Advancements in Multi-Agonist Therapies for Metabolic Disorders: A Comprehensive Review

Abstract

The global health burden imposed by metabolic disorders, predominantly type 2 diabetes mellitus (T2DM) and obesity, has necessitated the continuous innovation of therapeutic strategies. Traditional pharmaceutical interventions, often focused on single mechanistic pathways, have frequently fallen short in achieving comprehensive and sustained improvements in glycemic control, weight management, and related comorbidities. This report undertakes an extensive exploration of multi-agonist therapies, representing a significant paradigm shift in the treatment landscape. Specifically, it delves into the intricate pharmacology, robust clinical efficacy, meticulously monitored safety profiles, and expansive future prospects of agents like GLP-1/GIP dual agonists (e.g., tirzepatide) and GLP-1/GIP/glucagon triple agonists (e.g., retatrutide). These novel compounds have demonstrated unparalleled therapeutic benefits, achieving superior glycemic reductions and profound weight loss, thereby positioning them as potentially transformative agents in the integrated management of metabolic dysfunction. Through an in-depth analysis, this report aims to elucidate the mechanisms underpinning their success and critically evaluate their potential to redefine clinical practice in metabolic medicine.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Metabolic disorders, particularly type 2 diabetes mellitus and obesity, represent one of the most pressing global health crises of the 21st century. Affecting hundreds of millions worldwide, these interconnected conditions are major drivers of morbidity, mortality, and healthcare expenditure. The International Diabetes Federation (IDF) estimates that approximately 537 million adults globally live with diabetes, with T2DM accounting for the vast majority of cases, and this number is projected to rise to 783 million by 2045 [Simulated Reference 1: International Diabetes Federation (IDF) Diabetes Atlas]. Similarly, obesity has reached epidemic proportions, with the World Health Organization (WHO) reporting that over 1 billion people globally are obese, a condition strongly associated with T2DM, cardiovascular disease, certain cancers, and musculoskeletal disorders [Simulated Reference 2: World Health Organization (WHO) Obesity and overweight fact sheet].

Historically, therapeutic approaches for T2DM and obesity have been largely compartmentalized. T2DM management typically involves lifestyle modifications, metformin as a first-line agent, followed by a range of oral hypoglycemics (sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors) and injectable therapies (insulin, GLP-1 receptor agonists). Obesity treatment, while also commencing with lifestyle changes, has included pharmacotherapy with modest efficacy, and in severe cases, bariatric surgery. A significant limitation of these traditional monotherapies is their often suboptimal efficacy in achieving comprehensive metabolic control, defined not only by glycemic targets but also by substantial and sustained weight loss, improvements in cardiovascular risk factors, and prevention of long-term complications. Many patients struggle to reach or maintain target HbA1c levels without experiencing adverse effects such as hypoglycemia or weight gain, and sustained weight loss remains a considerable challenge with current pharmacological options.

The emergence of incretin-based therapies, initially with GLP-1 receptor agonists (GLP-1 RAs) and DPP-4 inhibitors, marked a crucial step forward. These agents leverage the body’s natural incretin system, a gut-brain axis signaling pathway essential for glucose homeostasis. GLP-1 RAs, in particular, demonstrated benefits beyond glycemic control, including modest weight loss and cardiovascular risk reduction, signaling the potential of therapies that address multiple facets of metabolic dysfunction. However, even GLP-1 RAs, while effective, still leave room for greater improvements in both glycemic control and weight reduction for many patients.

This landscape of unmet needs has spurred the development of a new class of pharmaceutical agents: multi-agonist therapies. These innovative drugs are engineered to simultaneously activate multiple receptors involved in metabolic regulation, thus offering a more holistic and potent therapeutic approach. By engaging several complementary pathways, these agents aim to achieve superior clinical outcomes compared to single-receptor agonism. This report focuses on two prominent categories of these multi-agonist therapies: GLP-1/GIP dual agonists, exemplified by tirzepatide, and GLP-1/GIP/glucagon triple agonists, exemplified by retatrutide. Through a detailed analysis of their pharmacological mechanisms, rigorous clinical trial data, comprehensive safety assessments, and broader therapeutic implications, this report aims to provide an in-depth understanding of their capacity to revolutionize the management of T2DM, obesity, and their associated comorbidities.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Pharmacology of Multi-Agonist Therapies

The remarkable efficacy of multi-agonist therapies stems from their sophisticated engagement with multiple endogenous hormonal pathways central to metabolic regulation. To fully appreciate their mechanism of action, it is essential to first understand the physiology of the incretin system and the lesser-explored metabolic roles of glucagon.

2.1 The Incretin System: GLP-1 and GIP

2.1.1 Glucagon-Like Peptide-1 (GLP-1): GLP-1 is a gut-derived incretin hormone secreted by L-cells primarily in the distal ileum and colon, and to a lesser extent, in the brainstem. Its secretion is stimulated by the presence of nutrients, particularly carbohydrates and fats, in the gut lumen. The physiological actions of GLP-1 are extensive and include:

• Glucose-dependent insulin secretion: GLP-1 potentiation of insulin release from pancreatic beta-cells occurs only when blood glucose levels are elevated, thereby reducing the risk of hypoglycemia.
• Glucagon suppression: It inhibits glucagon secretion from pancreatic alpha-cells, reducing hepatic glucose output.
• Delayed gastric emptying: This slows the absorption of nutrients, preventing postprandial glucose excursions and promoting satiety.
• Satiety and appetite reduction: GLP-1 acts on receptors in the hypothalamus and brainstem, leading to reduced food intake and increased feelings of fullness.
• Beta-cell proliferation and anti-apoptosis: Preclinical data suggest GLP-1 may promote the growth and survival of beta-cells, although human data is still evolving.
• Cardioprotective effects: GLP-1 receptors are found in the heart and vasculature, suggesting potential benefits on cardiac function, blood pressure, and endothelial health.

GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), giving it a very short half-life (1-2 minutes) in its native form. Therapeutic GLP-1 receptor agonists are engineered to resist DPP-4 degradation or have a prolonged half-life through albumin binding or other modifications.

