Amylin Analogs: The Next Major Class of Weight Loss Therapy: A Review of Experimental Data and Early‐Phase Clinical Trials

ABSTRACT

Aims

The management of the disease of obesity has been transformed by incretin‐based therapies; however, additional and alternative therapeutic strategies are needed to address its biological complexity. This narrative review examines the physiology of amylin and the emerging role of amylin‐based therapies in obesity management.

Materials and Methods

We conducted a narrative review of amylin‐based therapies that were approved or remained in human clinical development for obesity as of 30 April 2026. PubMed/MEDLINE, ClinicalTrials.gov, Google Scholar, company press releases, investor reports, and major congress abstracts were searched for relevant preclinical and clinical evidence.

Results

Amylin, co‐secreted with insulin from pancreatic β‐cells, slows gastric emptying, suppresses glucagon secretion, and promotes meal termination through central mechanisms. Pramlintide, the first approved amylin analogue, established proof of concept but was limited by modest efficacy and frequent dosing. More recently, long‐acting amylin‐based therapies, including cagrilintide, eloralintide, petrelintide, MET‐233i, ABBV‐295, and AZD6234, as well as combination approaches such as cagrilintide with semaglutide and zenagamtide, have demonstrated clinically meaningful weight loss with generally favorable tolerability profiles.

Conclusions

Amylin‐based therapies represent a promising addition to the evolving treatment landscape of obesity. Their emerging efficacy as both standalone and combination therapies supports a multi pathway approach to addressing the biological complexity and heterogeneity of the disease.

Plain Language Summary

Obesity is a chronic disease driven by complex biological mechanisms, meaning that no single treatment is likely to work for everyone. Amylin based therapies are an emerging group of medications that target appetite regulation through pathways different from those used by current glucagon‐like peptide‐1 (GLP‐1) based treatments. Amylin is a natural hormone released by the pancreas after meals that helps people feel full, slows stomach emptying, and reduces food intake.

The first amylin medicine, pramlintide, demonstrated that this pathway could promote weight loss, but its clinical use was limited by the need for multiple daily injections and relatively modest efficacy. Newer long acting amylin analogues have overcome many of these limitations. Early clinical trials show that agents such as cagrilintide, eloralintide, petrelintide, MET‐233i, ABBV‐295, and AZD6234 can produce clinically meaningful weight loss with very good tolerability profiles. Combining amylin with GLP‐1 based therapy has produced even greater weight loss, with reductions exceeding 20% in clinical studies.

Although most of these medicines are still under clinical development, the available evidence suggests that amylin based therapies could become an important addition to obesity treatment. By targeting complementary biological pathways, they may expand treatment options, improve long term management, and allow a more personalised approach to caring for people with the disease of obesity.

1. Introduction

The expansion of obesity medications should not be viewed as a luxury but as a clinical necessity. Obesity is a chronic disease that is not currently curable, and its biological heterogeneity requires therapies targeting multiple pathways, similar to how different anti‐hypertensive medications with distinct mechanisms are used to treat resistant hypertension. The therapeutic landscape of obesity pharmacotherapy has evolved substantially over the past decades, progressing from traditional oral agents such as orlistat and phentermine/topiramate to the transformative era of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) [1, 2, 3, 4]. These agents have significantly improved the efficacy of medical obesity treatment by targeting the disease of obesity in the subcortical areas of the brain, thus addressing central regulation of adipocyte mass and peripheral metabolic pathways [5, 6]. GLP‐1RA therapy itself has also advanced through successive stages of innovation, beginning with the once‐daily injectable liraglutide, followed by the more effective once‐weekly injections semaglutide, and most recently the introduction of oral semaglutide and oral orforglipron, illustrating the rapid and continuous evolution of pharmacologic obesity management [3, 7, 8, 9].

