Incretin polyagonists as an alternative to bariatric surgery to manage obesity

Abstract

Incretins are gut hormones involved in maintaining metabolic homeostasis in the human body, and disorders of the incretin system are recognized as contributing to the pathobiology of metabolic dysfunction and obesity. Incretin polyagonists are transforming the landscape of obesity treatment by offering potent, non-surgical alternatives to bariatric procedures. Acting on multiple incretin and related receptors, these novel pharmacological agents harness the synergistic effects of gut hormones such as glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon to achieve unprecedented weight loss and metabolic improvements. Recent clinical trials demonstrate that dual and triple agonists can produce weight reductions comparable to, or in some cases approaching, those seen with bariatric surgery, while simultaneously improving glycemic control, lipid profiles, liver fat, and cardiovascular risk factors. Unlike conventional monotherapies, these polyagonists address the complexity of energy homeostasis and metabolic dysfunction in obesity, with some agents displaying a favorable side effect profile and thereby enhancing patient tolerability. Practical considerations, such as ease of administration, cost, long-term safety, and accessibility, remain evolving challenges; yet, incretin polyagonists have rapidly gained prominence in clinical guidelines for the management of obesity and type 2 diabetes mellitus. As evidence mounts regarding their efficacy, safety, and potential to modify cardiometabolic disease risk, incretin polyagonists emerge as promising alternatives, especially for patients unable or unwilling to undergo bariatric surgery. Ongoing research will further define their long-term role, comparative effectiveness, and optimal integration into multidisciplinary obesity care. This review discusses the current evidence-base for optimal use of incretin polyagonists as an alternative to bariatric surgery.

Key Words: Incretin polyagonists; Obesity; Bariatric surgery; Weight loss; Metabolic health; Tirzepatide; Type 2 diabetes mellitus

Core Tip: Incretins are gut hormones involved in metabolic homeostasis of human body and disorders of the incretin system is recognized as the main reason for the pathobiology of metabolic dysfunction and obesity. Incretin polyagonists are transforming the landscape of obesity treatment by offering potent, non-surgical alternatives to bariatric procedures with remarkable improvements in complications of adiposity including type 2 diabetes and metabolic dysfunction-associated fatty liver disease. Recent clinical trials demonstrate that dual and triple agonists can produce weight reductions comparable to, or in some cases approaching, those seen with bariatric surgery, while simultaneously improving glycemic control, lipid profiles, liver fat, and cardiovascular risk factors. This review discusses the current evidence base for optimal use of incretin polyagonists as an alternative to bariatric surgery.

INTRODUCTION

The historical journey of obesity management has undergone transformative shifts over the past few decades. Initially, pharmacological approaches were limited and often fraught with safety concerns, exemplified by the withdrawal of drugs such as amphetamines, fenfluramine, and sibutramine due to adverse cardiovascular or psychiatric effects. Surgical obesity management evolved significantly with the advent of bariatric procedures in the late 20^th century, notably gastric bypass and sleeve gastrectomy, which demonstrated dramatic, durable weight loss and improvements in metabolic comorbidities[1]. Despite the effectiveness of bariatric surgery, its invasive nature, cost, and eligibility criteria limited widespread adoption, underscoring the need for alternative therapies suitable for a larger proportion of people with obesity.

The conceptual breakthrough in anti-obesity pharmacology emerged with the discovery of the “incretin effect” in the 1960s, in which oral glucose was found to elicit a greater insulin response than intravenous glucose, suggesting the involvement of gut-derived hormones in glucose homeostasis[2]. Subsequent research led to the identification of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which became central targets for metabolic intervention[3]. The development of GLP-1 receptor agonists (GLP-1 RAs) for diabetes revealed their secondary benefits in weight reduction, spurring a paradigm shift toward hormones as therapeutic agents for obesity. These insights laid the groundwork for polyagonists’ strategies that simultaneously target multiple gut hormone pathways to amplify weight loss and metabolic benefits.

From early mono-agonists such as exenatide and liraglutide, the field rapidly progressed to multi-receptor agonists, including dual and triple agonists capable of harnessing additive or synergistic effects on appetite regulation, insulin secretion, and energy expenditure[4]. This evolution represents a culmination of decades of understanding both drug mechanisms and surgical outcomes, positioning incretin-based polyagonists as a promising, less invasive alternative to bariatric surgery and ushering in a new era of personalized obesity pharmacotherapy.