2.1.2 Glucose-Dependent Insulinotropic Polypeptide (GIP): GIP, also known as gastric inhibitory polypeptide, is another incretin hormone secreted by K-cells in the duodenum and jejunum, primarily in response to oral glucose and fat intake. While its name suggests gastric inhibition, its primary role is its potent insulinotropic effect, particularly after meals. The key actions of GIP include:

• Glucose-dependent insulin secretion: Similar to GLP-1, GIP stimulates insulin release from pancreatic beta-cells in a glucose-dependent manner, albeit potentially at lower glucose thresholds than GLP-1.
• Beta-cell survival and proliferation: GIP also supports beta-cell health.
• Lipid metabolism: GIP may directly influence adipose tissue function, promoting fat storage when energy is abundant.
• Potential glucagonotropic effects: In some physiological contexts, GIP can stimulate glucagon release, particularly in hypoglycemia or type 2 diabetes, which has historically complicated its therapeutic potential as a monotherapy. However, in the context of dual agonism with GLP-1, this effect is often mitigated or beneficial.

Like GLP-1, native GIP is rapidly inactivated by DPP-4.

2.2 GLP-1/GIP Dual Agonists: The Case of Tirzepatide

Tirzepatide (Mounjaro®), approved for T2DM and obesity, represents a groundbreaking advancement as the first GIP and GLP-1 receptor dual agonist. It is a synthetic polypeptide, a single molecule designed to bind and activate both the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R). This unique design capitalizes on the complementary and synergistic actions of these two incretin hormones.

2.2.1 Molecular Design and Affinity: Tirzepatide is an acylated peptide with a C20 fatty diacid moiety that enables albumin binding, extending its half-life to approximately five days, allowing for once-weekly subcutaneous administration. Crucially, tirzepatide exhibits an ‘imbalanced agonism’ profile, meaning it has a higher binding affinity and potency for the GIP receptor compared to the GLP-1 receptor (approximately five-fold higher affinity for GIPR than GLP-1R). This specific affinity profile is hypothesized to be key to its superior efficacy. Early research suggested that individuals with T2DM might have impaired GIP sensitivity, and by preferentially activating the GIPR, tirzepatide may overcome this GIP resistance [Simulated Reference 3: Finan et al., Diabetes, Obesity and Metabolism, 2013].

2.2.2 Biased Agonism at the GLP-1 Receptor: Beyond imbalanced affinity, tirzepatide demonstrates ‘biased agonism’ at the GLP-1 receptor. G-protein coupled receptors (GPCRs), like the GLP-1R, can signal through multiple intracellular pathways. Upon ligand binding, they can activate G-proteins (leading to cAMP production) or recruit β-arrestins (involved in receptor desensitization and internalization). Traditional GLP-1 RAs typically activate both pathways to varying degrees. Tirzepatide, however, selectively favors the G-protein mediated pathway, leading to enhanced cAMP generation over β-arrestin recruitment at the GLP-1 receptor, as demonstrated in in vitro studies [1]. This biased signaling theoretically translates to more potent and sustained downstream effects related to insulin secretion and beta-cell function, potentially contributing to its superior efficacy in glycemic control and beta-cell improvement, while possibly mitigating certain adverse effects associated with β-arrestin pathways.

2.2.3 Synergistic Metabolic Effects: The co-activation of GIPR and GLP-1R by tirzepatide yields a powerful synergistic effect on various metabolic parameters:

• Enhanced Insulin Secretion and Sensitivity: Both hormones independently stimulate glucose-dependent insulin release. Their combined action leads to a more robust insulinotropic response, particularly postprandially. Additionally, both GIP and GLP-1 can improve peripheral and hepatic insulin sensitivity, helping overcome key pathophysiological defects in T2DM.
• Improved Beta-Cell Function: The synergistic action supports beta-cell health, enhancing their ability to respond to glucose challenges and potentially preserving their mass and function over time.
• Profound Weight Loss: Both GLP-1 and GIP contribute to appetite suppression and delayed gastric emptying, leading to reduced caloric intake. While GLP-1’s role in satiety is well-established, GIP has also been shown to play a part in regulating food intake and energy balance. The profound weight loss observed with tirzepatide is a testament to this combined effect, exceeding that seen with GLP-1 monotherapy.
• Lipid Metabolism: Tirzepatide has demonstrated beneficial effects on lipid profiles, including reductions in triglycerides and improvements in cholesterol levels, likely mediated through improved insulin sensitivity and direct effects on adipose tissue and liver.

2.3 GLP-1/GIP/Glucagon Triple Agonists: The Case of Retatrutide

Retatrutide (LY3437943), currently in advanced clinical development, takes multi-agonism a step further by simultaneously activating the GLP-1, GIP, and glucagon receptors. This innovative approach introduces a third hormonal pathway, aiming for even more comprehensive metabolic improvements.

2.3.1 Re-evaluating Glucagon’s Role: Glucagon, produced by pancreatic alpha-cells, is traditionally known as a counter-regulatory hormone that raises blood glucose levels by stimulating hepatic glucose production. However, glucagon also possesses metabolic effects that, when strategically leveraged, can be highly beneficial, particularly for weight loss and liver fat reduction:

• Increased Energy Expenditure and Thermogenesis: Glucagon can stimulate brown adipose tissue activity and increase overall energy expenditure, potentially contributing to greater caloric deficit and weight loss.
• Enhanced Lipid Oxidation: Glucagon promotes lipolysis in adipose tissue and beta-oxidation in the liver, leading to reduced hepatic lipid accumulation and improved lipid profiles.
• Direct effects on Satiety: Glucagon receptors are also found in the brain, suggesting a potential role in appetite regulation, although this is less pronounced than GLP-1.

The challenge with glucagon agonism in diabetes therapy has been the risk of hyperglycemia. Retatrutide’s design, as a balanced triple agonist, seeks to harness glucagon’s beneficial catabolic effects while mitigating its hyperglycemic potential through the robust glucose-lowering effects of GLP-1 and GIP agonism. This balance is crucial for its therapeutic viability.

2.3.2 Molecular Design and Triple Agonism: Retatrutide is also a synthetic polypeptide engineered to bind and activate all three receptors (GLP-1R, GIPR, and GCGR). Like tirzepatide, it incorporates modifications for an extended half-life, enabling once-weekly administration. The design aims for a balanced activation of these three receptors, allowing their complementary actions to collectively drive metabolic improvements.

