormone and a neuropeptide, exerting its biological effects by activating amylin receptors (AMYRs) [33, 40,41,42,43]. AMYRs are complex structures belonging to the family of G protein-coupled receptors (GPCR) [40]. Each receptor is composed of the calcitonin (CT) receptor (CTR), which is a classic GPCR, combined with one of three receptor activity-modifying proteins (RAMPs), AMY1R, AMY2R and AMY3R [29, 33, 40, 44]. The pairing of the CTR with different RAMPs generates distinct AMYR subtypes with different pharmacological profiles and signaling properties [33, 44, 45]. The close relationship between AMYRs and CTRs complicates the understanding of their contributions to different physiological processes [33, 40, 43, 44]. AMYRs are widely distributed across the CNS and peripheral tissues [46] and are found in regions involved in satiety regulation and reward pathways, including the hypothalamus and distinct nuclei within the dorsal-vagal complex in the hindbrain, such as the area postrema (AP), nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagal nerve [46, 47]. Additionally, AMYRs are found in areas connected to cognition, such as the hippocampus and cortex [46, 48]. Beyond the CNS, AMYRs are present in multiple peripheral tissues, including the lung, spleen, liver, gastric fundus, duodenum, jejunum, kidney, testes and bone [46].
Amylin's Role in Glucose Regulation
Amylin plays a critical role in regulating postprandial glucose [29]. While supraphysiological insulin concentrations can achieve glucagon suppression, amylin potently suppresses meal-induced glucagon secretion at physiologically relevant concentrations [29]. By inhibiting glucagon secretion postprandially, amylin suppresses glucagon-stimulated hepatic gluconeogenesis and glycogenolysis, thereby reducing postprandial endogenous glucose production or glucose spikes [50, 51]. This glucagon-static action seems to be centrally mediated and is attenuated during low glucose values, ensuring proper contra-regulatory glucagon response in case of hypoglycemia [29, 32].
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Through its direct action on AMYRs in the AP, amylin correspondingly slows gastric emptying, which delays the inflow of nutrients into the small intestine and slows the absorption of glucose into the circulation [32, 51, 52]. Additionally, gastric-wall distension generates an anorectic signal transmitted to the nucleus of the solitary tract via gastric vagal and splanchnic afferents, which impacts glucose homeostasis [38]. Since this anorectic action depends on the glycemic state, it is reversed during hypoglycemia [32, 53].
Amylin's Impact on Weight Management
Amylin is physiologically involved in the control of eating, energy expenditure and body weight [29]. It plays a key role in regulating satiety as it affects both the homeostatic and hedonic aspects of eating [63]. Amylin primarily binds to receptors in the AP, initiating signals that are relayed to the NTS and lateral parabrachial nucleus (LPBN) [47, 64]. These signals are further transmitted to the amygdala, the bed nucleus of the stria terminalis and various hypothalamic nuclei, all of which are areas with critical roles in the regulation of energy metabolism [47, 64]. Additionally, amylin binds to receptors in the arcuate nucleus, possibly activating the proopiomelanocortin (POMC) neurons which have a key role in satiety induction and reduction of food intake [47]. Amylin promotes meal-ending satiation and dose-dependently reduces meal size and length, which leads to …
Amylin Analogues: Promising Anti-Obesity Medications
Amylin analogues are synthetic versions of the amylin hormone designed to overcome the limitations of native amylin, such as its short half-life and tendency to self-aggregate.
Pramlintide: An Approved Amylin Analogue
The synthetic amylin analogue pramlintide is an approved treatment for diabetes mellitus which promotes better glycaemic control and small but significant weight loss. As amylin is an incretin hormone, pramlintide was developed to treat hyperglycaemia in both type 1 and type 2 diabetes mellitus (T2DM) patients.25 As such, the use of pramlintide in this context is associated with a reduction in glycosylated hemoglobin (HbA1c) as well as modest weight loss.26-28 To this end, early clinical trials demonstrated a decrease in body weight in people with obesity when treated with pramlintide (Table 1).12,29,30 In individuals with suboptimal glycaemic control in the setting of type 1 diabetes mellitus, pramlintide successfully lowered HbA1c through inhibition of glucagon secretion (a native hormone that liberates glucose from glycogen stores in the body). The most common adverse events associated with pramlintide are gastrointestinal side-effects, particularly mild to moderate nausea which typically is temporary, dose-dependent, and easily managed.