Amylin analogues represent a re‐emerging class of obesity therapies that target complementary subcortical brain satiety pathways to incretin‐based drugs [10]. Amylin is a peptide hormone co‐secreted with insulin from pancreatic β‐cells that acts centrally, particularly in the area postrema and hypothalamus, to regulate glycemic control by addressing appetitive behaviour [10, 11]. Amylin also partly achieves this via peripheral actions such as slowing gastric emptying [12]. These physiological effects make amylin signalling an attractive therapeutic target for the management of the disease of obesity [10]. However, earlier attempts in 2003 to utilise this quality into obesity treatment were limited by the pharmacologic properties of first‐generation agents such as pramlintide [13]. Multiple daily injections due to a short half‐life were inconvenient and only modest weight loss with relatively frequent gastrointestinal adverse effects further limited uptake [13]. The first GLP‐1 analogue, exenatide, was approved by the American Food and Drug Administration (FDA) in 2005 1 month after the first amylin analogue, but the rapid success of GLP‐1 receptor agonists shifted focus away from amylin‐based therapies for several years. Recent advances enabled the development of long‐acting amylin analogues and selective amylin receptor agonists with once weekly or even longer dosing intervals and substantially greater weight loss efficacy, while having a remarkably good tolerability profile [10, 14].

The aim of this review is to summarize the currently available and emerging amylin‐based therapies already in human clinical trials. The review will also examine their potential role in obesity management. This includes single‐agent drugs such as cagrilintide, eloralintide, petrelintide, MET‐233i, ABBV‐295, and AZD6234 as well as combination approaches such as the combination of cagrilintide and semaglutide, and zenagamtide that integrate amylin with GLP‐1 receptor signalling.

2. Methodology

This narrative review was designed to provide a structured and comprehensive overview of amylin based therapies for obesity that were approved or continuing in human clinical development by 30 April 2026. We searched PubMed/MEDLINE, ClinicalTrials.gov, Google Scholar, company press releases, investor reports, and major congress abstracts up to 30 April 2026. Search terms included: “amylin analogue,” “amylin analog,” “amylin receptor agonist,” “selective amylin receptor agonist,” “dual amylin and calcitonin receptor agonist,” “obesity,” “weight loss,” “cagrilintide,” “eloralintide,” “petrelintide,” “MET‐233i,” “ABBV‐295,” “GUBamy,” “AZD6234”, “cagrilintide and semaglutide,” “amycretin,” and “zenagamtide”.

We included amylin‐based agents with available human clinical trial evidence in obesity, provided that clinical development had not been publicly stopped by the search cutoff date. Agents were included whether studied as monotherapy or in combination with incretin‐based therapies. Early compounds that have not yet entered human trials, discontinued programs, non‐obesity indications without relevant weight data, and agents without identifiable human trial entry were excluded.

Based on this strategy, the amylin‐based therapies identified were: pramlintide, cagrilintide, eloralintide, petrelintide, MET‐233i, ABBV‐295/GUBamy, AZD6234, fixed compound cagrilintide and semaglutide, and zenagamtide. Pramlintide was included as the first approved amylin analogue and historical proof‐of‐concept agent.

3. Physiological Mechanisms of Amylin Based Obesity Therapies

Amylin is often thought of as a companion to insulin, because it is co‐secreted from the pancreas. It may be better to think of amylin as a postprandial regulator of metabolic rhythm. After a meal, pancreatic β‐cells release amylin alongside insulin in a coordinated response to nutrient intake [10, 11, 12]. While insulin guides glucose into tissues, amylin adjusts how quickly that glucose appears in the circulation. Amylin slows gastric emptying, suppresses inappropriate glucagon secretion, and signals the brain; particularly the area postrema and hypothalamus to terminate the meal [11, 12, 15]. Amylin has been postulated in animal studies to enhance leptin sensitivity [16]. This may occur because amylin amplifies hypothalamic leptin signalling, by increased leptin‐stimulated phosphorylated STAT3 in the arcuate nucleus and increased leptin binding in hypothalamic nuclei in these models [16]. This has not been explicitly pursued in dedicated human mechanistic studies. Leptin changes have been measured in most of the human late phase clinical trials [17] and leptin levels have been broadly as would have been expected by the weight loss observed [17]. In rodent studies, leptin sensitivity isn't measured by a single test but is inferred from variant complementary approaches. These include assessing hypothalamic leptin signalling, particularly STAT3 phosphorylation, leptin receptor‐associated signalling, while observing physiological responses like changes in food intake and body weight after leptin administration [18, 19]. Together, these measures provide an integrated assessment of leptin responsiveness. This is more challenging in humans. Thus far the human data are not conclusive and more dedicated mechanistic studies will be required to explore leptin sensitization after weight loss due to amylin treatments. These studies could examine whether amylin improves leptin sensitivity through assessing responses to exogenous leptin before and after amylin induction. Changes in appetite, food intake, and energy expenditure could help determine whether amylin boosts leptin responsiveness beyond the effects of weight loss alone.

