Amylin Analog Research Articles

A Cross-Species Atlas of the Dorsal Vagal Complex Reveals Neural Mediators of Cagrilintide's Effects on Energy Balance.

Amylin analogs, including potential anti-obesity therapies like cagrilintide, act on neurons in the brainstem dorsal vagal complex (DVC) that express calcitonin receptors (CALCR). These receptors, often combined with receptor activity-modifying proteins (RAMPs), mediate the suppression of food intake and body weight. To understand the molecular and neural mechanisms of cagrilintide action, we used single-nucleus RNA sequencing to define 89 cell populations across the rat, mouse, and non-human primate caudal brainstem. We then integrated spatial profiling to reveal neuron distribution in the rat DVC. Furthermore, we compared the acute and long-term transcriptional responses to cagrilintide across DVC neurons of rats, which exhibit strong cagrilintide responsiveness, and mice, which respond poorly to cagrilintide over the long term. We found that cagrilintide promoted long-term transcriptional changes, including increased prolactin releasing hormone (Prlh) expression, in the nucleus of the solitary tract (NTS) Calcr/Prlh cells in rats, but not in mice, suggesting the importance of NTS Calcr/Prlh cells for sustained weight loss. Indeed, activating rat area postrema Calcr cells briefly reduced food intake but failed to decrease food intake or body weight over the long term. Overall, these results not only provide a cross-species and spatial atlas of DVC cell populations but also define the molecular and neural mediators of acute and long-term cagrilintide action.

Development of the novel amylin and calcitonin receptor activators by peptide mutagenesis

The amylin peptide hormone receptor is the complex of the calcitonin peptide hormone receptor and an accessory protein. The calcitonin receptor activation controls calcium homeostasis, while it also functions as the main component of the amylin receptor. Amylin receptor activation in brains controls blood glucose and appetite. Currently, non-selective amylin and calcitonin receptor activators have been tested for body weight reduction to treat obesity. Here, multiple peptide activators for human amylin and calcitonin receptors were developed by introducing comprehensive mutagenesis to rat amylin peptide. The rat amylin peptide C-terminal fragment that interacts with amylin receptor extracellular domain was used to screen for affinity-enhancing mutations. Up to twelve mutational combinations were found to significantly increase peptide affinity both for amylin and calcitonin receptor extracellular domains by over 100-fold. Using these affinity-enhancing mutations, three representative rat amylin analogs with thirty-seven amino acids were made to test the potency increase for amylin and calcitonin receptor activation. All three mutated rat amylin analogs showed significant potency increases by 5- to 10-fold compared to endogenous rat amylin. These mutated peptide activators also showed higher potency for human amylin and calcitonin receptor activation than a clinically available amylin receptor activator pramlintide. These amylin and calcitonin receptor activators developed in this study may be useful as the valuable pharmacological tools that activate amylin receptors in cell-based systems.

Insights from microcanonical thermostatistics into amylin analogues and amyloid-$${\upbeta }$$ cross-seeding

Insights from microcanonical thermostatistics into amylin analogues and amyloid-$${\upbeta }$$ cross-seeding

Unlocking the Potential: Amylin-Based Therapies as Novel Interventions for Addressing the Nexus of Obesity and Cardiovascular Health

The rising prevalence of obesity and cardiovascular diseases demands innovative therapeutic strategies. This paper explores the potential of amylin-based therapies in addressing the intricate interplay between obesity and cardiovascular health. Amylin, a hormone co-secreted with insulin, regulates glucose metabolism, appetite, and gastric emptying. Despite its established role in diabetes management, recent research highlights its promise in addressing obesity. Pramlintide, a synthetic amylin analog, emerges as a promising intervention for obesity, overcoming limitations of current treatments. Cardiovascular diseases, closely linked to obesity, prompt exploration of amylin's potential cardiovascular benefits. The study examines vasodilatory effects, anti-inflammatory properties, and anti-atherosclerotic effects associated with amylin. Amylin-based therapies, including pramlintide and the investigational drug AM833 (cagrilintide), are scrutinized for their impact on blood pressure, lipid profiles, and cardiovascular markers. Beyond weight loss, the study explores changes in body composition, insulin sensitivity, and lipid metabolism. The safety profile of amylin analogs, particularly pramlintide, is discussed, emphasizing their generally well-tolerated nature with manageable gastrointestinal side effects. In conclusion, amylin-based therapies present a novel approach to address the complex connections between obesity and cardiovascular diseases. The study highlights their potential in modifying body composition, improving metabolic parameters, and influencing cardiovascular outcomes. As research progresses, amylin-based strategies may offer innovative approaches to enhance metabolic and cardiovascular health, potentially reducing the global burden of cardiovascular diseases.

