Slim chance or fat profit: will the obesity market just keep on growing?

Introduction

Since the mid-twentieth century, the World Health Organization (WHO) has recognized "obesity" as a stand-alone, chronic, non-communicable and preventable disease that remains a major, global public health challenge ^{1, 2}. Today, more than a billion individuals, both adults and children, worldwide are obese ³, with 110 million obese people in the US alone ⁴. Without intervention, nearly half the adults in the US are expected to be obese by 2030 ⁴.

Objective criteria for diagnosis of clinical obesity and pre-obesity exist ⁵ , which provide a framework for clinical decision-making and prioritization of therapeutic interventions (Figure 1).

Figure 1: Overview of diagnostic criteria for different types of obesity. The state of excess adiposity leads to a diagnosis of obesity. The type of obesity is dependent on whether the excess adiposity negatively impacts organ structure and function. The risk of developing other co-morbid non-communicable conditions is increased for individuals with pre-clinical and clinical obesity. Generally, obesity is "a condition characterized by excess adiposity, with or without abnormal distribution or function of adipose tissue, and with causes that are multifactorial and still incompletely understood" ⁵.

Contents

• 1. Brief History of Early Weight-Loss Drugs in the US
• 2. Biological Targets for Weight-Loss Drug Development
• Figure 2: Simplified schematic overview of biological pathways targeted by weight-management drugs
• 3. US Weight Management Drug Development Pipeline
• Table 1: Novel weight-loss drugs approved in the US
• Table 2: Late-stage anti-obesity drug development pipeline in the US
• 4. Leveraging Incretin Hormone Biology for Drug Discovery and Development
• Noteworthy Successes
• Noteworthy Failures
• 5. Targeting the Melanocortin System to Treat Hereditary Obesity
• Table 3: Selected genetic causes of obesity
• Setmelanotide, an MC4R agonist and first-in-class treatment for hereditary obesity
• Drug Development Pipeline for Genetic Causes of Obesity
• 6. Other Anti-Obesity Drugs
• 7. Sales, Market Size and Opportunity
• 8. Future Prospects
• 9. References

1. Brief History of Early Weight-Loss Drugs in the US

The medicalization of obesity, which has been formerly underway since the mid twentieth century has been full of promise and demise. The first FDA approved drugs for weight management came in 1947 with Abbott Laboratories' Desoxyn and Endo Products' Hydrin ⁶. These anorectics were formulations of methamphetamine that served as pharmaceutical adjuncts to dietary management of obesity ^6,7. While amphetamine-based anorectics were considered useful weight-loss drugs because they suppressed appetite, they carried a risk of addiction. Consequently, amphetamine analogues were developed with the intention of reducing this risk ^{6, 7}. They were, however, indicated for short-term use which ultimately reduced their popularity ⁶. In the mid-1990s, dexfenfluramine was approved for long-term use in the treatment of obesity, but its dubious safety profile restricted its use, and it was eventually withdrawn from the US market ⁶.

Similarly, sibutramine (Meridia), a serotonin and dopamine reuptake inhibitor that works by inducing satiety and increasing energy expenditure ⁸, was approved in 1997 against a background of divided opinion on its safety profile because, while effective for weight-loss, it tended to increase blood pressure and pulse rate ⁶. At the request of the European Medical Agency, the SCOUT (Sibutramine Cardiovascular OUTcome Trial) study was undertaken to provide post-marketing assurance of cardiovascular safety for use of the drug in high-risk individuals. The drug was voluntarily withdrawn in 2010 ^{9, 10} following an FDA request based on the increased risk of non-fatal myocardial infarction and non-fatal stroke in patients with preexisting cardiovascular disease identified via the SCOUT study, despite the drug not being indicated for such patients ^{8, 11}.

More recently, lorcaserin (Belviq), a 5-hydroxytryptamine receptor agonist that functioned as an appetite suppressant ¹², was approved in 2012 but was withdrawn in 2020, due to the increased risk of cancer based on emergent clinical data ¹³.