4. Type 1 Diabetes: A Unique Metabolic Outlier

Patients with type 1 diabetes (T1D) are deficient of both insulin and amylin due to β‐cell destruction [20]. Although amylin promotes satiety, slows gastric emptying, and suppresses glucagon, its deficiency does not lead to obesity because it does not appear to be a dominant regulator of energy balance and appears to be outweighed by stronger metabolic and treatment‐related factors [21]. The dominant phase of insulin deficiency in T1D creates a catabolic state with increased lipolysis, proteolysis, hepatic glucose output, and significant caloric loss via glycosuria, leading to weight loss despite absent amylin signalling [20, 21]. With the presence of insulin therapy, body weight increases due to exogenous insulin exposure, promoting an anabolic action with reduced glycosuria and behavioural factors such as hypoglycaemia‐related defensive eating [22]. Importantly, amylin replacement with pramlintide results in only modest weight reduction (~1–3 kg), supporting that amylin acts as a secondary modulator rather than a primary determinant of adiposity [23]. Moreover, the historical perception of T1D as a lean condition is outdated, as contemporary data show a rising prevalence of obesity in T1D populations, driven by intensive insulin therapy and modern environmental factors rather than any protective effect of amylin deficiency [24]. However, studies show that treating individuals with type 1 diabetes using amylin leads to only modest weight loss, and less than what is observed in people without type 1 diabetes (~3% vs. ~7%) [23, 25]. This suggests that replacing amylin in a population with complete endogenous deficiency may not produce the robust metabolic effects that may have been expected [23, 25]. This may be related to the fact that the appetite and weight loss effects of pramlintide could be partly offset by intensive insulin therapy and hypoglycaemia‐related food intake in patients with T1D.

5. From Bench to Bedside

Bridging preclinical to clinical evidence, the amylin analogues have consistently shown a biologically coherent pattern. In rodents, amylin reliably reduces food intake and body weight. These findings are consistent with the appetite and weight reduction effects seen with the GLP‐1 receptor agonists in preclinical obesity models, supporting the concept that amylin represents an additional pathway that can be targeted to regulate body weight [4]. This has been translated to humans, although the magnitude of weight loss remains more variable and dependent on the specific agent [10, 26]. Importantly, amylin does not simply mimic caloric restriction. Compared with pair‐feeding, amylin analogues produce greater fat loss, showing approximately three‐fold higher fat reduction despite similar decreases in food intake and weight change [27]. This may suggest additional metabolic actions beyond reduced energy intake. In recent preclinical work, subcutaneous cagrilintide reduced food intake and body weight primarily through loss of fat mass while preserving lean tissue, an effect possibly mediated through central amylin receptors (AMYRs), particularly AMY1R and AMY3R [28]. Together, these findings support a signal for appetite suppression and preferential fat loss in rodents, while the degree of weight loss in humans remains agent‐dependent.

6. Amylin Based Obesity Therapy

We can categorise amylin analogues generally into two groups: (1) Selective Amylin Receptor Agonists (SARAs) and (2) Dual Amylin and Calcitonin Receptor Agonists (DACRAs). They differ primarily in their receptor targeting, potency, and duration of action. While SARAs only target the amylin receptor, DACRAs activate both the amylin and calcitonin receptors [10]. This classification is useful, but it should not be viewed as absolute. Functional amylin receptors are formed by the calcitonin receptor together with receptor activity modifying proteins, and individual agents may vary in their activity across amylin receptor subtypes and the calcitonin receptor [10]. Clinically, it remains unclear whether differences in receptor pharmacology would manifest as a meaningful difference in weight loss efficacy, as available studies vary considerably in molecular design, dose escalation, treatment duration, and study population. An additional theoretical distinction lies in the wider physiological mechanisms of DACRAs through calcitonin receptor activation. This includes a possible role in bone metabolism, where dual receptor agonism may contribute to preservation of bone mass during weight loss [10, 29].