Novel Pharmaceuticals in Appetite Regulation: Exploring emerging gut peptides and their pharmacological prospects.

Obesity, a global health challenge, necessitates innovative approaches for effective management. Targeting gut peptides in the development of anti-obesity pharmaceuticals has already demonstrated significant efficacy. Ghrelin, peptide YY (PYY), cholecystokinin (CCK), and amylin are crucial in appetite regulation offering promising targets for pharmacological interventions in obesity treatment using both peptide-based and small molecule-based pharmaceuticals. Ghrelin, a sole orexigenic gut peptide, has a potential for anti-obesity therapies through various approaches, including endogenous ghrelin neutralization, ghrelin receptor antagonists, ghrelin O-acyltransferase, and functional inhibitors. Anorexigenic gut peptides, peptide YY, cholecystokinin, and amylin, have exhibited appetite-reducing effects in animal models and humans. Overcoming substantial obstacles is imperative for translating these findings into clinically effective pharmaceuticals. Peptide YY and cholecystokinin analogues, characterized by prolonged half-life and resistance to proteolytic enzymes, present viable options. Positive allosteric modulators emerge as a novel approach for modulating the cholecystokinin pathway. Amylin is currently the most promising, with both amylin analogues and dual amylin and calcitonin receptor agonists (DACRAs) progressing to advanced stages of clinical trials. Despite persistent challenges, innovative pharmaceutical strategies provide a glimpse into the future of anti-obesity therapies.

NN1213 - A Potent, Long-Acting, and Selective Analog of Human Amylin.

Amylin, a member of the calcitonin family, acts via amylin receptors in the hindbrain and hypothalamus to suppress appetite. Native ligands of these receptors are peptides with short half-lives. Conjugating fatty acids to these peptides can increase their half-lives. The long-acting human amylin analog, NN1213, was generated from structure-activity efforts optimizing solubility, stability, receptor affinity, and selectivity, as well as in vivo potency and clearance. In both rats and dogs, a single dose of NN1213 reduced appetite in a dose-dependent manner and with a long duration of action. Consistent with the effect on appetite, studies in obese rats demonstrated that daily NN1213 dosing resulted in a dose-dependent reduction in body weight over a 21-day period. Magnetic resonance imaging indicated that this was primarily driven by loss of fat mass. Based on these data, NN1213 could be considered an attractive option for weight management in the clinical setting.

Obesity management for the treatment of type 2 diabetes: emerging evidence and therapeutic approaches.

Excess adiposity can contribute to metabolic complications, such as type 2 diabetes mellitus (T2DM), which poses a significant global health burden. Traditionally viewed as a chronic and irreversible condition, T2DM management has evolved and new approaches emphasizing reversal and remission are emerging. Bariatric surgery demonstrates significant improvements in body weight and glucose homeostasis. However, its complexity limits widespread implementation as a population-wide intervention. The identification of glucagon-like peptide 1 (GLP-1) and the development of GLP-1 receptor agonists (GLP-1RAs) have improved T2DM management and offer promising outcomes in terms of weight loss. Innovative treatment approaches combining GLP-1RA with other gut and pancreatic-derived hormone receptor agonists, such as glucose-dependant insulinotropic peptide (GIP) and glucagon (GCG) receptor agonists, or coadministered with amylin analogues, are demonstrating enhanced efficacy in both weight loss and glycemic control. This review aims to explore the benefits of bariatric surgery and emerging pharmacological therapies such as GLP-1RAs, and dual and triple agonists in managing obesity and T2DM while highlighting the caveats and evolving landscape of treatment options.

Narrative literature review of antidiabetic drugs' effect on hyperuricemia: elaborating actual data and mechanisms.