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2. Biological Targets for Weight-Loss Drug Development

Anti-obesity drugs target either central nervous system pathways that regulate sensations of satiety and fullness, or peripheral modulators of digestion, metabolism and lipogenesis (Figure 2).

Figure 2: Simplified schematic overview of biological pathways targeted by weight-management drugs. Anorexigenic effects are mediated through stimulation of MC4R, which may be achieved via input signals, specifically insulin, amylin and leptin, from peripheral organs, including stomach, intestines and adipose tissue that act on POMC expressing neurons in the arcuate nucleus of the hypothalamus. Amylin also stimulates leptin signaling. Peptides AgRP and NPY are MC4R antagonists that are co-expressed in response to signals from elsewhere in the body that inform on energy stores. These signals are mediated through leptin and the so called "hunger hormone" ghrelin. Peripherally produced PYY also transmits a satiety signal to the brain by binding receptors on the vagus nerve. This signal prevents and stimulates NPY and POMC production by neurons in the arcuate nucleus respectively, resulting in orexigenic effects.  GLP1, glucagon-like-peptide-1; GLP1R, glucagon-like-peptide-1-receptor; GIP, glucose-dependent insulinotropic polypeptide; LEPR, leptin receptor; NPY, neuropeptide Y; PYY, peptide YY; POMC, proopiomelanocortin; PCSK1, Proprotein convertase subtilisin/kexin type 1; AgRP, Agouti-related protein; NPY, neuropeptide Y; αMSH, α-melanocyte stimulating hormone; MC4R, melanocortin receptor 4. Adapted from ¹⁴. Blue arrows are indicative of stimulation, while the red lines are indicative of inhibition.

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3. US Weight Management Drug Development Pipeline

Presently, there are five patent-protected anti-obesity drugs approved for the US market (Table 1), and 149 novel drug candidates in clinical development either in the United States or globally ¹⁵. Across the various development stages, from Phase I to pre-registration, 101 different companies have contributed at least one novel drug candidate to the development pipeline, (Figure 3 a), indicative of the perceived opportunity that continues to exist in the medical management of obesity. Approximately 16% of drug candidates in the pipeline are being developed by either Novo Nordisk or Eli Lilly, underlining their status as leaders in the field and emphasising their commitment to the obesity market.

Biologics are generally well represented across Phase I to Phase III, with peptide-based drugs among the most numerically dominant at each stage (Figure 3 b). Twenty-seven small molecule drug candidates exist at Phase I, and at Phase II, small molecule drugs match the number of peptide-based drugs in development. Oligonucleotide drugs represent a new modality for treatment of obesity, and all candidates are currently in Phase I trials. Three monoclonal antibody drug candidates are also being developed, two of which (apitegromab and trevogrumab) are intended for use alongside marketed weight-loss drugs to preserve lean muscle mass during medicalised weight-loss.

Leveraging incretin biology for weight-loss remains popular, with ~35% of drug candidates exploiting this mechanism of action, (Figure 3 c). Amylin receptor biology is a mechanistic focus of ~7% of drug candidates, and ~3% of drugs in clinical development target both incretin and amylin receptor biology for weight-loss. Indicative of the innovation that exists within the pipeline, more than thirty mechanisms of action are represented by the ~33% of drug candidates with mechanism of action classified as "Other", (Figure 3 c).

In recognition of the need for alternatives to injectable drugs, ~44% of drug candidates are intended for oral delivery, either exclusively, or as an alternative to another mode of delivery, (Figure 3 d).

With ~7% of all drug candidates already in the later stages of development, (Phase III, pre-registration), (Figure 3 e; Table 2), it is likely that new weight-loss drugs will be marketed in the near-term future 

Table 1: Novel weight-loss drugs approved in the US

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Table 2: Late-stage anti-obesity drug development pipeline in the US

Figure 3: Overview of US and global anti-obesity drug development pipeline. The pipeline currently includes 149 drug candidates, (Phase I to Pre-registration inclusive) in development in the US or globally. (a) Companies with anti-obesity drug candidates in development. (b) Drug candidates in the various phases of development across various modalities. (c) Proportion of drugs in development at each development stage. (d) Biology targeted by mechanisms of action of drug candidates in development. "Multiple" refers to drug candidates that target more than one of the named biological targets, e.g. Incretin biology and amylin receptor biology. (e) Intended delivery modes for drugs candidates in development. Note that percentages in panels (c-e) are rounded to the nearest whole number.