Specific to the calcitonin receptor (CTR), amylin binding occurs with low affinity and has limited and unclear physiological relevance for metabolic effects [10]. Instead, CTR functions as a structural component of functional amylin receptors (AMYRs), which are heterodimeric complexes formed by CTR and receptor activity–modifying proteins (RAMPs), generating distinct receptor subtypes that mediate appetite and metabolic regulation [30]. CTR also retains its classical physiological role in calcium and bone metabolism, which may have a role for bone preservation during weight loss with amylin based therapies [29, 31]. Supporting this, pramlintide infusion has been associated with reductions in the bone resorption marker CTX‐1 [32]. Importantly, any bone related advantage of DACRAs remains theoretical and has not yet been conclusively demonstrated in clinical trials [10, 29]. Table 1 refers to Single Agent Amylin Therapies, Selective Amylin Receptor Agonists (SARAs) and Dual Amylin and Calcitonin Receptor Agonists (DACRAs).

TABLE 1.

Single Agent Amylin Therapies, Selective Amylin Receptor Agonists (SARAs) and Dual Amylin and Calcitonin Receptor Agonists (DACRAs).

Medication	Mechanism of Action	Targeted Receptors	Frequency of Administration	Weight Loss	Nausea	Vomiting	Discontinuation Rate related to AE	Number of the patients	Clinical Trial Phase
Pramlintide [25, 33]	Short‐acting SARA amylin analogue	AMY1R, AMY2R, and AMY3R	360 μg twice daily, subcutaneous	~7% at 52 weeks	9%–29%	Not reported	3%–16%	411	Approved
Cagrilintide [34, 35]	Long‐acting DACRA amylin analogue	AMY1R, AMY2R, AMY3R and CTR.	2.4 mg once weekly, subcutaneous	~12% at 68 weeks	23.8%	7.0%	2.6%	302	Phase 3
Eloralintide [36, 37, 38]	Non‐aggregating SARA amylin analogue	AMY1R	9 mg once weekly, subcutaneous	~20% at 48 weeks	25%–64%	4%–8.3%	8%–21%	100–263	Phase 2
Petrelintide [39, 40, 41]	Long‐acting DACRA amylin analogue	AMY3R and CTR	4.8 mg weekly, subcutaneous	8.6% at 16 weeks, 10.7% at 42 weeks	16.7%–33.3%	2.8%	2.8%	132–493	Phase 2
MET‐233i [42]	Ultra–long acting amylin analogue	Not fully disclosed yet	1.2 mg weekly, subcutaneous	~8.4% at 5 weeks	Not fully disclosed yet	Not fully disclosed yet	Not fully disclosed yet	144	Phase 1
ABBV‐295 [43]	Long‐acting DACRA amylin analogue	Not fully disclosed yet	2–14 mg weekly, every other week, and monthly dosing (after week 5)	~9.8% at 12 weeks	Not fully disclosed yet	Not fully disclosed yet	Not fully disclosed yet	76	Phase 1
AZD6234 [43, 44]	Long‐acting SARA amylin analogue	AMY3R	Single dose 2.7 mg subcutaneous	3.8% at day 5	32.1%	17.9%	Not fully disclosed yet	54	Phase 1

Abbreviations: AE = adverse event; AMY1R = amylin receptor 1; AMY2R = amylin receptor 2; AMY3R = amylin receptor 3; CTR = calcitonin receptor; DACRA = dual amylin and calcitonin receptor agonist; mg = milligram; SARA = Selective Amylin Receptor Agonist; μg = microgram.

6.1. Single Agent Amylin Therapies

Pramlintide was the first amylin drug approved and validated the concept that amylin agonists may be a treatment for obesity [45]. This synthetic analogue of human amylin was marketed as an adjunct therapy for both type 1 and type 2 diabetes mellitus [23, 46]. Early clinical trials demonstrated that pramlintide, when added to lifestyle intervention, could produce modest but meaningful reductions in body weight. In a 12‐month randomised trial, pramlintide treatment resulted in approximately 5%–7% weight loss compared with lifestyle intervention alone [25].