THE INCRETIN SYSTEM AND PATHOPHYSIOLOGY OF OBESITY

The incretin system comprises key gut-derived hormones - GLP-1, GIP, and glucagon - which intricately regulate glucose homeostasis and energy balance[3]. GLP-1 is primarily secreted from intestinal L-cells after nutrient intake and acts via its receptor on pancreatic β cells to enhance insulin secretion in a glucose-dependent manner, while simultaneously suppressing glucagon release from α cells. GIP, produced by K cells in the proximal small intestine, also amplifies insulin secretion but, in contrast to GLP-1, can stimulate glucagon secretion[4,5]. Glucagon, derived from pancreatic α cells, promotes hepatic glucose production and maintains blood glucose during fasting. Together, these hormones fine-tune metabolic responses to food intake, and their rapid degradation by dipeptidyl peptidase-4 ensures tight physiological control of energy homeostasis[6,7].

Beyond their effects on glycemic control, incretin hormones play substantial roles in weight regulation and metabolic health. GLP-1 slows gastric emptying, reduces appetite, and increases satiety, thereby lowering caloric intake and promoting weight loss - effects that form the basis of current incretin-based obesity therapies[8]. GIP also affects adipose tissue biology by promoting fat storage in subcutaneous fat and impacts bone mass by limiting bone resorption and promoting bone formation. In addition, both GLP-1 and GIP modulate lipid metabolism, influence cardiovascular function, and participate in systemic energy balance[9]. The multifaceted actions of incretins across organ systems contribute not only to direct weight reduction but also deliver broader benefits such as reduced cardiovascular risk and improvement in obesity-related comorbidities[10].

The pathophysiology of obesity is marked by alterations in incretin secretion and response. In obese individuals, the “incretin effect” - the amplified insulin release after oral glucose - is blunted, primarily due to reduced pancreatic sensitivity to GIP; however, GLP-1 action may remain at least partially intact[4,5]. Fasting GLP-1 levels are typically similar between lean and obese people, but postprandial GLP-1 responses may be attenuated, potentially contributing to hyperphagia and dysregulated energy intake. Conversely, obese individuals often display elevated fasting and postprandial GIP levels, a compensatory mechanism that fails to normalize insulin secretion due to pancreatic resistance, further promoting hyperinsulinemia and adiposity[7]. Mechanisms such as leptin resistance, impaired ghrelin signaling, and hyperinsulinemia present in obesity can further compromise incretin pathways, exacerbating metabolic dysfunction and weight gain[9].

Collectively, the dysregulation of the incretin system in obesity underpins not only aberrant glucose metabolism but also maladaptive changes in appetite control, adipose tissue expansion, and energy balance[10]. These insights have propelled the development of incretin-based pharmacotherapies, which now rival bariatric surgery in their effectiveness for promoting weight loss and reducing metabolic risk[11].

EVOLUTION OF INCRETIN BASED THERAPIES

GLP-1 RAs: First generation

GLP-1 RAs represent the first generation of incretin-based therapies, revolutionizing the management of type 2 diabetes mellitus (T2DM) - and more recently, obesity - due to their efficacy in improving glycemic control and promoting weight loss[3]. Early agents such as exenatide (2005), liraglutide (2010), and lixisenatide (2012) were developed to resist rapid degradation by dipeptidyl peptidase-4, enabling prolonged pharmacological activity and effective glucose regulation. This was followed by dulaglutide (2014), albiglutide (2014), and semaglutide (2017). These drugs, administered as once or twice daily or weekly injections, demonstrated consistent reductions in glycated hemoglobin A1c and body weight, with participants losing 2-5 kg over several months[4]. The primary adverse effects reported were gastrointestinal - nausea, vomiting, diarrhea, and constipation - which often necessitate gradual dose escalations and sometimes led to treatment discontinuation. Other limitations included mild risk of injection site reactions, rare associations with pancreatitis, and potential risks related to delayed gastric emptying, such as increased aspiration risk in the perioperative period[12]. Additionally, some patients developed anti-drug antibodies (especially to exenatide), decreasing drug efficacy over time[13].