2.2.3 Multifaceted Synergistic Effects: The triple agonism of retatrutide leads to an even broader spectrum of metabolic benefits:

• Superior Weight Loss: The combination of appetite suppression from GLP-1 and GIP, coupled with the glucagon-mediated increase in energy expenditure and fat oxidation, results in profound and sustained weight loss that appears to surpass that observed with dual agonists [2]. This multi-pronged attack on energy balance is key to its exceptional efficacy.
• Improved Glycemic Control: The combined insulinotropic and glucagonostatic effects of GLP-1 and GIP are further supported by glucagon’s potential to improve insulin sensitivity, particularly in the liver, leading to enhanced glucose uptake and utilization. While glucagon itself raises glucose, its actions are counteracted and balanced by the potent glucose-lowering effects of GLP-1 and GIP in the context of this triple agonist.
• Hepatic Fat Reduction and Improved Liver Health: Glucagon’s role in promoting hepatic lipid oxidation is particularly relevant here. By reducing liver fat, retatrutide shows significant promise in addressing conditions like non-alcoholic steatohepatitis (NASH), a severe form of fatty liver disease [2]. The combination with improved insulin sensitivity further contributes to ameliorating hepatic steatosis.
• Enhanced Lipid Profiles: Beyond triglyceride reduction, the comprehensive impact on fat metabolism contributes to more favorable lipid profiles, potentially translating to enhanced cardiovascular benefits.

In essence, both dual and triple agonists represent sophisticated pharmacological engineering, moving beyond single-target therapies to harness the complex interplay of metabolic hormones, thereby offering a more potent and comprehensive solution for the multifaceted pathology of T2DM and obesity.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Clinical Efficacy

The advent of multi-agonist therapies has ushered in a new era of efficacy in the management of type 2 diabetes and obesity, demonstrating superiority over existing treatments in numerous clinical trials.

3.1 Type 2 Diabetes Management

3.1.1 Tirzepatide: The SURPASS Program

Tirzepatide’s efficacy in T2DM has been rigorously evaluated across a comprehensive clinical development program known as SURPASS, comprising several Phase 3 trials that compared tirzepatide to placebo or other established antidiabetic agents. The primary endpoints in these trials consistently focused on changes in glycated hemoglobin (HbA1c) from baseline and changes in body weight.

• SURPASS-1 (Monotherapy): This trial evaluated tirzepatide as monotherapy in patients with T2DM inadequately controlled with diet and exercise. Participants receiving tirzepatide achieved mean HbA1c reductions of up to 2.07% at the highest dose (15 mg weekly) compared to 0.04% with placebo. Weight reductions were equally impressive, reaching up to 9.5 kg (11.3%) with tirzepatide versus a modest 1.0 kg (1.1%) with placebo [Simulated Reference 4: Rosenstock et al., Diabetes Care, 2021].

• SURPASS-2 (vs. Semaglutide): A pivotal head-to-head study, SURPASS-2 compared tirzepatide to semaglutide 1 mg (a leading GLP-1 RA). Over 40 weeks, tirzepatide at its highest dose (15 mg) achieved a mean HbA1c reduction of 2.01% from baseline, surpassing semaglutide’s reduction of 1.86%. Furthermore, tirzepatide led to a mean weight loss of 11.2 kg (13.1%) compared to semaglutide’s 6.4 kg (7.5%) [3]. This trial was critical in establishing tirzepatide’s superior efficacy in both glycemic control and weight reduction compared to the current gold standard GLP-1 RA.

• SURPASS-3 (vs. Insulin Degludec): This trial compared tirzepatide to insulin degludec (a long-acting basal insulin) as an add-on to metformin with or without an SGLT2 inhibitor. Tirzepatide at 15 mg demonstrated a mean HbA1c reduction of 2.37% and weight loss of 11.3 kg, significantly outperforming insulin degludec (HbA1c reduction of 1.39% and weight gain of 1.9 kg) [Simulated Reference 5: Ludvik et al., The Lancet, 2021]. A higher proportion of patients on tirzepatide achieved target HbA1c (<7%) without hypoglycemia, and a greater percentage achieved both glycemic and weight loss targets.

• SURPASS-4 (vs. Insulin Glargine in High CV Risk): In patients with T2DM and increased cardiovascular risk, tirzepatide was compared to insulin glargine as an add-on to existing oral antidiabetic medications. Tirzepatide again demonstrated superior HbA1c reductions (up to 2.58% at 15 mg vs. 1.44% with glargine) and substantial weight loss (up to 11.7 kg vs. 1.9 kg weight gain with glargine) [Simulated Reference 6: Del Prato et al., NEJM, 2021]. This trial also provided important data on cardiovascular safety, although not powered for superiority in MACE.

• SURPASS-5 (vs. Insulin Glargine as Add-on to Basal Insulin): This trial investigated tirzepatide as an add-on to titrated basal insulin glargine, with or without metformin. Tirzepatide 15 mg resulted in a mean HbA1c reduction of 2.11% and weight loss of 10.9 kg, while insulin glargine titration led to an HbA1c reduction of 1.03% and a modest weight gain of 1.7 kg [Simulated Reference 7: Frias et al., Diabetes Care, 2021].

Collectively, the SURPASS program established tirzepatide as a highly efficacious agent for T2DM, capable of achieving unprecedented glycemic control alongside significant and clinically meaningful weight loss, often surpassing the efficacy of current standard-of-care therapies.

3.1.2 Retatrutide in T2DM: While retatrutide’s most striking results have been in obesity, its efficacy in T2DM management is also being evaluated. In a Phase 2 trial that included participants with T2DM, retatrutide demonstrated substantial reductions in HbA1c. For instance, participants receiving 12 mg weekly retatrutide experienced a mean HbA1c reduction of up to 2.0% from baseline over 48 weeks, alongside significant weight loss. This indicates that the triple agonism effectively addresses both hyperglycemia and the underlying metabolic dysregulation contributing to weight gain in T2DM [2]. Further dedicated T2DM-focused trials are expected to provide more detailed insights into its specific benefits in this population.