Subsequent drug development focused more on improving pharmacokinetics and potency to address the short lived and unwanted side effects. Cagrilintide is a DACRA and a long‐acting amylin analogue designed for once weekly administration. In clinical trials evaluating cagrilintide monotherapy, patients achieved approximately 11%–12% weight loss over 68 weeks [34]. These results confirmed that sustained amylin receptor activation alone can produce clinically meaningful weight reduction. Gastrointestinal adverse events such as nausea, vomiting, and constipation were among the most commonly reported adverse events. They were mild to moderate, transient, and led to treatment discontinuation in about 1% of participants [34]. Importantly, the once weekly dosing schedule represents a substantial improvement over earlier short‐acting amylin analogues.

The next selective amylin receptor agonist to go into phase 3 trials was eloralintide and is classified as a SARA. In the phase 1 study, eloralintide produced dose‐dependent and clinically meaningful weight reduction, reaching a placebo adjusted mean weight loss of 11.3% at 12 weeks with the 12 mg dose, while gastrointestinal adverse events remained relatively infrequent and were mainly observed at higher doses [36]. The most commonly reported gastrointestinal adverse events included diarrhoea, nausea, vomiting, and constipation, and most were mild in severity without leading to dose modification or treatment discontinuation [36]. In the subsequent 48‐week phase 2 randomised trial, higher doses of eloralintide achieved nearly 20% weight loss, although gastrointestinal adverse events increased with dose escalation, especially if dose titration was not used [37]. Nausea, fatigue, diarrhoea, and constipation were the most frequently reported adverse events, and approximately 10% of participants discontinued treatment because of adverse events [37]. No major safety signals, including pancreatitis, cholecystitis, or deaths, were reported in the phase 2 study [37]. Gradual dose escalation was initially thought to be unnecessary because of the potentially improved tolerability of selective amylin receptor agonism; however, the phase 2 study suggested that titration improved tolerability, although the optimal rate of dose escalation remains uncertain [37].

Petrelintide is a long‐acting amylin analogue currently classified as a DACRA. Phase 1 and 2 clinical studies demonstrating clinically meaningful weight loss alongside a favourable gastrointestinal tolerability profile [39, 40]. In phase 1 randomised multiple ascending dose trial, once weekly petrelintide achieved up to 8.6% mean weight loss after 16 weeks, while gastrointestinal adverse events were predominantly mild [39]. Nausea was the most common gastrointestinal adverse event, occurring in 16.7%–33.3% of participants compared with 16.7% with placebo, whereas diarrhoea and constipation were uncommon and vomiting occurred in only one participant who discontinued treatment because of moderate nausea and vomiting [39]. Nausea and vomiting were more frequent at higher single doses, emphasising the importance of gradual dose escalation to improve tolerability [39]. These findings were further supported by the phase 2 ZUPREME‐1 trial, in which once weekly petrelintide achieved up to 10.7% mean weight loss at 42 weeks compared with 1.7% with placebo, while maintaining placebo‐like tolerability [40]. Discontinuation rates due to adverse events were nearly identical between petrelintide and placebo (4.8% vs. 4.9%), with no vomiting events or gastrointestinal‐related discontinuations reported in the maximally effective treatment arm, and placebo‐level rates of diarrhoea and constipation [40].

MET‐233i, an ultra‐long acting amylin analogue engineered with the goal of monthly dosing in phase 1 clinical trials exhibited rapid reductions in body weight, with placebo adjusted weight loss exceeding 8% within approximately 5 weeks of treatment [42]. The compound has a reported half‐life of nearly 3 weeks, raising the possibility that future amylin therapies could be administered as infrequently as once per month. MET‐233i showed mild, dose‐dependent gastrointestinal adverse events primarily occurring in the first week of dosing, with no severe or serious adverse events observed over the 36 days of treatment [42].