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4. Leveraging Incretin Hormone Biology for Drug Discovery and Development

Incretin hormones were an obvious starting point for development of weight-loss drugs. GIP and GLP-1 are hormones released after ingestion of food to control insulin secretion and to maintain glucose homeostasis, among other physiological effects ^{16, 17}. Upon release, GLP-1 slows stomach emptying, stimulates insulin secretion in the pancreas, and via signalling in the brain, inhibits appetite and food intake. The "incretin effect" refers to the greater insulin secretion response stimulated by oral versus intravenous glucose delivery, even when identical blood glucose levels are achieved ¹⁸. This difference is attributed to the incretin hormones, GLP-1 and GIP, which are released in response to orally received, but not systemically delivered, glucose.

Noteworthy Successes

Foremost among the modern-day anti-obesity drugs are GLP-1 receptor agonists (GLP1RAs). These drugs mimic the binding of the naturally produced GLP-1 hormone to its cognate receptor after food intake, which has the effect of regulating glucose homeostasis, lipid metabolism, gastric emptying and feelings of satiety ¹⁹ (Figure 1).

Novo Nordisk has developed ²⁰ and marketed two GLP1RAs, liraglutide (Saxenda) and semaglutide (Wegovy), both recombinant peptides, for treatment of obesity. (Semaglutide is also marketed as Ozempic for type 2 diabetes (T2D)). Liraglutide is taken by daily subcutaneous injection, while semaglutide is injected weekly ¹⁵. The intravenous half-life of native human GLP-1 is mere minutes ²⁰. Consequently, enabling molecular engineering and chemistry was undertaken by Novo Nordisk to generate these GLP-1 analogues with a suitably long half-life and potency ²⁰. Both drugs are intended for use as adjuncts alongside caloric restriction and increased physical activity for weight management in obese or overweight adults and children aged 12 to 17 years with at least one weight-related comorbidity, such as T2D, dyslipidemia or hypertension, ^{15, 21}.

Novo Nordisk is currently progressing eleven drug candidates through clinical development, the most advanced of which are NN-9932 (semaglutide), CagriSema (cagrilintide + semaglutide), and cagrilintide, and are either in pre-registration or Phase III clinical trials (Table 2). Across Novo Nordisk's anti-obesity portfolio, at least half of all candidates are based on mechanisms of action that include GLP-1 receptor or GIP receptor agonism ¹⁵. Amylin receptor biology also features as a target for half of the emergent drug candidates ¹⁵.

Eli Lilly has developed tirzepatide, a novel, first-in-class, ¹⁵ synthetic peptide designed to be a dual agonist of GLP-1 and GIP ²². The drug is marketed as Zepbound for treatment of overweight/obese patients and Mounjaro for treatment of T2D. It is delivered weekly via subcutaneous injection. Eli Lilly sponsored SURMOUNT-5, (NCT05822830), a Phase IIIb, open label, multi-centre, randomised clinical trial to compare the efficacy and safety of tirzepatide (Zepbound) versus semaglutide (Wegovy) in overweight or obese adults and at least one additional named weight-related comorbidity that was not T2D ²⁴. Greater weight loss and reduction in waist circumference was achieved with tirzepatide compared to semaglutide at 72 weeks ²³.

Like Novo Nordisk, Eli Lilly also has a considerable portfolio of 11 novel drugs in development for treatment of obesity, five of which are either GLP1RAs or GIPRAs ¹⁵. The other assets are based on amylin receptor biology, activin receptor biology and peptide YY. Most products in this portfolio are peptides, though two small molecules and one monoclonal antibody are also being developed. Orforglipron calcium (licensed from Chugai Pharmaceutical Co. Ltd) and retatrutide are the most advanced and are in Phase III clinical trials (Table 2). At least three of the drug candidates in development are intended for oral delivery ¹⁵.