Development of dual and polyagonists

In response to the need for greater efficacy and fewer side effects, the field has rapidly advanced toward the development of dual and polyagonists, which simultaneously target multiple incretin receptors, such as GLP-1, GIP, and sometimes glucagon. Dual agonists - for example, those combining GLP-1 and GIP activities - have harnessed the complementary metabolic effects of both hormones, resulting in decreased energy intake, greater weight loss and improved glucose control compared to GLP-1 RAs alone[4]. Polyagonists go further by engaging three targets - GLP-1, GIP, and glucagon - with the latter offering an additional mechanism of increased energy expenditure. Critical to these advancements is the concept of biased vs balanced agonism: Balanced agonists engage receptors in a way that mimics physiological signaling, while biased agonists preferentially activate specific signaling pathways, such as those favoring weight loss or reduced side effects[12,14]. Studies demonstrate that biased agonism of GLP-1 or GIP receptors can lead to superior glycemic control, greater appetite suppression, and increased weight loss, while minimizing adverse events[15].

Biochemically, these multi-agonists are engineered peptides tailored for resistance to enzymatic degradation and optimized receptor selectivity. The pharmacological rationale for combining incretin receptor agonism is to leverage synergistic metabolic benefits, targeting multiple dysfunctional pathways typical in obesity and diabetes - such as impaired insulin sensitivity, inappropriate glucagon response, and dysregulated appetite signaling[4]. Notably, agents like tirzepatide, the first approved dual GLP-1/GIP agonist (2022), exemplify the clinical success of this strategy, achieving weight loss results approaching those of bariatric surgery and ushering in a new era of metabolic therapy[14].

Collectively, the evolution from first-generation GLP-1 RAs to sophisticated dual and polyagonists illustrates a paradigm shift in incretin-based therapy, driven by molecular innovation, pharmacological mechanism design, and clinical demand for efficacious, well-tolerated treatments for diabetes and obesity[3,15].

CLASSES OF INCRETIN POLYAGONISTS

The landscape of incretin-based anti-obesity pharmacotherapy has rapidly evolved to include a variety of single, dual, and triple agonists targeting GLP-1, GIP, and glucagon receptors. These agents are designed to harness and synergize multiple metabolic pathways, producing weight loss and metabolic benefits that approach or in some cases rival those of bariatric surgery[16]. A schematic diagram showing how the incretin poly-agonists work is depicted in the Figure 1 below. The main classes include dual GLP-1/GIP agonists, dual GLP-1/glucagon agonists, triple agonists (GLP-1/GIP/glucagon), and other novel combinations such as GLP-1/amylin co-agonists and emerging gut hormone polyagonists[17].

Figure 1 A schematic representation of the mechanisms of action of incretin polyagonists. GLP-1: Glucagon-like polypeptide-1; GIP: Glucose-dependent insulinotropic polypeptide.

Dual GLP-1/GIP receptor agonists

Tirzepatide is the most clinically advanced dual GLP-1/GIP receptor agonist. Multiple phase 3 randomized controlled trials, the SURPASS and SURMOUNT trials, have demonstrated that tirzepatide induces dose-dependent, substantial weight loss - up to 20.9% at 72 weeks in adults with obesity, which is at par with the average outcomes seen following bariatric surgery[17]. In addition to weight reduction, tirzepatide improves glycemic control, blood pressure, and lipid parameters, with most patients also experiencing improvements in metabolic dysfunction-associated steatohepatitis (MASH) and other metabolic comorbidities. Its overall tolerability is similar to GLP-1 RAs, with gastrointestinal adverse effects such as nausea and vomiting being most common, but generally transient and manageable[17]. Head-to-head data show that Tirzepatide’s efficacy exceeds that of established GLP-1 RAs like semaglutide, while major safety signals such as hypoglycemia, pancreatitis, or cardiovascular risk have not shown significant increases compared to GLP-1 RAs[17]. The high-end weight loss efficacy combined with oral and injectable formulations positions dual GLP-1/GIP agonists as transformative anti-obesity therapies, allowing for durable, nonsurgical weight loss in a broad spectrum of patients[17].

Dual GLP-1/glucagon receptor agonists

Several agents have entered late-stage trials in the dual GLP-1/glucagon receptor agonist class, including mazdutide (LY3305677), cotadutide (SAR425899), and survodutide. Mazdutide has demonstrated a mean placebo-corrected weight loss of 12.6% at 24 weeks in phase 2 trials, with improvements in glycemic, lipid, and liver enzyme profiles in patients with obesity and overweight[17]; it is now in phase 3 for both obesity and MASH. Cotadutide showed a weight loss of 5%-6% and promising efficacy in reducing liver fat, albeit generally considered less potent for body weight than GLP-1/GIP co-agonists[17]. SAR425899 displayed moderate efficacy in early clinical studies and is under further evaluation. The main limitation of this class is the risk of transient hyperglycemia or increased heart rate due to glucagon receptor activation, alongside the dose-dependent gastrointestinal side effects seen with GLP-1 RAs. Nonetheless, dual GLP-1/glucagon agonists hold promise for advanced steatotic liver disease and obesity, especially for patients with comorbid dyslipidemia or hepatic involvement[17].