ABBV‐295 (previously known as GUBamy) is another long‐acting DACRA for obesity [47, 48]. In the initial phase 1 Multiple Ascending Dose (MAD) analysis, once weekly GUBamy reached a mean weight reduction of −7.8% at 6 weeks [47]. In the subsequent ABBV‐295 MAD study, longer exposure resulted in greater reductions, reaching approximately −7.8% to −9.8% at 12 weeks and up to −9.7% at 13 weeks, reemphasizing a clear time and dose‐dependent effect [48]. The treatment was well tolerated, with only mild, dose‐dependent gastrointestinal symptoms occurring early in treatment [47, 48].

AZD6234 is a novel long‐acting SARA that is being developed for the treatment of obesity. In a first‐in‐human Phase 1 single ascending dose study involving healthy participants with overweight or obesity, AZD6234 demonstrated dose‐proportional pharmacokinetics and a terminal half‐life of approximately 4 days, supporting once‐weekly administration [43]. Single dose treatment resulted in statistically significant reductions in body weight, with the greatest mean weight loss reaching 3.8% from baseline by Day 5 following a 2.7 mg subcutaneous dose [43]. The most commonly reported adverse events were gastrointestinal and included nausea, vomiting, decreased appetite, constipation, and diarrhoea, with the frequency and severity of nausea and vomiting increasing with higher drug exposure [43].

6.2. Combined Amylin Based Therapies

The success of dual incretin agonism, particularly with GLP‐1 and glucose dependent insulinotropic polypeptide (GIP), has further intensified interest in combining amylin signalling with complementary metabolic pathways, most notably GLP‐1 [49]. Both amylin and GLP‐1 act predominantly at the level of subcortical brain centers, modulating energy balance through partially overlapping yet distinct mechanisms that influence satiation, appetite, and food‐related behaviour, ultimately regulating adiposity [11, 50]. This mechanistic complementarity provides a strong biological rationale for combination therapy; whereby simultaneous pathway activation may enhance central control of energy intake and produce greater and more sustained weight reduction [11, 50]. In the Study of Tirzepatide versus Semaglutide Once Weekly as Add‐on Therapy to Metformin in Participants with Type 2 Diabetes (SURPASS‐2) trial, tirzepatide, the dual GLP‐1/GIP agonist, demonstrated superior reductions in both glycated haemoglobin (HbA1c) (up to −2.3%) and body weight (up to −11.2 kg) compared with the single GLP‐1RA semaglutide, providing strong clinical evidence that dual receptor agonism enhances both glycemic control and weight loss beyond GLP‐1 monotherapy [51].

Cagrilintide/semaglutide is a fixed dose combination of cagrilintide and the GLP‐1 receptor agonist semaglutide. In large phase 3 clinical trials, this combination produced mean body‐weight reductions of approximately 22% after 68 weeks of treatment [34]. This degree of weight loss exceeded that observed with either component alone, but was not additive. Notably, the data suggest that when the combination of cagrilintide/semaglutide and cagrilintide both achieved a BMI < 27 kg/m² and a waist to height ratio < 0.53, cagrilintide/semaglutide had more cardiometabolic benefits compared with cagrilintide monotherapy. This may suggest that cagrilintide has less weight loss independent cardiometabolic benefits than when semaglutide and cagrilintide are combined [34]. The combination of cagrilintide/semaglutide was associated with predominantly gastrointestinal adverse events; mainly nausea (55%) and vomiting (24.7%). However, these side effects were reported as mostly mild to moderate and transient.

Zenagamtide (previously known as amycretin) is a unimolecular peptide engineered to simultaneously activate GLP‐1, amylin, and calcitonin receptors, integrating complementary pathways involved in appetite regulation and energy balance. Unlike fixed‐dose combination therapies, zenagamtide incorporates these activities within a single molecule [52, 53], thus also making oral formulation a possibility. In a phase 1b/2a trial, once‐weekly subcutaneous zenagamtide produced substantial and dose‐dependent weight loss, reaching 24.3% at 36 weeks with the 60 mg top dose and 22% with the 20 mg maintenance dose. After 36 weeks there were no signs yet of a weight‐loss plateau [53]. Gastrointestinal adverse events, predominantly nausea, vomiting, and diarrhoea, were the most commonly reported side effects and occurred more frequently at higher doses, particularly during dose escalation; however, most events were mild‐to‐moderate in severity and consistent with the known profile of GLP‐1 and amylin based therapies [52, 53]. In this context, the mode of delivery becomes equally important: a fixed‐dose combination simplifies treatment and may improve adherence, whereas administering each agent separately allows individualised dose titration and optimization of tolerability; evidence from hypertension therapies supports this, with fixed‐dose combinations improving adherence (OR 1.21, 95% CI 1.03–1.43) while maintaining comparable safety [54]. Table 2 summarises the combined amylin based therapies.