To optimize the treatment plan for patients with type 2 diabetes mellitus (T2DM) and hyperuricemia, this narrative literature review summarizes the effect of antidiabetic drugs on serum uric acid (SUA) levels using data from observational studies, prospective clinical trials, post hoc analyses, and meta-analyses. SUA is an independent risk factor for T2DM, and evidence has shown that patients with both gout and T2DM exhibit a mutually interdependent effect on higher incidences. We find that insulin and dipeptidyl peptidase 4 inhibitor (DPP-4i) except linagliptin could increase the SUA and other drugs including metformin, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), linagliptin, sodium-glucose cotransporter 2 inhibitors (SGLT2i), and α-glucosidase inhibitors have a reduction effect on SUA. We explain the mechanisms of different antidiabetic drugs above on SUA and analyze them compared with actual data. For sulfonylureas, meglitinides, and amylin analogs, the underlying mechanism remains unclear. We think the usage of linagliptin and SGLT2i is the most potentially effective treatment of patients with T2DM and hyperuricemia currently. Our review is a comprehensive summary of the effects of antidiabetic drugs on SUA, which includes actual data, the mechanisms of SUA regulation, and the usage rate of drugs.

Identification of potential DPP-4 inhibitors from Bryophyllum pinnatum by in-silico analysis

Background: An estimated 463 million people already live with diabetes and that figure is set to rise to over 700 million by 2045, as per the International Diabetes Federation (IDF). The current form of treatment for Type-2 DM can be done with sulfonylureas, meglitinides, metformin, thiazolidinediones, incretin mimetics: Glucagon-like peptide 1 (GLP-1), Glucose-dependent insulinotropic polypeptide (GIP), and amylin analogues (Pramlintide). Bryophyllum pinnatum (Lam.) Oken (B. pinnatum) belongs to the plant family crassulaceae used in traditional medicine in Asia. GLP-1 and Glucose-dependant Insulinotropic Polypeptide (GIP), both play a similar role in stimulating insulin secretion and are inactivated by dipeptidyl peptidase-4 (serine protease dipeptidyl peptidase-4) enzymes. Aims: To identify the potential anti-diabetic active compounds of Bryophyllum pinnatum against DPP-4 enzyme using in-silico methods. Methods and Material: The phytochemicals associated with Bryophyllum pinnatum were retrieved from ChEBI and canonical SMILES retrieved, followed by searching for its molecular properties and druglikeness using MolSoft LLC, toxicity test using ADVERPred, Swiss Target Prediction for predicting the DPP-4 inhibitors, molecular docking using Schrodinger software suite. Results: The in-silico study identified two phytochemicals from fourteen that have been predicted for DPP-4 inhibition potential against Type-2 DM. In CH2CL2 and CH3OH solvent compounds 3,5-dihydroxybenzoic acid (-5.623 kcal/mol) and 3,4-didehydro-N4-deethylbrinzolamide (-4.91 kcal/mol) displayed the highest docking scores against human DPP-4 (5Y7K). Conclusions: The above-mentioned compounds revealed no side effects. The in-silico results strongly favour the beneficial use of phytochemicals from Bryophyllum pinnatum as a probable herb that can be used for adjuvant therapy. Further in-vitro and in-vivo tests are needed for confirmation.

Chronic pramlintide decreases feeding via a reduction in meal size in male rats

Amylin, a pancreatic hormone, is well-established to suppress feeding by enhancing satiation. Pramlintide, an amylin analog that is FDA-approved for the treatment of diabetes, has also been shown to produce hypophagia. However, the behavioral mechanisms underlying the ability of pramlintide to suppress feeding are unresolved. We hypothesized that systemic pramlintide administration in rats would reduce energy intake, specifically by reducing meal size. Male rats were given b.i.d. administration of intraperitoneal pramlintide or vehicle for 1 week, and chow intake, meal patterns, and body weight were monitored throughout the test period. Consistent with our hypothesis, pramlintide decreased chow intake mainly via suppression of meal size, with corresponding reductions in meal duration on several days. Fewer effects on meal number or feeding rate were detected. Pramlintide also reduced weight gain over the 1-week study. These results highlight that the behavioral mechanisms by which pramlintide produces hypophagia are similar to those driven by amylin itself, and provide important insight into the ability of this pharmacotherapy to promote negative energy balance over a period of chronic administration.