Noteworthy Failures

While Novo Nordisk and Eli Lilly have enjoyed considerable success with their incretin mimetics, Pfizer has not yet reaped the reward of its efforts in developing similar drugs for chronic weight management. Pfizer has unsuccessfully attempted to develop two GLP1RA drug candidates, lotiglipron (PF-07081532), co-developed with Heptares Therapeutics Ltd., and danuglipron (PF-06882961), both small molecules and new molecular entities intended for oral delivery for treatment of obesity. Lotiglipron was discontinued in 2023 owing to unfavourable pharmacokinetic drug-drug interaction data from two Phase I studies and to elevated transaminases indicative of liver dysfunction in a subset of patients ²⁴.

Pfizer's refocused efforts on danuglipron also ended in a decision to discontinue its development in April 2025 following a review of all available clinical trial data, regulatory input and after a single asymptomatic clinical trial participant exhibited potential drug-induced liver injury that resolved after the drug was withdrawn ²⁵. Despite these setbacks, Pfizer appears committed to the obesity market and continues to progress PF-07976016, a first-in-class, orally delivered small molecule GIP receptor antagonist for treatment of obesity, for which safety and efficacy is currently being evaluated in a dose-ranging Phase II study, (NCT06717425).

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5. Targeting the Melanocortin System to Treat Hereditary Obesity

While obesity most often arises from lifestyle choices, particularly surrounding the balance of caloric intake and physical activity ^{26, 27}, genetics may also play a role in a small subset of individuals. Loss-of-function mutations affecting genes in the leptin-melanocortin pathway, particularly MC4R, POMC, PCSK1 and LEPR, (Figure 2), predispose individuals to hyperphagia and severe early onset obesity ²⁸ (Table 3).

The central melanocortin system is a neuro-immuno-endocrine hormone system that encompasses several central nervous system circuits ²⁹ and controls various physiological functions, including food intake ^{29, 30}. Melanocortins are a family of neuromodulatory peptides derived from the polypeptide, pro-opiomelanocortin (POMC), by tissue-specific cleavage ^{31, 32} through the action of prohormone convertases ³¹. Pro-peptide POMC expression is induced by binding of leptin to the LEPR on POMC neurons in the arcuate nucleus of the hypothalamus ^{28, 30}. Proprotein convertase subtilisin/kexin type 1 (PCSK1), initiates cleavage of POMC into melanocortin family peptides, including α- and β- melanocyte stimulating hormones (αMSH, βMSH) ³⁰. These melanocortin ligands activate the MC4R on neurons in the paraventricular nucleus of the hypothalamus ²⁸, thereby suppressing appetite, promoting satiety and stimulating energy expenditure ³³ (Figure 2).

Table 3: Selected genetic causes of obesity

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Setmelanotide, an MC4R agonist and first-in-class treatment for hereditary obesity

Setmelanotide, (Imcivree), is an MC4R agonist discovered by Ipsen SA and developed by Rhythm Pharmaceuticals that has been approved in the US since 2020 for treatment of obesity due to deficiencies of POMC, PCSK1 or LEPR confirmed by genetic testing ¹⁵ and since 2022 for syndromic obesity due to Bardet-Biedl Syndrome, a rare genetic ciliopathy ³⁴. Its utility in treating a variety of other syndromic obesities is still being evaluated ¹⁵. In patients aged two years and older ³⁵, Imcivree is delivered by daily subcutaneous injection ³⁶.

Setmelanotide is a disulfide cyclic synthetic peptide, eight amino acids long, capable of crossing the blood-brain barrier ³⁷ where at its site of action in the hypothalamus, it can activate several melanocortin receptors ³⁷. It is a potent MC4R agonist at nanomolar concentrations, ³⁸ and exhibits high affinity for the receptor. It is reasonably stable with an elimination half-life of approximately 11 hours ³⁶. By agonising MC4R, it restores appetite control and increases energy expenditure ³³ without directly treating the underlying genetic causes of obesity that occur upstream of MC4R activation. Setmelanotide was proven effective for weight loss in these genetically defined populations and is generally well tolerated ³⁹.