To overcome this, pramlintide, a long acting synthetic analogue, was developed with proline substitutions at positions 25, 28, and 29 to prevent aggregation.23,24 As such, the use of pramlintide in this context is associated with a reduction in glycosylated hemoglobin (HbA1c) as well as modest weight loss.26-28 To this end, early clinical trials demonstrated a decrease in body weight in people with obesity when treated with pramlintide (Table 1).12,29,30
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AM833 (Cagrilintide): A Novel Long-Acting Amylin Analogue
AM833 (cagrilintide) is a new investigational drug that exhibited some promising results in a recently completed phase II clinical trial for treatment of obesity.15 In this 26-week blinded phase 2 monotherapy trial, 706 people with obesity or overweight with at least one weight-related comorbidity and without history of diabetes were randomized to six active treatment arms including once-weekly cagrilintide at one of five doses (0.3, 0.6, 1.2, 2.4, or 4.5 mg; n=100-102 per arm), once-daily liraglutide 3.0 mg (n=99), or their volume-matched placebo arms (n=101). Cagrilintide resulted in more significant weight loss at all doses (0.3-4.5 mg, 6.0%-10.8% [6.4-11.5 kg]) versus placebo (3.0% [3.3 kg], P<0.001) and at 4.5 mg doses versus liraglutide 3.0 mg (10.8% [11.5 kg] vs. From a structural viewpoint, AM833 (cagrilintide) is very similar in sequence to pramlintide with differences in lipidation of the N-terminal lysine as well as substitutions of three amino acids (N14E, V17R, and P37Y) responsible for AM833 (cagrilintide), a non-selective AMYR and CTR agonist that can dually activate both class of receptors. Clinical trials on AM833 (cagrilintide) have demonstrated its safe and well-tolerated profile.
Petrelintide (ZP8396): A Novel Amylin and Calcitonin Receptor Agonist
Petrelintide (ZP8396) is a 36-amino-acid acylated peptide, based on the peptide sequence of human amylin [21] with chemical and physical stability at neutral pH, minimizing fibrillation [22]. Petrelintide showed potent balanced agonistic effects on both amylin and calcitonin receptors, being in clinical development for once-weekly subcutaneous (SC) administration as a monotherapy [23], for the treatment of overweight and obesity.
A 16-week treatment with petrelintide at maintenance doses of up to 9.0 mg demonstrated a favorable safety and tolerability profile. Gastrointestinal adverse events were mostly mild, transient, and occurred during dose escalation, with only one participant discontinuing treatment due to gastrointestinal symptoms after the third dose. Additionally, no antidrug antibodies were detected. Petrelintide exhibited dose proportionality across the full range tested, supporting its suitability for once-weekly dosing.
Clinically meaningful body weight reductions were observed, with petrelintide achieving up to -8.6% weight loss compared to -1.7% with placebo after 16 weeks. These results position petrelintide as a rising star in the treatment of obesity, offering efficacy comparable to current GLP-1 receptor agonists but with superior tolerability.
Combination Therapies: Enhancing Weight Loss Outcomes
Given the complex interplay of hormones involved in appetite regulation, combination therapies involving amylin analogues and other agents, such as GLP-1 agonists, are being explored to achieve greater weight loss.
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Amylin and GLP-1 Agonists: A Synergistic Approach
GLP-1 is a 37-amino acid peptide hormone released by enteroendocrine L cells of the distal small intestine in response to intraluminal contents.31 Known for their incretin effects, synthetic GLP-1 analogues, namely liraglutide and semaglutide, have been developed for treatment of T2DM and obesity.32,33 Like amylin, GLP-1 is a potent satiety hormone, acting on receptors in the ARC in the hypothalamus, the AP, and other appetite centres within the subcortical areas of the brain.34 GLP-1- and amylin receptor analogue-dependent weight loss are mediated through both distinct and overlapping neural pathways. To this end, combined therapy might yield a synergistic effect with respect to both glycaemic control and weight loss.
An AM833 (cagrilintide) and semaglutide phase 1 combination trial over 20 weeks 14 tested six dosages of AM833 (cagrilintide; 0.16, 0.3, 0.6, 1.2, 2.4, and 4.5 mg) versus placebo, alone and in combination with once-weekly subcutaneous semaglutide 2.4 mg. The drugs were administered in 95 individuals who were obese or classified as overweight (0.16-2.4 mg group, n=12; 4.5 mg group, n=11) or placebo (n=24). At week 20, participants given cagrilintide 0.16-2.4 mg in combination with semaglutide 2.4 mg had achieved weight loss from 8.3% to 17.1%.
The preliminary results of recent clinical trials support the benefits of combination therapy of amylin analogues with GLP-1 agonists to achieve greater weight loss in comparison with mono-therapy.
Challenges and Future Directions
While amylin analogues hold great promise, several challenges need to be addressed:
- Complex Receptor Biology: Amylin receptors are complex, and a better understanding of their activation is needed for developing more targeted drugs.
- Limitations of Animal Models: Research relies heavily on animal models, which may not fully reflect human physiology.
- Amyloidogenic Properties: Amylin's tendency to form amyloid fibrils needs to be carefully considered in drug development.
- Pharmacokinetic Challenges: Improving the stability and delivery of amylin analogues is crucial.
Current research focuses on:
- Enhancing amylin stability through various modifications.
- Developing oral amylin formulations for improved patient convenience.
- Exploring combination therapies targeting multiple receptors in metabolic pathways.