Obesity is linked to a multitude of chronic conditions, including type 2 diabetes (T2D), cardiovascular disease, cancer, and hypertension, among many others. From a global epidemiologic perspective, it is associated with increased morbidity and mortality, healthcare costs, absenteeism, and presenteeism (1). Of major concern, despite a long history of public health efforts, rates of global obesity, childhood obesity, and severe obesity have risen steadily (2). In the United States (US), it is estimated that 50% of the adult population will have obesity by 2030 (3). Economic analyses suggest that direct medical costs attributed to obesity among adults in the US are over $260 billion (4).

Evidence-based guidelines provide recommendations to healthcare professionals (HCP) for intense lifestyle interventions (ILI) with the aim of weight reduction and mitigation of cardiovascular risk (5). Unfortunately, multicomponent programs are often unreimbursed and poorly accessible, especially for individuals of lower socioeconomic status, who have disproportionate rates of obesity (3). Moreover, even the most intense, high-quality strategies do not result in long-term weight loss (6). Participants often find it difficult to continue with the healthy habits practiced during the intervention, especially without continued support for maintenance. Although such programs may help people achieve clinically meaningful weight reduction in the short-term, the modest effects have not translated into significant cardiovascular benefit (7).

Metabolic bariatric surgery (MBS) stands out as the most effective treatment for severe obesity, demonstrating significant and sustained weight loss while also improving various obesity-related health complications (8). Until recently, it was the only weight loss intervention to show reductions in mortality (9, 10). Despite its efficacy, the number of individuals opting for bariatric surgery remains low, with less than 1% of the eligible population receiving these procedures in the US (11). For decades, there has been a substantial therapeutic gap between lifestyle interventions and MBS.

The development of safe and effective pharmacological agents for obesity has encountered significant challenges, marked by the emergence and subsequent decline of many medications due to adverse side effects, such as cardiovascular risk (12, 13). The past decade, however, has witnessed a resurgence in the development and approval of anti-obesity medications (AOM). In the US, aside from phentermine and orlistat, approved by the Food and Drug Administration (FDA) in 1959 and 1999, respectively, phentermine/topiramate extended release (Qsymia^®) was approved in 2012. In 2014, naltrexone/bupropion sustained release (Contrave^®) and liraglutide 3 mg (Saxenda^®) were approved for chronic weight management. Adoption of these agents was underwhelming, however (14). These drugs, spanning diverse mechanistic pathways, have failed to achieve a reduction in mean body weight exceeding 10% (13, 15). Semaglutide 2.4 mg (Wegovy^®) and tirzepatide (Zepbound^®), approved for the treatment of obesity in 2021 and 2024, respectively, produced corresponding mean weight loss of 17% and 23% in clinical trials of subjects with obesity, but without T2D (16, 17). Given the efficacy and safety of these novel agents, utilization soared (18). Until recently, demand far outweighed supply in several markets, contributing to access challenges and fragmented treatment (19). However, the cost of these medications and coverage exclusion by many payors in the US results in access challenges for many patients that could benefit. Additionally, many public healthcare insurance programs do not reimburse for AOMs, further exacerbating access inequalities. Despite this, it is thought that this new generation of therapeutics represents a historical inflection point in the advancement for improving obesity and related chronic metabolic diseases. Moreover, compared to older medications, these agents show more weight loss in individuals with T2D, a population which is associated with inferior outcomes across many treatment modalities (20).

It is not a coincidence that AOMs are demonstrating progressively superior effectiveness. The adipocyte hormone leptin was discovered in 1994 (21). Since then, our understanding of the metabolic, cellular, and molecular physiology of human weight regulation has expanded greatly. These discoveries have further established obesity as a chronic, progressive biological disease requiring physiologic treatments beyond willful energy restriction and expenditure alone. Additionally, genetic predisposition plays a role, influencing metabolic processes and fat storage propensity (22). A negative energy balance lowers metabolic rate and intensifies hunger and cravings (23, 24). The central nervous system (CNS) is at the center of integration and regulation of long-term energy stores (adipose mass). Multiple brain areas, with genetic determinants, are involved in the control of ingestive behaviors, including centers that not only modulate satiety, but also those responsible for sensory inputs, learning, memory, emotions, cognitive control, and hedonic behaviors (25). The CNS mediates metabolic processes that regulate weight in response to peripheral signals derived from nutrients, hormones, and neurological inputs. Given that the gastrointestinal (GI) tract contains the sentinel tissues to first encounter ingested nutrients, many of these signals are gut peptides that inform the brain, either through stimulated hormones or through the vagus nerve, a connection known as the gut-brain axis. These hormones include glucagon-like peptide 1 (GLP-1), glucose dependent insulinotropic polypeptide (GIP), oxyntomodulin, and peptide tyrosine-tyrosine (PYY) secreted from intestinal endocrine cells, and the pancreatic hormones glucagon and amylin (26). They peak postprandially and are considered “metabolic switches”, involved in shifting metabolic processes from the fasting to the fed state (27). Detailed reports on cellular and molecular physiologic mechanisms for specific agents have been published (28).