Triple GLP-1/GIP/glucagon receptor agonists

Retatrutide is the leading triple incretin agonist with robust phase 2 data showing up to 22% body weight loss after 48 weeks and normalization of hepatic fat in a vast majority of patients with MASH. Up to 26% of patients achieved more than 30% weight reduction, a magnitude previously seen only after metabolic/bariatric surgery[7,14]. Retatrutide was well tolerated, with adverse events predominantly gastrointestinal and declining with dose titration. Efocipegtrutide (formerly HM15211), another triple agonist, is in early clinical development with evidence of superior weight and liver parameter reductions in preliminary studies[17]. Triple agonists offer the potential to further expand metabolic benefits - combining the satiety, insulinotropic, and energy expenditure effects of their targets. Safety signals are similar to dual agonists, though longer-term cardiovascular and skeletal effects remain under investigation[17].

Other novel combinations

A promising novel combination is the GLP-1/amylin receptor agonist, semaglutide with cagrilintide, which combines once-weekly semaglutide with the amylin mimetic cagrilintide. Phase 2 trials show a mean 16% weight loss at 32 weeks - superior to either monotherapy - with additional glycemic and cardiovascular benefits and a tolerability profile consistent with incretins, mainly gastrointestinal events[16]. Combinations of peptide YY with GLP-1 and other gut hormone polyagonists are in preclinical or early clinical development. These approaches aim to better emulate the hormonal milieu seen after bariatric surgery (where augmented peptide YY, GLP-1, and amylin responses drive appetite suppression and weight loss), with anticipation of further efficacy gains and improved tolerability[17]. Table 1 shows a summary of the pharmacology of incretin analogues[9,16,17].

Table 1 A Summary of the pharmacology of incretin analogues[9,16,17].

Drug	Mechanism of action	Contraindications	Side effects	Peculiar features
Tirzepatide	Dual GLP-1/GIP receptor agonist	Personal/family history of medullary thyroid carcinoma; MEN2; hypersensitivity to drugs	GI upset (nausea, vomiting, diarrhea), increased heart rate, and possible gallbladder/biliary disease	Greatest body weight loss among incretin dual agonists; weekly injection; potent glucose-lowering effects
Mazdutide (LY3305677)	Dual GLP-1/glucagon receptor agonist	Same as above (GLP-1 class), caution in pancreatitis	GI upset, increased heart rate, possible transient hyperglycemia	Also reduces liver fat; superior effect on dyslipidemia/liver enzymes; once-weekly injection
Cotadutide	Dual GLP-1/glucagon receptor agonist	As above, severe GI disease	GI upset (nausea/diarrhea mostly), mild increase in heart rate	Strong hepatic fat/lipid-lowering effects; less potent on body weight than the GIP combination
Survodutide	Dual GLP-1/glucagon receptor agonist	As above	GI symptoms (similar to GLP-1), ↑heart rate	Potent weight and liver fat reduction; phase 3 for obesity and MASH
SAR425899	Dual GLP-1/glucagon receptor agonist	As above	GI upset, possible increased heart rate	Early clinical studies: Moderate efficacy
Retatrutide	Triple GLP-1/GIP/glucagon receptor agonist	As above, caution in severe heart disease	GI upset is very common; increased heart rate, and some reports of mild hypoglycemia	Highest %body weight loss (up to 24%); reduces hepatic fat, robust metabolic effects
Efocipegtrutide	Triple GLP-1/GIP/glucagon receptor agonist	As above	GI side effects, increased heart rate	In the early clinical stage of development, phase 2 trials are ongoing
Semaglutide + cagrilintide	GLP-1 and amylin analogue co-agonist	As above: Severe GI disease; gastroparesis	Nausea, vomiting (higher than semaglutide alone), constipation	Superior weight loss to monotherapies; once-weekly injection; appetite suppression
PYY/GLP-1 and other gut hormone combos	Multi-gut hormone co-agonism varies per molecule	Unknown, not established yet	GI upset (anticipated), long-term safety data pending	Aims to mimic post-bariatric physiology; most are in early development

GLP-1: Glucagon-like polypeptide-1; GIP: Glucose-dependent insulinotropic polypeptide; PYY: Peptide YY; MEN2: Multiple endocrine neoplasia type 2; GI: Gastro-intestinal; MASH: Metabolic dysfunction-associated steatohepatitis.