Recent advances in peptide-based therapies for obesity and type 2 diabetes

Options for the treatment of type 2 diabetes mellitus (T2DM) and obesity have recently been expanded by the results of several large clinical trials with incretin-based peptide therapies. Most of these studies have been conducted with the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, which is available as a once weekly subcutaneous injection and once daily tablet, and the once weekly injected dual agonist tirzepatide, which interacts with receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In individuals with T2DM these therapies have achieved reductions of glycated haemoglobin (HbA1c) by >2% and lowered body weight by >10%. In some studies, these agents tested in non-diabetic, obese individuals at much higher doses have lowered body weight by >15%. Emerging evidence suggests these agents can also offer cardio-protective and potentially reno-protective effects. Other incretin-based peptide therapies in early clinical development, notably a triple GLP-1/GIP/glucagon receptor agonist (retatrutide) and a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), have shown strong efficacy. Although incretin therapies can incur adverse gastrointestinal effects these are for most patients mild-to-moderate and transient but result in cessation of treatment in some cases. Thus, the efficacy of new incretin-based peptide therapies is enhancing the opportunity to control body weight and blood glucose and improve the treatment of T2DM and obesity.

Risks and Benefits of SGLT-2 Inhibitors for Type 1 Diabetes Patients Using Automated Insulin Delivery Systems-A Literature Review.

The primary treatment for autoimmune Diabetes Mellitus (Type 1 Diabetes Mellitus-T1DM) is insulin therapy. Unfortunately, a multitude of clinical cases has demonstrated that the use of insulin as a sole therapeutic intervention fails to address all issues comprehensively. Therefore, non-insulin adjunct treatment has been investigated and shown successful results in clinical trials. Various hypoglycemia-inducing drugs such as Metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, amylin analogs, and Sodium-Glucose Cotransporters 2 (SGLT-2) inhibitors, developed good outcomes in patients with T1DM. Currently, SGLT-2 inhibitors have remarkably improved the treatment of patients with diabetes by preventing cardiovascular events, heart failure hospitalization, and progression of renal disease. However, their pharmacological potential has not been explored enough. Thus, the substantial interest in SGLT-2 inhibitors (SGLT-2is) underlines the present review. It begins with an overview of carrier-mediated cellular glucose uptake, evidencing the insulin-independent transport system contribution to glucose homeostasis and the essential roles of Sodium-Glucose Cotransporters 1 and 2. Then, the pharmacological properties of SGLT-2is are detailed, leading to potential applications in treating T1DM patients with automated insulin delivery (AID) systems. Results from several studies demonstrated improvements in glycemic control, an increase in Time in Range (TIR), a decrease in glycemic variability, reduced daily insulin requirements without increasing hyperglycemic events, and benefits in weight management. However, these advantages are counterbalanced by increased risks, particularly concerning Diabetic Ketoacidosis (DKA). Several clinical trials reported a higher incidence of DKA when patients with T1DM received SGLT-2 inhibitors such as Sotagliflozin and Empagliflozin. On the other hand, patients with T1DM and a body mass index (BMI) of ≥27 kg/m2 treated with Dapagliflozin showed similar reduction in hyperglycemia and body weight and insignificantly increased DKA incidence compared to the overall trial population. Additional multicenter and randomized studies are required to establish safer and more effective long-term strategies based on patient selection, education, and continuous ketone body monitoring for optimal integration of SGLT-2 inhibitors into T1DM therapeutic protocol.

Oral delivery of the amylin receptor agonist pramlintide

AbstractAmylin receptor agonism safely benefit diabetic patients, reducing the insulin requirements and glycemic excursions. Pramlintide is the triple proline human amylin analogue first used as injectable drug, but lacking physico‐chemical compatibility when co‐formulated with insulin. Here, we report the design and characterization of polymeric microparticles for oral delivery of pramlintide. Eudragit S100, a gastric‐resistant polymer, was used in preparation of pramlintide‐loaded spherical microcapsules by double emulsion and solvent evaporation technique, with approximately 66 μm ± 11 particle size, with 83.2% ± 2.7 efficiency for pramlintide entrapment and 67.6% ± 2.1 yield. Intra‐venous pramlintide free in solution showed a plasmatic half‐life of 6.8 min in mice. In contrast, oral delivery of acid‐resistant pramlintide‐loaded microparticles in mice showed a protracted release for 120 min compared to 30 min obtained for pramlintide in solution. Our data provide evidences for the potential use of the oral route in the therapeutic development of pramlintide formulations.

Postprandial glucose-management strategies in type 1 diabetes: Current approaches and prospects with precision medicine and artificial intelligence.