Endogenous gut hormones however, are enzymatically metabolized within a few minutes (29). These peptides have been modified with fatty acid moieties to promote albumin binding, thereby extending their half-lives significantly for pharmacotherapeutic effectiveness (30). Not surprisingly, these advances have resulted in more targeted pharmacological strategies. Despite the array of available medications, there remains an urgent and ongoing effort to formulate novel drugs that comprehensively address the unmet needs related to heterogeneity of obesity and response to a given therapy. Since neuro-enteroendocrine pathways are redundant and coordinated, targeting more than one of these signals results in more potent and synergistic effects on weight loss outcomes. The clinical rationale for this strategy, utilized in other chronic metabolic diseases, is manifested in established therapies like combining phentermine and topiramate, or bupropion and naltrexone. Using a more refined tactic, unimolecular agents can stimulate more than one receptor, augmenting desired therapeutic outcomes, tirzepatide being a prime example. In more refractory cases, drugs with varied mechanisms of action (MOA) in combination are used in clinical practice (31). Notably, all biologic therapies for obesity should be used as adjuncts to optimal lifestyle modification. Obesity is a result of an obesogenic environment exerting its effects in genetically predisposed individuals, manifested as poor nutrition, reduced physical activity, and maladaptive behaviors. AOMs can help patients overcome biological forces that promote unhealthy dietary habits. Pharmacotherapy can produce even better results when used together with more intense lifestyle interventions, especially with older generation medications (32–34). Moreover, even with the use of these therapies, patients need to be appropriately supported so that nutrition is optimized, muscle mass is maintained, and nutritional deficiencies are prevented. The ultimate combination treatment is applying AOMs before and/or after MBS (35–37).

The aim of this narrative review is to provide the most up to date presentation of molecules under development for the chronic treatment of obesity. Because the presentation of data related to emerging progress in this space changes literally from week to week, the purpose of this report is to provide the reader a view into the world of future therapies. As such, the present review includes all publicly available human data and is not restricted exclusively to peer-reviewed publications. We only include drugs in development that have reported effects on weight loss. Figure 1 shows the various agents presented in this report and their corresponding mechanistic groups.

For this narrative review, we searched PubMed, clinicaltrials.gov, conference proceedings, pharmaceutical websites, and press releases from June 2008 through June 2025. The search terms used to identify emerging medications for obesity treatment included: ‘obesity,’ ‘pharmacotherapy,’ ‘anti-obesity medications’, and ‘clinical phases’. Pipeline drugs, defined as pharmaceuticals for chronic weight management in development that have not yet been approved for clinical use, were included in the narrative review if human trial data were publicly available with sufficient information on the drug’s time of development, clinical phase, MOA, dosing information, and reporting on weight loss outcomes. Preclinical data were excluded. We included only data for adult subjects unless studies pooled adult and pediatric participants for the therapy of rare genetic or syndromic obesity. Data were excluded if the development on a particular agent was terminated. Descriptions of adverse effects are beyond the scope of this report. Tables 1 and 2 list the agents reviewed with their MOA, phase of development, trial data, and associated biopharmaceutical companies, for target populations with and without T2D, respectively.

Figures 2A-C show the mean weight loss outcomes segmented in their investigation phases and periods of observation.

Obesity and related complications are stubborn conditions that defy long-term improvement with lifestyle interventions alone (7). Until recently, bariatric surgery was the only therapy to produce significant durable weight loss and amelioration of metabolic comorbidities. The recent appearance of highly effective AOMs, semaglutide and tirzepatide, heralds a new era in the treatment of obesity. Beyond weight loss, data are emerging for the undeniable benefits on a wide variety of maladies, including cardiovascular disease (155–157), obstructive sleep apnea (158), MASLD (159), addiction disorders (160, 161), and dementia (162). In people with prediabetes, both medications have shown remarkable effects on glycemic control (163, 164). There is also observational evidence that GLP-1 RAs may protect against obesity-associated cancers (165).

Despite these promising benefits, unmet needs remain. Not all patients can tolerate current therapies, mostly due to adverse GI symptoms. Some individuals have contraindications to incretin-based medications, such as clinically significant gastroparesis or history of pancreatitis. Because of heterogeneity of response, some patients may exhibit suboptimal weight loss. In fact, at one year after initiation, only 20-50% of patients may remain on therapy (166, 167). Aside from adverse effects, other reasons that have been implicated for real-world discontinuation include perceived or realized suboptimal effectiveness, cost and access challenges, and socioeconomic inequalities (167). Moreover, the expected weight reduction in those with extreme obesity may be insufficient to meet all desired health outcomes and goals. HCPs and patients should not lose sight that AOMs are adjuncts to optimal lifestyle behaviors. In modern high volume, fast paced clinic settings it is tempting to rely on pharmacotherapy as the sole intervention. Some patients may need extra support for the continuance of healthy lifestyle behaviors, even with long-term use of pharmacologic agents. Finally, the high cost and lack of reimbursement for many patients limits access to these therapies for considerable numbers that could benefit. As many of these nascent molecules reach the market, the hope is that economic forces will drive down prices.