COMPARATIVE EFFICACY WITH BARIATRIC SURGERY

Weight loss outcomes: Medications vs surgery

Metabolic or bariatric surgery (MBS) - especially procedures like gastric bypass and sleeve gastrectomy - typically leads to greater absolute weight loss compared to anti-obesity medications, with patients often experiencing 25%-35% body weight reduction over two years. In contrast, novel medication regimens using GLP-1 RAs (e.g., semaglutide, tirzepatide) and oral GLP-1 analogues like orforglipron have demonstrated an average 15%-20% reduction, a figure unprecedented for medical therapy. While surgery offers formidable and sustained weight loss, medications provide a meaningful, durable alternative for many, especially considering the risks and recovery associated with surgery. Importantly, pharmacotherapy may be preferable for those with surgical contraindications or a personal preference for noninvasive therapy[18]. Additionally, medications are increasingly able to promote remission of comorbidities, though surgery may still edge out in terms of the magnitude and speed of resolution for conditions like T2DM and metabolic dysfunction-associated fatty liver disease. As next-generation drugs continue to close the efficacy gap, the appeal of medications as a first-line or bridging strategy is gaining ground[19].

Impact on related metabolic parameters

MBS and new obesity medications both provide substantial improvements across metabolic health parameters, but outcomes can differ by magnitude and persistence[20,21]. Surgery routinely delivers strong reductions in glycated hemoglobin A1c, blood pressure, and improvements in lipid profiles, often leading to partial or complete remission of T2DM and marked regression of liver fat and fibrosis in patients with metabolic dysfunction-associated steatotic liver disease[22]. Anti-obesity medications - especially GLP-1 and dual GIP/GLP-1 agonists - yield significant reductions in glycated hemoglobin A1c, systolic and diastolic blood pressure, and improvements in lipid markers, though these changes are generally less pronounced than those observed with surgery[23]. Tirzepatide, for example, can produce up to 18.4% weight loss and notable reductions in blood pressure and sleep apnea severity, as evidenced by the need for fewer patients to use continuous positive airway pressure post-treatment[24,25]. Both approaches are associated with cardiovascular risk reduction, but MBS confers a more potent effect on metabolic resolution in most head-to-head analyses[26].

GLP-1 RAs show lower long-term risks of nutritional deficiencies, gastrointestinal events, and fractures compared to bariatric surgery, suggesting a potentially protective profile for lean mass and bone health. Triple agonists like retatrutide require investigation for long-term skeletal effects, while bariatric surgery carries higher fracture risks as noted in pooled randomized controlled trials with 7-12-year follow-up[9,17]. No specific data from studies on lean body mass preservation (e.g., dual-energy X-ray absorptiometry scan results) or bone density changes (e.g., T-scores) with polyagonists like tirzepatide or retatrutide have been done. Nutritional status outcomes remain undetailed, though incretin therapies generally exhibit fewer deficiency risks than bariatric surgery.

Quality of life and patient preferences

Quality of life generally improves more after MBS than with pharmacological therapies, impacting both physical and mental domains over extended follow-up[24]. Physical quality of life, including mobility, energy, and self-esteem, tends to show the greatest gains, while mental health improvements may depend on individual factors and the type of surgery performed. Differences in quality-of-life improvement are found between surgical modalities, with Roux-en-Y gastric bypass and sleeve gastrectomy showing the most substantial benefits. However, medications also improve quality of life, primarily related to weight loss and reduced comorbidity burden, and are favored by patients who prefer noninvasive treatment, slower and reversible interventions, or are ineligible for surgery[25]. Patient preferences often hinge on perceived effectiveness, risk tolerance, and lifestyle compatibility, with many opting for medications initially but switching to surgery for more sustained and dramatic results or if medical therapy proves insufficient[24,25].