3.2 Obesity Management

The weight loss efficacy of multi-agonist therapies is arguably their most groundbreaking attribute, offering hope to millions struggling with obesity and its complications.

3.2.1 Tirzepatide: The SURMOUNT Program

Tirzepatide’s dedicated obesity clinical development program, SURMOUNT, has yielded highly impressive results, leading to its recent approval for chronic weight management.

• SURMOUNT-1 (Obesity with or without T2DM): This landmark Phase 3 trial enrolled participants with obesity (BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity) but without T2DM. Over 72 weeks, tirzepatide at the highest dose (15 mg weekly) resulted in a staggering mean weight loss of 22.5% (approximately 24 kg) from baseline, while the 10 mg dose achieved 21.2% weight loss, and the 5 mg dose achieved 15.7% weight loss. A remarkable proportion of participants achieved significant weight loss: 63% on 15 mg and 50% on 10 mg achieved at least 20% weight loss, a threshold previously primarily achieved with bariatric surgery. Nearly 90% achieved at least 5% weight loss [Simulated Reference 8: Jastreboff et al., NEJM, 2022]. These results redefined expectations for pharmacological weight loss.

• SURMOUNT-2 (Obesity with T2DM): This trial specifically focused on participants with obesity and established T2DM. After 72 weeks, tirzepatide 15 mg led to a mean weight reduction of 15.7% (approximately 15.6 kg), while the 10 mg dose achieved 13.4% weight loss. These significant reductions were accompanied by excellent glycemic control, further highlighting the compound’s dual benefit in this challenging patient population [Simulated Reference 9: Kushner et al., The Lancet, 2023].

• SURMOUNT-3 (Weight Loss Maintenance): This study investigated the efficacy of continued tirzepatide treatment for weight loss maintenance after an initial intensive lifestyle intervention-induced weight loss. Participants who continued tirzepatide achieved substantial additional weight loss or maintained their weight, demonstrating the importance of chronic treatment for obesity [Simulated Reference 10: Aronne et al., NEJM, 2023].

• SURMOUNT-4 (Withdrawal and Maintenance): This trial assessed the effects of continued tirzepatide versus switching to placebo after an initial 36-week tirzepatide treatment phase. Those who continued tirzepatide maintained or further reduced their weight, while those switched to placebo experienced significant weight regain, underscoring the chronic nature of obesity and the need for sustained pharmacological intervention [Simulated Reference 11: Wilding et al., JAMA, 2023].

3.2.2 Retatrutide: Impressive Phase 2 Results

Retatrutide has demonstrated even more profound weight loss efficacy in its Phase 2 clinical trials, particularly in participants with obesity (with or without T2DM). In a pivotal 48-week Phase 2 study in individuals with obesity (mean baseline BMI of 37.3 kg/m²), retatrutide administered at 12 mg weekly resulted in an astonishing mean weight loss of 24.2% from baseline. Lower doses also showed substantial weight reductions (e.g., 22.8% with 8 mg, 17.3% with 4 mg). The proportion of participants achieving significant weight loss milestones was exceptionally high, with 100% achieving at least 5% weight loss, and 83% achieving at least 20% weight loss at the highest dose [2, 9]. These results set a new benchmark for pharmacological obesity treatment and suggest that triple agonism offers a distinct advantage in terms of sheer weight reduction.

3.2.3 Mechanisms Contributing to Superior Weight Loss: The enhanced weight loss observed with these multi-agonists, particularly retatrutide, can be attributed to their multifaceted mechanisms:

• Potent Appetite Suppression: Both GLP-1 and GIP agonism contribute significantly to reduced food intake by promoting satiety, reducing hunger, and affecting reward pathways in the brain related to food.
• Delayed Gastric Emptying: This contributes to prolonged feelings of fullness and reduced postprandial caloric absorption.
• Increased Energy Expenditure (Retatrutide): The inclusion of glucagon agonism in retatrutide is hypothesized to be a key differentiator, as glucagon can directly increase thermogenesis and energy expenditure, creating a greater caloric deficit beyond appetite suppression alone [2].
• Improved Metabolic Efficiency: By improving insulin sensitivity and shifting fuel utilization towards fat oxidation, these agents optimize the body’s metabolic state, facilitating weight loss and potentially improving body composition.

The clinical trial data unequivocally demonstrate that multi-agonist therapies represent a step-change in the efficacy of T2DM and obesity management, providing patients with significantly improved glycemic control and unprecedented levels of weight loss, moving closer to the outcomes previously associated only with bariatric surgery.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Safety and Tolerability

While the efficacy of multi-agonist therapies is undeniably impressive, their safety and tolerability profiles are equally critical for their widespread adoption and long-term use. Across both dual and triple agonists, a consistent pattern of adverse events has emerged, primarily gastrointestinal in nature, which are generally manageable.

4.1 Gastrointestinal Adverse Events

The most commonly reported adverse events (AEs) for both tirzepatide and retatrutide are gastrointestinal (GI), reflecting the physiological actions of GLP-1 and GIP on the gut and brain. These include:

• Nausea: Reported by a significant proportion of patients, particularly during dose escalation.
• Vomiting: Less frequent than nausea but still a notable AE.
• Diarrhea: Common, especially in the initial weeks of treatment.
• Constipation: Also reported, though less frequently than diarrhea.
• Abdominal Discomfort/Pain: General sensations of unease or pain in the abdominal region.

4.1.1 Incidence and Management: The incidence and severity of these GI side effects are generally dose-dependent, meaning they become more common and pronounced at higher doses. Importantly, they tend to be most prevalent during the initial weeks of treatment and often diminish over time as the body adapts to the medication. This transient nature highlights the importance of a gradual dose escalation strategy, which is standard practice for these agents. For instance, in tirzepatide clinical trials, the incidence of nausea, vomiting, and diarrhea decreased with higher doses in some contexts, suggesting that while higher starting doses might be associated with more AEs, the overall discontinuation rate due to AEs remained relatively low (e.g., around 3-6% in SURPASS trials for tirzepatide) [3].

4.1.2 Mechanisms: These GI effects are primarily mediated by GLP-1 receptor activation, particularly in the brainstem (area postrema), which influences the vomiting center, and through delayed gastric emptying. While GIP agonism may contribute to some GI effects, GLP-1 is generally considered the primary driver. The delay in gastric emptying, while beneficial for postprandial glucose control and satiety, can also contribute to feelings of fullness, bloating, and nausea.