Postprandial glucose control can be challenging for individuals with type 1 diabetes, and this can be attributed to many factors, including suboptimal therapy parameters (carbohydrate ratios, correction factors, basal doses) because of physiological changes, meal macronutrients and engagement in postprandial physical activity. This narrative review aims to examine the current postprandial glucose-management strategies tested in clinical trials, including adjusting therapy settings, bolusing for meal macronutrients, adjusting pre-exercise and postexercise meal boluses for postprandial physical activity, and other therapeutic options, for individuals on open-loop and closed-loop therapies. Then we discuss their challenges and future avenues. Despite advancements in insulin delivery devices such as closed-loop systems and decision-support systems, many individuals with type 1 diabetes still struggle to manage their glucose levels. The main challenge is the lack of personalized recommendations, causing suboptimal postprandial glucose control. We suggest that postprandial glucose control can be improved by (i) providing personalized recommendations for meal macronutrients and postprandial activity; (ii) including behavioural recommendations; (iii) using other personalized therapeutic approaches (e.g. glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter inhibitors, amylin analogues, inhaled insulin) in addition to insulin therapy; and (iv) integrating an interpretability report to explain to individuals about changes in treatment therapy and behavioural recommendations. In addition, we suggest a future avenue to implement precision recommendations for individuals with type 1 diabetes utilizing the potential of deep reinforcement learning and foundation models (such as GPTand BERT), employing different modalities of data including diabetes-related and external background factors (i.e. behavioural, environmental, biological and abnormal events).

A Narrative Review Unveiling Novel Molecular Targets in Advancing Antidiabetic Medications: An Emerging Perspective

Diabetes Mellitus (DM) is a persistent metabolic disorder characterised by elevated glucose concentration in blood. Approximately, 422 million individuals globally suffer from diabetes, with the majority residing among middle-class and lower-class countries as per the reports of World Health Organisation (WHO) 2023. Strict blood sugar control in conjunction with high-dose insulin therapy might potentially prevent or delay the progression of microvascular issues, lower overall mortality, and lessen the chance of macrovascular problems. These conclusions were supported by the Diabetes Control and Complications Trial and the large longitudinal investigation known as the epidemiology of diabetes and its complications. Numerous drugs and receptors involved in glucose metabolism are currently being used to treat diabetes, including α-Glucosidase inhibitors, dopamine D-2 agonists, biguanides, glinides, amylin analogues, Peroxisome Proliferator-activated Receptors (PPARs), Glucagon-like Peptide-1 (GLP-1), and biguanides. Due to the associated side effects and the financial difficulties in obtaining traditional antidiabetic regimens, the current review has placed a higher priority on investigating novel molecular targets for the development of antidiabetic medications intended to manage the progression of the illness. This emphasises how important it is to find new molecular targets associated with the illness’s onset instead of only treating its symptoms or outward signs.

A review on the use of adjunctive therapies in artificial pancreas systems

Artificial Pancreas systems facilitate glucose management for people with Type 1 Diabetes (T1D). However, insulin action is sometimes not enough to counteract every disturbance. One approach devoted to improving these systems consists of introducing additional control actions to the system that either act in the opposite direction to insulin or modify the system's dynamics to ease the control task, for instance, by attenuating disturbances, such as meals. The main representative of these systems would be insulin-plus-glucagon strategies. However, recent advances have introduced other hormones, such as pramlintide (an amylin analog), in closed-loop systems. Also, drugs developed for the treatment of Type 2 Diabetes have drawn attention to be used concomitantly with insulin delivery in T1D, such as GLP-1 receptor agonists, SGLT2 inhibitors, Metformin, etc. This work presents a summary of the most representative drugs being researched as adjunctive therapies in T1D and a qualitative review of their presence alongside AP systems. These therapies have diverse effects, and they provide some improvement to the patients’ glucose metrics, but they still require further pharmaceutical developments since most present several adverse effects.

The Insulin Sensitizer KBP-336 Prevents Diabetes-Induced Cognitive decline in ZDF Rats.