TABLE 2.

Combined amylin based therapies.

Medication	Mechanism of action	Targeted receptors	Frequency of administration	Weight loss	Number of the patients	Nausea	Vomiting	Discontinuation rate related to AE	Clinical trial phase
cagrilintide/semaglutide [34, 35]	DACRA Amylin & GLP‐1 receptor agonist	AMY1R, AMY2R, AMY3R, CTR, and GLP‐1	2.4 mg weekly, subcutaneous	~22% at 68 weeks	2108	55%	26.1%	5.9%	Phase 3
Zenagamtide [52, 53]	DACRA Amylin & GLP‐1 receptor agonist	Not fully disclosed yet	60 mg weekly, subcutaneous	~24% at 36 weeks	125–144	50%–82%	25%–53%	0%–35%	Phase 1b/2a

Abbreviations: AE = adverse event; AMY1R = amylin receptor 1; AMY2R = amylin receptor 2; AMY3R = amylin receptor 3; CTR = calcitonin receptor; DACRA = dual amylin and calcitonin receptor agonist; GLP‐1 = glucagon‐like peptide‐1 pathways; mg = milligram.

7. Conclusions

The emerging evidence suggests that for more severe forms of obesity, amylin receptor activation may function most effectively in combination with other obesity treatments. The alternative view would be that if amylin analogues have a very good tolerability profile, then patients with less severe forms of obesity, who may struggle to tolerate other nutrient‐stimulating hormone therapies, may benefit from a moderately effective but highly tolerable treatment. It remains important to address the disease of obesity from different angles and multiple mechanisms, since it is unlikely that a single pathway will be sufficient for all patients. In this context, targeting multiple routes is not just a luxury but necessary, much like the use of different anti‐hypertensive medications with distinct mechanisms, to effectively treat resistant hypertension in patients with a previous major cardiovascular event. Amylin analogues may thus be effective standalone treatments but may also be ideal to combine with other treatments to effectively treat the disease of obesity.

Funding

The authors have nothing to report.

Disclosure

Carel W. le Roux has received personal fees from Boehringer Ingelheim, GI Dynamics, Herbalife, Johnson and Johnson, Keyron, Eli Lilly, and Novo Nordisk outside the submitted work.

Conflicts of Interest

Abdulhameed Alhazmi declares no conflicts of interest. Professor Carel le Roux reports grants from the EU Innovative Medicine Initiative, Irish Research Council, Science Foundation Ireland, Anabio, and the Health Research Board. He serves on advisory boards and speakers panels of Abbvie, Altimmune, Amgen, Arrowhead Pharma, Astrazeneca, Boehringer Ingelheim, Eli Lilly, Gila Pharmaceuticals, Herbalife, Irish Life Health, Johnson and Johnson, Keyron, Medscape, Metsera, Morphic Medical, Novo Nordisk, Nymble, Olympus, Pfizer, Rhythm Pharma, Roche, Wave, Zealand Pharma. ClR is the Chair of the Irish Society for Nutrition and Metabolism. ClR received stock options as payment for scientific advisory board functions from Nymble. ClR provides obesity clinical care in the My Best Weight clinic and Beyond BMI clinic and is a co‐owner of these clinics.

Alhazmi A. and le Roux C. W., “Amylin Analogs: The Next Major Class of Weight Loss Therapy: A Review of Experimental Data and Early‐Phase Clinical Trials,” Diabetes, Obesity and Metabolism 28, no. S5 (2026): 42–50, 10.1111/dom.71074.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.