Drug Development Pipeline for Genetic Causes of Obesity

Rhythm Pharmaceuticals is also developing investigational drugs, RM-718 and bivamelagon, both MC4R agonists for treatment of hypothalamic obesity ¹⁵. RM-718, described by Rhythm Pharmaceuticals as a "next-generation MC4R agonist" is a synthetic heptamer (seven amino-acid peptide) delivered subcutaneously weekly ¹⁵. Unlike setmelanotide, which can activate melanocortin receptors MC3R and MC1R in addition to MC4R ³⁶, RM-718 by design, avoids stimulating MC1R ⁴⁰ and thereby avoids the common hyperpigmentation adverse event ⁴¹ that can arise when MC1R is stimulated ⁴². RM-718 is currently in Phase I for obesity and hypothalamic obesity indications, ⁴³.

As an alternative to injectables, Rhythm Pharmaceuticals is also developing bivamelagon, (LB54640), for daily oral delivery ⁴⁴. LB54640 is a small molecule MC4R agonist licenced from LG Chem Ltd. ¹⁵ presently in Phase II clinical trials for hypothalamic obesity ⁴⁵. Preclinical and Phase I work suggests that LB54640 should not cause hyperpigmentation ⁴⁴.

Palatin Technologies is targeting selective agonism of melanocortin receptors to treat inflammatory and autoimmune conditions, with a particular focus on ocular indications ⁴⁶. In 2019, the company received FDA-approval for Vyleesi (bremelanotide acetate), an injectable α-MSH analogue, making it the first FDA-approved melanocortin agent ^{15, 47}. While Vyleesi is indicated for Hypoactive Sexual Desire Disorder (HSDD) in premenopausal women ¹⁵, bremelanotide is also in development as an obesity treatment. Topline results from a recent Phase II study ⁴⁸ in which bremelanotide was co-administered alongside tirzepatide suggest that bremelanotide may help to prevent weight regain, a known issue after tirzepatide treatment ceases ^{49, 50}. Palatin Technologies has two additional MC4R agonists, PL-7737 which is an oral small molecule, and PL-8905 which is a synthetic peptide, both in preclinical development for obesity indications, with the former specifically targeting obesity caused by LEPR deficiency ¹⁵.

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6. Other Anti-Obesity Drugs

Qsymia was approved in 2012 ¹⁵ and includes two active agents, phentermine and topiramate, in an extended-release capsule ⁵¹. Qsymia is used in combination with recommendations for diet and physical activity to achieve weight loss in obese individuals at least 12 years old and in overweight adults with at least one weight-related comorbidity. One of the active ingredients, phentermine, inhibits reuptake of serotonin, noradrenaline and dopamine, effectively increasing their concentration and leading to appetite suppression or feelings of satiety ^{52, 53}. The other active agent in Qsymia, topiramate, is a neurostabiliser that achieves weight loss via an unknown mechanism of action ^{54, 55}. During its use in seizures and migraine, topiramate-induced weight-loss was considered a major adverse event ^{15, 55}. Contributing factors for weight-loss may include dysgeusia ⁵⁶ and GABA activation culminating in appetite suppression and increases in satiety ⁵⁷.

Like Qsymia, Contrave, (bupropion hydrochloride + naltrexone), marketed in the US since 2014, is also a combination of two active ingredients delivered orally in an extended-release tablet ¹⁵. The drug is an anorexiant designed to reduce hunger and cravings ⁵⁸, and is used as a medical support to diet and exercise interventions for weight loss in overweight individuals with a weight-related co-morbidity or obesity ⁵⁸. Its active ingredients are small molecules that have been individually marketed as drugs for applications other than weight loss ⁵⁸. The precise mechanism of action of Contrave is unknown though it is believed to work by targeting the hypothalamic melanocortin system (Figure 2) and the mesolimbic reward system ⁵⁹. Bupropion, a dopamine reuptake inhibitor ¹⁵, activates POMC neurons to secrete neurotransmitters that reduce the desire to eat, and naltrexone, an opioid antagonist ¹⁵, blocks the autoinhibitory feedback loop in the hypothalamus to keep POMC neurons activated ^{58, 59}.