SAFETY AND TOLERABILITY OF INCRETIN POLYAGONISTS

Incretin polyagonists - particularly dual and triple agonists targeting GLP-1, GIP, and glucagon receptors - have demonstrated a favorable safety and tolerability profile in both clinical trials and real-world practice. The most frequently reported adverse events are gastrointestinal symptoms, such as nausea, diarrhea, vomiting, and constipation, which are typically mild-to-moderate and transient, especially during the initial dose-escalation period[16]. For example, in phase 3 trials of tirzepatide, a GLP-1/GIP receptor dual agonist, up to 81.8% of participants reported at least one adverse event, but most were gastrointestinal, and the rates of discontinuation due to side effects were relatively low (4.3%-7.1% across doses), similar to other incretin-based agents. Polyagonists such as retatrutide (GIP/GLP-1/glucagon tri-agonist) and investigational combinations have shown comparable gastrointestinal side-effect profiles, though the magnitude and frequency can increase at higher doses or with rapid titration[17]. Rare but noteworthy adverse events include gallbladder-related issues (cholelithiasis, cholecystitis), mild increases in heart rate (typically 1-7 beats per minute), and a potential small increased risk of worsening of diabetic retinopathy, particularly with rapid glycemic control, highlighting the need for gradual titration and careful patient selection[27].

CARDIOVASCULAR SAFETY AND ORGAN PROTECTION

A defining feature of the incretin class - including polyagonists - is their favorable or neutral cardiovascular safety profile. Large cardiovascular outcome trials have established that GLP-1 RAs reduce major adverse cardiovascular events (MACEs) in high-risk populations with T2DM, and similar benefits are expected with polyagonists due to their overlapping and synergistic mechanisms[16]. Tirzepatide, for instance, is under ongoing investigation in a dedicated cardiovascular outcome trial, but meta-analyses of existing studies suggest non-inferiority (and possible superiority) to placebo regarding MACE, with additional benefits of blood pressure and lipid reduction attributable to weight loss and direct vascular effects[17]. Beyond the heart, incretin polyagonists have demonstrated organ-protective actions such as improved renal outcomes (reduced progression of albuminuria, preserved epidermal growth factor receptor), reduced hepatic fat and fibrosis progression (notably in metabolic dysfunction-associated steatotic liver disease), neuroprotection in preclinical neurodegenerative models, attributed to anti-inflammatory and anti-apoptotic properties[17]. These effects often appear greater than those achieved by GLP-1 RAs alone, particularly when weight loss is more pronounced, suggesting an additive benefit of polyagonism on cardiometabolic health.

PRACTICAL AND SOCIO-ECONOMIC CONSIDERATIONS

Accessibility and cost-effectiveness

The recent surge in the development of incretin-based polyagonists such as tirzepatide and retatrutide has heightened interest in their role as alternatives to MBS for obesity. While MBS remains a well-established, effective intervention - achieving 25%-30% weight loss in many individuals - its scalability and applicability are limited due to cost, infrastructure requirements, peri-operative risk, and eligibility criteria, restricting its use to a small subset of patients with the most severe obesity or associated comorbidities[16,17]. By contrast, pharmacotherapy with incretin polyagonists offers a less invasive, more broadly accessible option, demonstrating mean weight loss of 15%-22.5% over 72 weeks in large clinical trials, approaching results typical of surgical interventions[27]. However, cost remains a significant barrier: These medications are expensive and, in many health systems, not yet widely reimbursed for obesity, though access may improve as they become more established and generic options emerge. Other barriers that would cause inequities in access to pharmacotherapy with incretin polyagonists include decreased healthcare access, decreased medical literacy, and physician awareness bias. Furthermore, the chronic nature of obesity and the high likelihood of weight regain upon discontinuation mean that long-term cost-effectiveness must consider both the medication’s price and sustained clinical benefit[28].

Adherence and route of administration (oral vs injectable)

Patient adherence is central to the real-world success of any long-term therapy. The only approved incretin polyagonists, tirzepatide, is administered as once-weekly subcutaneous injections, which, though less frequent than earlier peptide therapies, can still pose barriers for some individuals due to needle aversion or logistical issues. Importantly, oral small molecule GLP-1 RAs like orforglipron represent a meaningful advancement: Phase 2 data indicate similar efficacy and a tolerable safety profile compared to injectable agents, with once-daily oral administration[16,17]. This route could improve uptake and persistence in the broader obesity population, especially those who are reluctant to use injectable therapies. Across the class, gastrointestinal adverse events (nausea, vomiting, diarrhea) remain the most frequent cause of treatment discontinuation - reported in about 10%-17% of patients in oral GLP-1 RA studies and up to 7% for injectable polyagonists - yet these events are typically dose-related and often transient, more common during dose escalation[27,28]. Emerging oral agents thus have the potential to improve adherence and acceptability, but long-term real-world data are still needed. Table 2 shows a summary of recent studies and trials on anti-obesity medications and bariatric surgery for obesity treatment.