Even if these challenges are addressed, questions remain. For example, as multiple agents with similar MOA, efficacy, and safety enter an increasingly crowded market, how will each of them be positioned to address specific patient phenotypes? For patients with T2D, perhaps duration of their disease and degree of glycemic control will dictate choice of therapy based on effectiveness for HbA1c reduction. Should patients with cardiovascular disease be treated with drugs that have proven morbidity and mortality benefit, or are these outcomes a class effect? Will AOMs that target glucagon receptors be superior for reversing liver fibrosis? For which patients would an amylin receptor agonist be the first choice? Are there clinical outcomes for which the use of muscle preserving therapies are desired? And if so, which patients would benefit the most? Much research will be needed to answer these questions, both from prospective randomized controlled trials and real-world observational studies.

Similarly, beyond targeting multiple receptors with one molecule, more work is needed to assess enhanced efficacy and safety of combining drugs with divergent MOA. As previously noted, the pharmaceutical industry has already begun to examine possible synergistic strategies, such as targeting receptors for NuSH’s and the melanocortin system, or incretin therapies with myostatin and activin receptor antagonists. Likewise, would CMAs safely push weight loss and metabolic benefits beyond the plateau commonly experienced with existing AOMs? Since effectiveness of cannabinoid receptor antagonists is limited by brain penetration and neuropsychiatric side effects, perhaps using lower doses or agents with less access to the CNS in combination with NuSH mimetics would result in superior outcomes. Finally, there is much to learn for how best to combine emerging therapies in bariatric surgery patients with insufficient weight loss or recurrent weight gain. Many unanswered issues remain, including choosing the best agent, timing of initiation after a procedure, appropriate monitoring for vitamins and micronutrients, and knowing when weight loss may be excessive. Just a few years ago, these questions were not being asked because our pharmacologic therapies were very limited.

Despite the pleiotropic benefits increasingly observed for existing novel AOMs, HCPs and patients should temper enthusiasm with potential long-term adverse effects, and costs to society and healthcare systems. This is especially true if overweight and obesity are excessively medicalized, leading to overutilization of expensive treatments, including current and emerging pharmacotherapies (168). The Lancet Diabetes & Endocrinology Commission on the Definition and Diagnosis of Clinical Obesity aims to refine definitions of excess adiposity to help prioritize therapeutic interventions and public health policies (169).These efforts are quite relevant as economic analyses have challenged the cost effectiveness of novel agents despite their efficacy and benefits (170). In the United Kingdom, the National Institute for Health and Care Excellence (NICE) has provided guidance to the National Health Service (NHS) regarding cost effective use of novel AOMs, prioritizing patients with higher BMI and related complications, thereby limiting access for those with less complicated obesity (171). Additionally, given the tremendous increase in utilization of incretin hormone medications, unforeseen adverse events may emerge that were not identified in the pivotal clinical trials, such as psychiatric events, hair loss, and ocular complications (172). Because they cause C-cell hyperplasia in rodent models, GLP-1 based drugs are contraindicated in patients with personal or family histories of medullary thyroid cancer or multiple endocrine neoplasia type 2. Large observational studies show mixed results with respect to associations between use of GLP-1 medications and incidence of thyroid cancer (173, 174), without proven causality in humans. Preclinical studies have indicated that chronic activation of GLP-1 receptors may induce dysplastic pancreatic lesions (175), but large human datasets have not shown a causal relationship between GLP-1 RAs and pancreatic cancer (173, 176).

This report has significant limitations that should be considered. Given the aim of introducing the reader to novel AOMs in the pipeline, much of the data are limited by small sample sizes and early stages of development. As such, due to the narrative nature of the present review, it lacks systematic control for multiple biases and the power of a meta-analytic approach. Because of incongruent phases of development and heterogeneous study designs, it is impossible to compare efficacy, safety, and tolerability between the reported agents. It is also possible other nascent molecules may have been overlooked if they were not identified by our search strategy.

Nevertheless, the medical profession should carefully embrace the new era of treating excess adiposity and related complications. As our therapeutic toolbox grows, the horizon appears bright for people living with obesity and metabolic diseases.

Safe and effective treatments for obesity have lagged behind the relentless epidemic of excess adiposity. In the last few years, highly effective and safe AOMs have appeared for clinical use, a culmination of decades of work by many to better understand the complexity of human weight regulation. We are starting to witness the fruits of that work with dozens of agents in development that will be more efficacious for obesity and its related complications. As they emerge, research is needed to learn how best to use them in combination with each other and with other modalities. The field is primed for optimizing precision approaches for the benefit of patients suffering with chronic metabolic disease.