4.1.3 Retatrutide Specifics: For retatrutide, the GI safety profile appears similar to tirzepatide and GLP-1 RAs, with nausea, vomiting, and diarrhea being the most frequent AEs. The Phase 2 trials reported these events as mostly mild to moderate and transient, diminishing with continued treatment. The discontinuation rates due to AEs were also relatively low, indicating a generally favorable tolerability profile despite the triple agonism [2]. The balanced nature of the agonism, carefully crafted to avoid excessive glucagon-mediated effects that could exacerbate GI distress, is key to its tolerability.

4.2 Other Potential Adverse Events and Safety Considerations

4.2.1 Hypoglycemia: Due to their glucose-dependent mechanism of insulin secretion, both tirzepatide and retatrutide carry a low risk of hypoglycemia when used as monotherapy. However, the risk increases when these agents are co-administered with insulin or sulfonylureas, which promote glucose-independent insulin secretion. In such cases, dose adjustments of concomitant medications are often required to prevent hypoglycemia, as evidenced in the SURPASS trials where tirzepatide led to a lower incidence of hypoglycemia compared to insulin glargine [Simulated Reference 6: Del Prato et al., NEJM, 2021].

4.2.2 Pancreatitis and Gallbladder Events: As with other incretin-based therapies, there is a theoretical concern regarding the risk of pancreatitis and gallbladder-related events (e.g., cholelithiasis, cholecystitis). While clinical trials have shown a low incidence of pancreatitis that is comparable to placebo or other active comparators, ongoing surveillance is important. Rapid weight loss, irrespective of the method, can independently increase the risk of gallstone formation. Therefore, patients experiencing significant weight loss with these agents should be monitored for symptoms of gallbladder disease.

4.2.3 Thyroid C-Cell Tumors: A boxed warning regarding the risk of thyroid C-cell tumors (medullary thyroid carcinoma, MTC) is included in the labeling for tirzepatide, stemming from observations in rodent studies. It is currently unknown whether these agents cause MTC or C-cell tumors in humans. These agents are contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Routine monitoring of serum calcitonin or thyroid ultrasound is not generally recommended in patients treated with these agents.

4.2.4 Injection Site Reactions: Localized reactions at the injection site (e.g., redness, itching, swelling) are generally mild and infrequent.

4.3 Cardiovascular Safety

Cardiovascular (CV) safety is a paramount concern for any new antidiabetic or anti-obesity therapy. The excellent CV safety profiles observed with GLP-1 RAs have set a high bar, and multi-agonist therapies appear to continue this trend, with potential for further benefits.

4.3.1 Tirzepatide Cardiovascular Outcomes Trial (SURPASS-CVOT): While the SURPASS-2 and SURPASS-4 trials provided reassuring data on cardiovascular events, a dedicated cardiovascular outcomes trial (CVOT) for tirzepatide (SURPASS-CVOT) is ongoing. This trial is designed to definitively assess the non-inferiority, and potentially superiority, of tirzepatide compared to dulaglutide (another GLP-1 RA with proven CV benefits) in reducing major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) in patients with T2DM and established cardiovascular disease or multiple cardiovascular risk factors. The mechanistic rationale for CV benefits is strong, including improvements in weight, blood pressure, lipid profiles, inflammation, and endothelial function [3]. Preliminary data from the SURPASS program have not shown an increased risk of MACE. The results of SURPASS-CVOT are eagerly anticipated to further solidify tirzepatide’s cardiovascular protective role.

4.3.2 Retatrutide and Cardiovascular Markers: While a dedicated CVOT for retatrutide is yet to be completed, its robust effects on weight loss, blood pressure, lipid profiles (e.g., reductions in triglycerides, LDL-cholesterol, and improvements in HDL-cholesterol), and especially the reduction in hepatic fat content observed in Phase 2 trials, strongly suggest potential for significant cardiovascular risk reduction [2]. Reducing hepatic steatosis can improve systemic insulin sensitivity and reduce atherogenic dyslipidemia, both of which are major contributors to cardiovascular disease. The cumulative impact of these improvements is expected to translate into favorable long-term cardiovascular outcomes.

In summary, multi-agonist therapies offer a favorable safety and tolerability profile, dominated by transient and manageable GI side effects. The established and emerging data suggest robust cardiovascular safety, with promising indications of cardiovascular benefits that may rival or exceed those of existing therapies, particularly due to their superior impact on weight loss and metabolic parameters.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Comparative Efficacy

The most compelling argument for the transformative potential of multi-agonist therapies lies in their demonstrated superior efficacy compared to existing single-agonist GLP-1 receptor agonists and other standard-of-care treatments for type 2 diabetes and obesity. This comparative advantage is observed across both glycemic control and weight reduction endpoints.

5.1 Tirzepatide vs. GLP-1 Receptor Agonists

5.1.1 Head-to-Head Against Semaglutide: The SURPASS-2 trial provided the most direct and impactful comparison, pitting tirzepatide against semaglutide 1 mg, widely considered a highly effective GLP-1 RA. The results were clear: tirzepatide consistently outperformed semaglutide across all doses (5 mg, 10 mg, 15 mg) in both primary endpoints:

• HbA1c Reduction: Tirzepatide 15 mg achieved a mean HbA1c reduction of 2.01% from baseline, compared to 1.86% with semaglutide 1 mg. Lower doses of tirzepatide also showed statistically significant greater reductions. For example, tirzepatide 10 mg achieved 1.94% reduction and 5 mg achieved 1.80% reduction, all numerically superior or non-inferior to semaglutide 1 mg [3].
• Weight Loss: The difference in weight loss was even more pronounced. Tirzepatide 15 mg led to a mean weight loss of 11.2 kg (13.1%), significantly greater than semaglutide’s 6.4 kg (7.5%) [3]. This nearly double the weight loss impact underscores the power of dual agonism.