Diabetes and especially insulin resistance are associated with an increased risk of developing cognitive dysfunction, making anti-diabetic drugs an interesting therapeutic option for the treatment of neurodegenerative disorders. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on glycemic control and insulin sensitivity. However, whether DACRAs affect cognition is unknown. Zucker Diabetic Fatty rats were treated with either the DACRA KBP-336 (4.5 nmol/kg Q3D), the amylin analog AM1213 (25 nmol/kg QD), or vehicle for 18 weeks. Further, the efficacy of a late KBP-336 intervention was evaluated by including a group starting treatment on day 30. Glucose control and tolerance were evaluated throughout the study and spatial learning and memory were evaluated by Morris Water Maze after 17 weeks of treatment. When evaluating spatial learning, rats receiving KBP-336 throughout the study performed significantly better than AM1213, vehicle, and late intervention KBP-336. Both KBP-336 and AM1213 treatments improved spatial memory compared to the vehicle. The overall performance in the cognitive tests was reflected in the treatment efficacy on glycemic control, where KBP-336 was superior to AM1213. In summary, the DACRA KBP-336 ameliorates diabetes-induced spatial learning and memory impairment in diabetic rats. Further, KBP-336 improves long-term glycemic control superior to the amylin analog AM1213. Taken together, KBP-336 is, due to its anti-diabetic and insulin-sensitizing properties, a promising candidate for the treatment of cognitive impairments.

Appetite and its Regulation: Are there Palatable Interventions for Heart Failure?

Obesity is a major driver of heart failure (HF) incidence, and aggravates its pathophysiology. We summarized key reported and ongoing randomized clinical trials of appetite regulation and/or dietary energy restriction in individuals with HF. Weight loss can be achieved by structured supervised diet programs with behavioural change, medications, or surgery. The new glucagon-like peptide-1 receptor agonists alone or in combination with other agents (e.g., glucose-dependent insulinotropic polypeptide and glucagon receptor agonists or amylin analogues) potently and sustainably reduce appetite, and, taken together with dietary advice, can produce substantial, life-changing, weight loss approaching that achieved by surgery. To date, data from the STEP-HFpEF trial show meaningful improvements in health status (Kansas City Cardiomyopathy Questionnaire). Effective weight management could relieve several drivers of HF, to complement the existing treatments for HF with both reduced and preserved ejection fraction. Further trials of weight loss interventions will provide more definitive evidence to understand their effects on clinical events in patients with HF.

A model of subcutaneous pramlintide pharmacokinetics and its effect on gastric emptying: Proof-of-concept based on populational data

Pramlintide, an amylin analog, has been coming up as an agent in type 1 diabetes dual-hormone therapies (insulin/pramlintide). Since pramlintide slows down gastric emptying, it allows for easing glucose control and reducing the burden of meal announcements. Pre-clinical in silico evaluations are a key step in the development of any closed-loop strategy. However, mathematical models are needed, and pramlintide models in the literature are scarce. This work proposes a proof-of-concept pramlintide model, describing its subcutaneous pharmacokinetics (PK) and its effect on gastric emptying (PD). The model is validated with published populational (clinical) data. The model development is divided into three stages: intravenous PK, subcutaneous PK, and PD modeling. In each stage, a set of model structures are proposed, and their performance is assessed using the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC). In order to evaluate the modulation of the rate of gastric emptying, a literature meal model was used. The final pramlintide model comprises four compartments and a function that modulates gastric emptying depending on plasma pramlintide. Results show an appropriate fit for the data. Some aspects are left as open questions due to the lack of specific data (e.g., the influence of meal composition on the pramlintide effect). Moreover, further validation with individual data is necessary to propose a virtual cohort of patients.

Cagrilintide: A Long-Acting Amylin Analog for the Treatment of Obesity.

Despite the worldwide epidemic of obesity, there remain few approved pharmacological treatment options to bridge the gap between lifestyle therapy and bariatric surgery. Cagrilintide is an amylin-analog, now being developed in combination with the GLP-1 agonist semaglutide to achieve sustained weight loss in persons with overweight and obesity. Amylin, released with insulin from beta cells in the pancreas, induces its satiating effect via both the homoeostatic and hedonic regions of the brain. Semaglutide, a GLP-1 receptor agonist, reduces appetite via GLP-1 receptors in the hypothalamus and increases the production of insulin, and reduces glucagon secretion, delaying gastric emptying. These separate, but related mechanisms of action of an amylin-analog and a GLP-1 receptor agonist appear to have an additive effect on appetite reduction. Given the heterogeneity and complex pathogenesis of obesity, combination therapy with multiple pathophysiological targets is a logical approach to increasing weight loss response with pharmacotherapy. Cagrilintide alone, as well as cagrilintide in combination with semaglutide have shown promising weight loss in clinical trials that supports the further development of this therapy for sustained weight management.