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7. Sales, Market Size and Opportunity

The US obesity market is buoyant and has not yet peaked. The US market alone, which was worth ~$12B in 2024 is expected to be worth ~ $149B by 2031 ¹⁵.

Global annual sales for Zepbound, which were ~$4.9B USD in 2024 are forecast to grow to ~$26B-$28B USD by 2031, most of which is expected to be achieved through significant US sales (~$27.8B USD) versus the rest of the world, (~$204M USD).

Although Wegovy reported greater global annual sales than Zepbound in 2024, (~$8.4B USD), global annual sales for Wegovy (~$22B USD) are forecast to be similar but lower than Zepbound (~$26B-$28B USD) by 2031. This is likely due to competition from Zepbound in the US, where annual sales of Wegovy are projected to peak at ~$13B USD by 2027, which is approximately half of the anticipated peak sales value for Zepbound. The ex-US market for Wegovy is anticipated to generate ~$10B USD of annual sales by 2031.

Sales of setmelanotide are forecast to exceed $1B USD by 2030 ¹⁵, with the US market expected to represent ~80% of global sales. Annual global sales of Qsymia and Contrave are comparatively modest. Nevertheless, Contrave has recently reported increasing its year-on-year revenues for two consecutive years, citing greater access in the US and expansion into other markets as the reasons behind its recent sales growth ⁶⁰. A patient-based forecast of sales for Qsymia in obesity anticipates year-on-year increases in sales to the end of the forecast period (2031), when annual US sales are expected to reach $58M.

The market is set to expand as more treatment options are approved. For example, the availability of oral formulations and the approval of drugs with greater efficacy and durability are likely to be favoured by patients, and by offering alternative treatment options, new drugs will likely expand the overall patient population eligible for weight-loss pharmacotherapy.

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8. Future Prospects

Though it is widely acknowledged that being overweight generally increases an individual's risk of ill-health, weight-loss is often difficult to achieve through willpower alone and pharmaceutical support to aid weight-loss has existed since the mid-twentieth century. In recent years, the emergence of safe and effective weight-loss pharmacotherapy has offered patients non-invasive alternatives to bariatric surgery to restore a healthy body weight and metabolic status.

Despite the evident success of marketed weight-loss pharmacotherapies like peptide drugs, developers realise that patients would prefer alternatives to regular dosing by subcutaneous injection, which is currently the most commonly available route of administration. Some of the most advanced drug candidates in the pipeline, NN-9932 (Novo Nordisk), cagrilintide (Novo Nordisk) and orforglipron calcium (Eli Lilly) are intended for oral delivery. Long-acting formulations that would increase the intervals between dosing would also be attractive to patients and offer a significant market advantage to drug developers.

Drugs with mechanisms of action that differ from or build upon those of already marketed drugs are also promising. For example, amylin receptor (AMYR) agonists are an emerging class of anti-obesity medications. The AMYRs are heterodimers formed by combining a cell surface expressed calcitonin G protein coupled receptor (CTR) with any one of three transmembrane proteins, known as receptor activity modifying proteins (RAMPs). Therefore, three different AMYR subtypes exist. Binding with a RAMP alters the structure and function of the CTR. Consequently, the AMYR has a great affinity for amylin, but not for calcitonin, (a hormone that regulates calcium and phosphate levels in blood).

Amylin is a 37 amino-acid polypeptide gut hormone that regulates satiety postprandially. It is co-secreted with insulin from the pancreas upon arrival of nutrients to the small intestine and regulates glucose homeostasis by slowing gastric emptying, suppressing glucagon secretion and ultimately suppressing hunger. In the hypothalamus, amylin can work synergistically with, or independent of leptin to affect anorexigenic signalling.

Late-stage drug candidates that agonise AMYRs include cagrilintide, and the combination drug CagiSema, (Novo Nordisk). Others in earlier clinical development are AZD-6234 (AstraZeneca), eloralintide (Eli Lilly), petrelintide (Eli Lilly via Zealand Pharma) and NN-9490 (Novo Nordisk).