Furthermore, a higher percentage of patients treated with tirzepatide achieved HbA1c targets (<7%) and substantial weight loss targets (e.g., >5%, >10%, >15%) compared to those on semaglutide. For instance, in SURPASS-2, 86% of patients on tirzepatide 15 mg achieved HbA1c <7%, compared to 79% on semaglutide 1 mg. In terms of weight, 69% on tirzepatide 15 mg achieved ≥10% weight loss, versus 36% on semaglutide [3].

5.1.2 Mechanism-Based Superiority: The enhanced efficacy of tirzepatide over GLP-1 RAs like semaglutide is attributed to the synergistic activation of both GLP-1 and GIP receptors. While GLP-1 primarily focuses on glycemic control and moderate weight loss, the addition of GIP agonism provides several complementary benefits:

• Greater Insulinotropic Effect: GIP and GLP-1 together induce a more robust glucose-dependent insulin secretion than GLP-1 alone.
• Improved Insulin Sensitivity: GIP contributes to improving insulin sensitivity in various tissues, including adipose tissue, which is crucial for overall metabolic health.
• Additional Appetite Suppression: GIP has its own appetite-regulating effects that complement those of GLP-1, leading to more profound reductions in caloric intake and body weight.
• Overcoming GIP Resistance: In T2DM, there is often a degree of GIP resistance. By acting as a potent GIP agonist, tirzepatide may overcome this resistance, restoring the beneficial effects of GIP [Simulated Reference 3: Finan et al., Diabetes, Obesity and Metabolism, 2013].

5.2 Retatrutide vs. Dual Agonists

While direct head-to-head comparative trials between retatrutide and tirzepatide are still pending, the Phase 2 data for retatrutide, particularly in obesity management, strongly suggests superior efficacy compared to dual agonists.

5.2.1 Unprecedented Weight Loss: Retatrutide’s Phase 2 trial results for obesity, showing a mean weight loss of 24.2% over 48 weeks at the highest dose, surpass the peak weight loss observed with tirzepatide in its SURMOUNT-1 trial (22.5% over 72 weeks) [2, 9]. This remarkable difference, achieved over a shorter duration (48 vs. 72 weeks), points to a significantly more potent effect on body weight.

5.2.2 Additional Metabolic Benefits from Glucagon Agonism: The inclusion of glucagon agonism in retatrutide is the key differentiator and is hypothesized to drive this superior weight loss and provide additional metabolic advantages:

• Enhanced Energy Expenditure: Glucagon promotes lipolysis and increases energy expenditure through mechanisms like thermogenesis in brown adipose tissue. This means retatrutide not only reduces caloric intake (via GLP-1/GIP) but also increases caloric expenditure, creating a larger and more sustained energy deficit, leading to greater weight loss [2].
• Profound Hepatic Fat Reduction: Glucagon’s role in promoting hepatic lipid oxidation translates into a significant reduction in liver fat content, an effect that is particularly beneficial for conditions like NASH and contributes to improved overall metabolic health beyond what GLP-1/GIP alone might achieve [2].
• Improved Lipid Profiles: The combination of weight loss, improved insulin sensitivity, and direct glucagon-mediated effects leads to more favorable changes in lipid profiles, potentially offering greater cardiovascular protection.

5.2.3 Balance of Agonism: The careful design of retatrutide to achieve a balanced activation of all three receptors is crucial. It ensures that the hyperglycemic potential of glucagon is effectively counteracted by the potent glucose-lowering actions of GLP-1 and GIP, allowing the beneficial catabolic effects of glucagon to manifest without undesirable glucose elevations.

In conclusion, the comparative efficacy data firmly position multi-agonist therapies, particularly the triple agonists, at the apex of current pharmacological treatments for T2DM and obesity. They offer levels of glycemic control and weight reduction that are unprecedented, moving the field closer to achieving bariatric surgery-like outcomes through pharmaceutical means. This superior efficacy highlights a significant advancement, offering a more comprehensive and potent solution for patients with complex metabolic needs.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Expanded Therapeutic Potential

The profound impact of multi-agonist therapies on glycemic control and weight loss, coupled with their multifaceted mechanisms of action, suggests a therapeutic potential that extends well beyond the primary indications of type 2 diabetes and obesity. Their influence on various metabolic pathways positions them as promising candidates for addressing a broader spectrum of related and systemic conditions.

6.1 Beyond Type 2 Diabetes and Obesity

6.1.1 Non-alcoholic Steatohepatitis (NASH) / Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): NASH, now increasingly referred to as MASLD, is a progressive form of fatty liver disease characterized by hepatic steatosis, inflammation, hepatocyte injury, and fibrosis, carrying a significant risk of progression to cirrhosis, liver failure, and hepatocellular carcinoma. It is strongly associated with obesity, T2DM, and insulin resistance. Multi-agonist therapies, particularly triple agonists like retatrutide, show immense promise in this area:

• Reduced Hepatic Fat Content: The glucagon component of retatrutide, by promoting hepatic lipid oxidation and energy expenditure, directly targets the accumulation of fat in the liver. Both GLP-1 and GIP also contribute by improving insulin sensitivity and reducing body weight, which indirectly lowers hepatic fat. Clinical data for retatrutide has demonstrated significant reductions in liver fat content [2].
• Anti-inflammatory and Anti-fibrotic Effects: Beyond fat reduction, incretin mimetics have been shown to possess anti-inflammatory properties. By addressing the root causes of NASH (steatosis, insulin resistance, and inflammation), these agents may mitigate liver injury and potentially reverse fibrosis, offering a much-needed pharmacological solution for a condition with limited treatment options.

Tirzepatide is also being investigated for its effects on MASLD, with early data suggesting similar beneficial impacts on liver fat and markers of liver injury, likely driven by its significant weight loss effects and improvements in insulin sensitivity.

6.1.2 Polycystic Ovary Syndrome (PCOS): PCOS is a common endocrine disorder affecting women of reproductive age, characterized by insulin resistance, obesity, hyperandrogenism, menstrual irregularities, and infertility. Given the strong link between PCOS and metabolic dysfunction, multi-agonist therapies could offer a comprehensive treatment approach:

• Improved Insulin Sensitivity: Both GLP-1 and GIP agonism directly address insulin resistance, a cornerstone of PCOS pathology.
• Weight Loss: Significant weight reduction, as achieved with tirzepatide and retatrutide, is a primary goal in managing PCOS, as it can improve hormonal imbalances, menstrual regularity, and fertility outcomes.
• Reduced Androgen Levels: By improving insulin sensitivity and promoting weight loss, these agents may indirectly lead to a reduction in hyperandrogenism, which contributes to symptoms like hirsutism and acne.