Table 2 Recent studies and trials on anti-obesity medications and bariatric surgery for obesity treatment.

Ref.	Study type	Population/setting	Comparison groups	Main outcomes	Complications/notes
Dicker et al[36], 2024	Large retrospective matched cohort	6070 adults with obesity and diabetes; Israel, 2008-2022; median 6.8 years follow-up	MBS vs GLP-1 RAs	MBS: 62% reduction in mortality vs GLP-1 RAs for diabetes ≤ 10 years. No difference if diabetes > 10 years. Weight loss: MBS (-31.4% BMI) vs GLP-1 RAs (-12.8%). No difference in MACEs	MBS survival benefit mediated by greater weight loss. Similar glycemic control long term. Complications were not directly compared
American Society for Metabolic and Bariatric Surgery[32]	Real-world retrospective comparative study	51085 adults BMI ≥ 35, New York city 2018-2024	Bariatric surgery (sleeve gastrectomy or gastric bypass) vs GLP-1 RAs (semaglutide, tirzepatide)	2 years: Bariatric surgery = 58-pound average loss (24% body weight); GLP-1 = 12-pound average (4.7%), 7% for those on drugs all year. Surgery: About 5 times more weight loss	Over 50% discontinued GLP-1 in 1 year, 72% by 2 years. Surgery is more durable. Complication rates for surgery are not detailed, but surgery is found to be effective and safe
Yan et al[37], 2019	Meta-analysis (4 RCTs, 6 cohorts)	Adults with severe obesity and T2DM (> 5 years follow-up)	Bariatric surgery vs conservative (non-surgical, includes meds and lifestyle)	Bariatric surgery: Lower macrovascular complications (RR = 0.43), lower MI (RR = 0.40), and greater weight and glycemic improvement	Surgery is superior for CV outcomes and weight. Complications depend on the surgical type, but risks are higher than with medication
Newman[38], 2025	Review/expert summary	General adult obesity population	Bariatric surgery vs anti-obesity medications	Bariatric surgery provides greater and longer-lasting weight loss compared to anti-obesity meds	Surgery: More durable weight loss. Meds are easier to administer and reversible, but have fewer profound effects
Courcoulas et al[39], 2024	Pooled RCTs (7-12 years follow-up)	Diabetes + obesity/overweight	Surgery vs medical/lifestyle	Surgery: Greater long-term weight loss, improved glycemic control, and increased diabetes remission	Surgery: Higher long-term risk of nutritional deficiencies, GI events, and fractures. Meds have a lower risk profile but less efficacy
Lincoff et al[40], 2023	Randomized, double-blind, placebo-controlled trial	17604 adults (BMI ≥ 27) with preexisting CV disease, no diabetes; 41 countries, mean 39.8 months follow-up	Semaglutide 24 mg weekly vs placebo	Semaglutide: 6.5% CV events vs placebo: 8.0% (HR = 0.80, 95%CI: 0.72-0.90, P < 0.001). Reduced death from CV causes, nonfatal MI, or nonfatal stroke	More adverse events led to discontinuation in the semaglutide group (16.6% vs 8.2%). No surgery arm. Strong CV benefit among anti-obesity drugs in high-risk patients without diabetes
Hernandez et al[41], 2018	Randomized, double-blind, placebo-controlled trial	9463 adults with T2DM and established cardiovascular disease, global, median 1.6 years follow-up	Albiglutide 30-50 mg weekly vs placebo	Primary composite (CV death, MI, stroke): 7% albiglutide vs 9% placebo (HR = 0.78, 95%CI: 0.68-0.90; superiority P = 0.0006)	Incidence of acute pancreatitis, pancreatic cancer, and medullary thyroid carcinoma is low and not different between groups. Confirms the CV benefit of GLP-1 RA in T2DM with CVD

RCT: Randomized controlled trial; BMI: Body mass index; T2DM: Type 2 diabetes mellitus; CV: Cardiovascular; MBS: Metabolic or bariatric surgery; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; MACE: Major adverse cardiovascular event; RR: Relative risk; MI: Myocardial infarction; HR: Hazard ratio; CI: Confidence interval; GI: Gastro-intestinal; CVD: Cardiovascular disease.