Drug products formed by combining anti-obesity agents is also promising. This approach allows for repurposing of approved drugs and may improve potency by invoking multiple mechanisms of action. The most advanced of these, CagriSema (Novo Nordisk) is at Phase III and combines cagrilintide, a lipidated amylin analogue with semaglutide. At Phase I, (insulin lispro + pramlintide) (Adocia SAS) combines a fast-acting insulin formulation with pramlintide, an amylinomimetic drug marketed for T2D, while the combination of two ultra long-acting peptides, MET-233i, a nutrient-stimulated hormone analogue that targets amylin, with MET-097i, a GLP1RA, form another drug product, (MET-233i + MET-097i) (Metsera Inc).

One of the potentially undesirable side-effects of weight-loss drugs is loss of lean mass, which, if excessive, could increase an individual's frailty and reduce their strength and functionality. Lean mass loss was reported for patients on semaglutide (~10% loss relative to baseline) and tirzepatide (~11% loss relative to baseline) during Phase III clinical trials, STEP-1, NCT03548935 and SURMOUNT-1, NCT04184622, respectively ^{61, 62}. Notably, in SURMOUNT-1, lean mass loss as a proportion of total mass lost was similar (~25%) across the treatment and placebo groups⁶², and in the treatment group, physical function scores were improved relative to baseline and by comparison to the placebo group at the end of the study ^{62, 63}. This suggested that the lean mass loss was generally not debilitating. Moreover, despite the lean-mass losses, STEP-1 reported an overall improvement in the lean body mass:fat mass ratio, which may be indicative of improved physical condition.

Lending further support, a study of anti-diabetic drugs and sarcopenia risk found no significant association between GLP1RAs and sarcopenia (low skeletal muscle mass and poor muscle function) ⁶⁴. Nevertheless, the question of whether loss of lean body mass is an issue of concern remains open ^{65, 66, 67}.

Candidate drugs are in development for treatment of sarcopenic obesity, often a disease of aging and defined by the coexistence of obesity and sarcopenia ⁶⁸. For example, Immunis Inc is developing IMM01-STEM for sarcopenic obesity ⁶⁹ and Biophytis SA has progressed BIO101 (20-hydroxyecdysone) through a Phase I clinical trial ⁷⁰ for age-related sarcopenia, including sarcopenic obesity.

Long-term durability of weight-loss from pharmacotherapy has yet to be mastered. Amongst a cohort of overweight or obese individuals with preexisting cardiovascular disease, weight-loss on semaglutide was sustainable for at least four years ⁷¹. In overweight and obese adults, weekly tirzepatide treatment yielded weight loss sustained over three years ⁷². Without lifestyle adjustments, however, rapid and substantial weight regain has been reported when these drug interventions were withdrawn ^{50, 73} reflective of the chronicity of obesity. Some options have successfully prevented weight regain in these scenarios, such as low dose bremelanotide (Palatin Technologies) used as a maintenance therapy following withdrawal of tirzepatide ^{48, 74}.

Looking to the future, the availability of safe and effective weight loss pharmacotherapy will directly impact the health and wellbeing of obese individuals and has the potential to impact the delivery of population-level healthcare and influence public health messaging around weight-management. While good progress has already been made in bringing safe and efficacious weight-loss drugs to market, the field continues to evolve. Formulations compatible with oral dosing are expected to increase use of these medicines and to benefit patient compliance. Opportunities exist to develop drugs with a durable weight-loss effect in the absence of ongoing pharmacotherapy which would be greatly attractive to patients. Co-therapies and drugs that preserve lean-mass, prevent excessive lean-mass loss or that promote loss of fat- over lean- mass may also find a sizeable market. As we come to a more comprehensive understanding of the signalling and molecular mechanisms underlying obesity it is very likely that new drugs with novel mechanisms of action will also enter clinical development.

Overall, the medicine cabinet for treating obesity is filling up, demonstrating what scientific innovation and endeavour can deliver for complex and multi-factorial metabolic diseases.

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9. References

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