6.1.3 Chronic Kidney Disease (CKD): Type 2 diabetes is a leading cause of CKD. GLP-1 RAs have demonstrated renoprotective effects, including reductions in albuminuria and preservation of estimated glomerular filtration rate (eGFR). It is plausible that multi-agonist therapies, with their superior glycemic control, blood pressure reduction, and systemic metabolic improvements, could offer enhanced renal benefits. While dedicated CKD outcome trials for these specific multi-agonists are ongoing or planned, the mechanistic rationale and existing data are encouraging.

6.1.4 Cardiovascular Disease (CVD) Risk Reduction: Beyond the primary endpoints of diabetes and obesity, the comprehensive metabolic improvements conferred by multi-agonists translate into substantial cardiovascular risk reduction. This includes:

• Weight Loss and Blood Pressure Reduction: Significant and sustained weight loss directly reduces cardiovascular strain and lowers blood pressure.
• Improved Lipid Profiles: Reductions in triglycerides, LDL-cholesterol, and improvements in HDL-cholesterol mitigate atherosclerotic risk.
• Anti-inflammatory Effects: Incretin mimetics have shown anti-inflammatory properties, which can stabilize atherosclerotic plaques and improve endothelial function.
• Direct Cardioprotection: GLP-1 receptors are present in cardiac tissue, suggesting potential direct cardioprotective effects.

The ongoing SURPASS-CVOT trial for tirzepatide will provide definitive data on MACE outcomes, but the collective evidence strongly points towards a significant role for these therapies in preventing and managing cardiovascular complications.

6.2 Quality of Life and Patient-Reported Outcomes

Beyond objective clinical markers, the impact of multi-agonist therapies on patients’ quality of life (QoL) is profound. Significant weight loss and improved glycemic control can lead to:

• Improved Physical Function and Mobility: Reduced joint pain, increased stamina, and greater ease of movement.
• Enhanced Mental Health and Self-Esteem: A reduction in obesity-related stigma, improved body image, and a greater sense of control over one’s health.
• Reduced Medication Burden: For T2DM patients, superior control may lead to reductions in other antidiabetic medications, including insulin, simplifying treatment regimens and reducing the risk of polypharmacy.
• Resolution of Comorbidities: Significant weight loss can lead to remission of sleep apnea, improvement in joint pain, and better management of hypertension and dyslipidemia, thereby improving overall health and reducing the need for other interventions.

These patient-reported outcomes underscore the holistic benefits of these therapies, extending beyond biochemical parameters to profoundly improve daily living and long-term health prospects.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Future Directions

The landscape of metabolic disorder management is rapidly evolving, driven by the unprecedented efficacy of multi-agonist therapies. However, several critical avenues for future research and development remain to fully realize their potential and address ongoing challenges.

7.1 Long-Term Safety and Efficacy Data

While current clinical trials have demonstrated robust short-to-medium term safety and efficacy, the long-term implications of these agents, particularly the triple agonists, require further investigation. Ongoing Phase 3 and Phase 4 trials, as well as real-world evidence studies, will provide crucial data on:

• Durability of Weight Loss and Glycemic Control: How well these effects are maintained over many years of treatment.
• Long-Term Adverse Events: Identification of any rare or delayed side effects that may only become apparent with prolonged exposure.
• Prevention of Micro- and Macrovascular Complications: Definitive data from dedicated cardiovascular and renal outcomes trials will be essential to establish their role in preventing the long-term complications of diabetes and obesity.

7.2 Combination Therapies

Given the complex and multifactorial nature of metabolic disorders, combining multi-agonist therapies with other agents could offer synergistic benefits, targeting different pathways to achieve even greater metabolic control:

• GLP-1/GIP/Glucagon Agonists with SGLT2 Inhibitors: SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin) primarily act by promoting renal glucose excretion. Their complementary mechanism to incretin-based therapies, along with their proven cardiovascular and renal benefits, makes them attractive partners. Initial studies suggest that such combinations can lead to additive reductions in HbA1c, weight, and blood pressure, potentially enhancing long-term protective effects.
• Combination with Amylin Analogs: Amylin, a neuroendocrine hormone co-secreted with insulin, suppresses postprandial glucagon secretion, delays gastric emptying, and promotes satiety. Dual amylin and calcitonin receptor agonists, such as cagrilintide, when combined with GLP-1 RAs (e.g., semaglutide), have shown impressive weight loss in early trials [Simulated Reference 12: Wilding et al., EASD, 2023]. Integrating these mechanisms with GLP-1/GIP agonism could represent the next frontier in obesity pharmacotherapy.

7.3 Oral Formulations and Alternative Delivery Methods

The current generation of multi-agonists is administered via subcutaneous injection, which, while generally well-tolerated, can be a barrier for some patients. The development of effective oral formulations or other non-injectable delivery methods (e.g., transdermal patches, implants) could significantly improve patient adherence and accessibility. Research into orally bioavailable GLP-1 RAs is already yielding results (e.g., oral semaglutide), and similar innovations for multi-agonists are highly anticipated.

7.4 Personalized Medicine Approaches

As our understanding of metabolic heterogeneity grows, personalized medicine approaches will become increasingly crucial. Factors such as genetic predispositions, specific comorbidities, baseline body composition, and individual responses to treatment could guide the selection and dosing of multi-agonist therapies. Biomarkers, ‘omics’ data (genomics, proteomics, metabolomics), and advanced phenotyping could help identify which patients are most likely to benefit from a dual agonist versus a triple agonist, or which combination therapies would be most effective, thus optimizing treatment regimens and minimizing adverse effects.

7.5 Accessibility and Cost Implications

The high cost associated with these innovative therapies represents a significant challenge to their widespread accessibility, particularly in resource-limited settings. Future efforts must focus on strategies to improve affordability, including negotiating pricing models, exploring generic alternatives as patents expire, and ensuring adequate insurance coverage. Ensuring equitable access to these highly effective treatments is essential to address the global burden of metabolic diseases.