LIMITATIONS AND UNANSWERED QUESTIONS

While incretin-based polyagonists such as dual and triple receptor agonists have shown significant short-term benefits in weight loss and glycemic control, robust long-term efficacy and safety data remain limited[4]. Most available studies demonstrate cardiovascular risk reductions of 12%-26% in MACE primarily with GLP-1 RAs, but extrapolating these results to novel polyagonists is not yet justified[29]. Although emerging evidence supports favorable effects on cardiovascular outcomes - including reductions in stroke, myocardial infarction, and improved atheroprotection - there remains uncertainty regarding the durability of these benefits beyond several years of therapy[30]. Cardiovascular event rates, even among patients prescribed these agents, remain high, and ongoing global studies are expected to define long-term impacts more clearly.

Recent retrospective head-to-head studies suggest that, while the newest incretin polyagonists can approach the efficacy of bariatric surgery for diabetes and obesity management, surgical interventions (such as sleeve gastrectomy and gastric bypass) still outperform pharmacotherapy in terms of absolute weight loss. For example, bariatric procedures were associated with approximately five times more weight loss than GLP-1 RA injections in real-world cohorts. Nevertheless, discontinuation rates with pharmacotherapy are high - over 50% at one year, growing to more than 70% at two years - while uptake of surgery remains low despite its superior efficacy[31,32]. More prospective, randomized controlled trials that directly compare the most effective pharmacological regimens with surgical treatments are needed to provide definitive guidance, especially for distinct subgroups of patients.

FUTURE DIRECTIONS

Ongoing research in incretin polyagonists highlights a rapidly expanding pipeline, with dual and triple agonists undergoing advanced clinical trials to address obesity and its comorbidities[4]. Notable agents such as retatrutide (GLP-1/GIP/glucagon polyagonists) and survodutide (GLP-1/glucagon dual agonist) are showing weight loss efficacy that approaches or even rivals bariatric surgery, sometimes exceeding 20%-25% mean weight loss in clinical studies[33]. Semaglutide with cagrilintide also shows promise, producing significant weight reductions in both diabetic and nondiabetic populations. The research community is additionally pursuing molecular fine-tuning, dosing strategies, and long-term follow-up for safety and sustainability of weight loss[34]. Many of these agents are in phase 3 clinical trials, and multiple early-phase agents are targeting individualized pharmacological profiles to further maximize outcomes.

Personalized medicine is increasingly recognized as essential for optimizing the use of incretin polyagonists. Clinical experience with GLP-1 and dual receptor agonists demonstrates wide variability in patient response due to genetic, behavioral, and metabolic differences[3]. Future directions emphasize biomarker discovery (including genetic markers), integration with digital health monitoring, and multidisciplinary care teams that include dietitians, endocrinologists, and behavioral psychologists[31]. Combining pharmacotherapy with lifestyle modifications and leveraging real-world data will be critical to tailor therapy, improve adherence, and mitigate risks, especially gastrointestinal side effects and rare but serious complications[35].

CONCLUSION

Multiple randomized controlled trials and real-world data demonstrate that incretin polyagonists - particularly dual GLP-1/GIP and triple GLP-1/GIP/glucagon receptor agonists - are redefining medical therapy for obesity. These agents achieve weight loss previously seen only with bariatric procedures, while also improving glycemic control and cardiometabolic health. Safety is generally favorable, dominated by manageable gastrointestinal symptoms, but long-term surveillance is still needed, and comparative data with surgery are evolving.

Given these advances, incretin polyagonists are positioned as a viable alternative to metabolic and bariatric surgery for many patients, especially those for whom surgery is contraindicated or undesirable. Policy recommendations should include improving access to these therapies, reimbursement alignment with established obesity treatments, supporting head-to-head comparator trials with bariatric surgery, and expanding multidisciplinary obesity clinics to provide individualized care. Prioritizing research into mechanisms of response, long-term outcomes, and optimal integration into existing treatment pathways will be critical to maximizing public health impact and establishing these agents as a mainstay of obesity management in the coming decades.

ACKNOWLEDGEMENTS

We are thankful to Jovitta Fernandez Jerrin for her help in providing the audio core tip of this article.