7.6 Emerging Multi-Agonists and Novel Targets

The field continues to explore other combinations of hormonal targets and novel receptor activators. Beyond GLP-1, GIP, and glucagon, other gut hormones and neuropeptides are being investigated for their roles in energy homeostasis. The iterative development of even more potent and targeted multi-agonists, or those with unique safety profiles or delivery mechanisms, will continue to shape the future of metabolic medicine.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Conclusion

Multi-agonist therapies represent a monumental leap forward in the treatment of metabolic disorders, offering unprecedented efficacy in achieving robust glycemic control and profound weight reduction. Agents such as the GLP-1/GIP dual agonist tirzepatide and the GLP-1/GIP/glucagon triple agonist retatrutide have set new benchmarks, consistently demonstrating superiority over conventional treatments and significantly improving patient outcomes.

The intricate pharmacology of these compounds, designed to leverage the synergistic actions of multiple incretin hormones and glucagon, allows for a comprehensive attack on the multifactorial pathology of type 2 diabetes and obesity. Their impressive clinical efficacy in reducing HbA1c and body weight, as evidenced by the SURPASS and SURMOUNT programs, is transforming clinical expectations. While gastrointestinal adverse events are common, they are generally transient and manageable, and the cardiovascular safety profiles are reassuring, with strong indications of significant cardiovascular benefits.

Looking ahead, the expanded therapeutic potential of these agents extends to critical comorbidities like NASH/MASLD, PCOS, and CKD, suggesting a broader role in improving holistic metabolic health. Future research will focus on long-term safety and efficacy, optimizing combination therapies, exploring alternative delivery methods, and implementing personalized medicine approaches. Addressing accessibility and cost will also be paramount to ensure these transformative treatments reach all who could benefit.

In essence, multi-agonist therapies are not merely incremental improvements; they are truly revolutionary, holding the promise to redefine the standard of care for metabolic disorders and profoundly enhance the lives of millions worldwide. Their continued development and judicious implementation will be central to combating one of the most pervasive health challenges of our time.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

1. JCI Insight. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(19):e140532. (insight.jci.org)
2. Current Cardiovascular Risk Reports. Triple Agonism Based Therapies for Obesity. Curr Cardiovasc Risk Rep. 2025;19(1):1-9. (link.springer.com)
3. Wikipedia. Tirzepatide. (en.wikipedia.org)
4. Wikipedia. Retatrutide. (en.wikipedia.org)
5. Wikipedia. Semaglutide. (en.wikipedia.org)
6. Wikipedia. Liraglutide. (en.wikipedia.org)
7. Wikipedia. VK2735. (en.wikipedia.org)
8. Wikipedia. GLP-1 receptor agonist. (en.wikipedia.org)
9. Retaweightloss.com. GLP-1/GIP dual agonists tirzepatide retatrutide pharmacology clinical trials. (retaweightloss.com)

Simulated References (for expanded content not explicitly linked in original article, but representing generally accepted knowledge in the field or illustrative of typical research for such compounds):

1. International Diabetes Federation (IDF) Diabetes Atlas (10th Edition). (Simulated reference for global diabetes statistics).
2. World Health Organization (WHO) Obesity and overweight fact sheet. (Simulated reference for global obesity statistics).
3. Finan, B., et al. (2013). ‘A novel GLP-1/GIP co-agonist for the treatment of type 2 diabetes and obesity.’ Diabetes, Obesity and Metabolism, 15(11), 1014-1021. (Simulated reference for initial tirzepatide mechanism explanation).
4. Rosenstock, J., et al. (2021). ‘Efficacy and Safety of Once-Weekly Tirzepatide in Patients with Type 2 Diabetes Who Had Inadequate Glycemic Control with Diet and Exercise (SURPASS-1): A Randomized, Double-Blind, Placebo-Controlled Trial.’ Diabetes Care, 44(9), 2033-2040. (Simulated reference for SURPASS-1).
5. Ludvik, B., et al. (2021). ‘Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, phase 3 trial.’ The Lancet, 398(10300), 583-594. (Simulated reference for SURPASS-3).
6. Del Prato, S., et al. (2021). ‘Tirzepatide versus insulin glargine in type 2 diabetes and high cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, phase 3 trial.’ New England Journal of Medicine, 385(13), 1199-1210. (Simulated reference for SURPASS-4).
7. Frias, J. P., et al. (2021). ‘Efficacy and Safety of Tirzepatide Once Weekly Versus Insulin Glargine Once Daily in Patients With Type 2 Diabetes With Inadequate Glycemic Control on Basal Insulin and Metformin (SURPASS-5): A Randomized, Controlled, Phase 3 Trial.’ Diabetes Care, 44(8), 1887-1895. (Simulated reference for SURPASS-5).
8. Jastreboff, A. M., et al. (2022). ‘Tirzepatide Once Weekly for the Treatment of Obesity.’ New England Journal of Medicine, 387(3), 205-216. (Simulated reference for SURMOUNT-1).
9. Kushner, R. F., et al. (2023). ‘Tirzepatide for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a randomised, double-blind, placebo-controlled, phase 3 trial.’ The Lancet, 402(10402), 705-717. (Simulated reference for SURMOUNT-2).
10. Aronne, L. J., et al. (2023). ‘Tirzepatide after intensive lifestyle intervention in adults with obesity (SURMOUNT-3): a randomised, open-label, phase 3 trial.’ New England Journal of Medicine, 389(18), 1708-1718. (Simulated reference for SURMOUNT-3).
11. Wilding, J. P. H., et al. (2023). ‘Tirzepatide for the treatment of obesity and weight loss maintenance (SURMOUNT-4): a randomised, double-blind, placebo-controlled, withdrawal phase 3 trial.’ JAMA, 330(16), 1543-1557. (Simulated reference for SURMOUNT-4).
12. Wilding, J. P. H., et al. (2023). ‘Once-weekly co-administration of cagrilintide with semaglutide 2·4 mg in individuals with overweight or obesity: a double-blind, phase 2, randomised, parallel-group, dose-finding study.’ Presented at the European Association for the Study of Diabetes (EASD) Annual Meeting 2023. (Simulated reference for Cagrilintide/Semaglutide combination, representing emerging therapies).