Dual Agonists in Type 2 Diabetes Mellitus: Mechanisms, Clinical Efficacy, and Future Perspectives

Abstract

Type 2 Diabetes Mellitus (T2DM) represents a multifaceted chronic metabolic disorder with escalating global prevalence, necessitating innovative therapeutic strategies. While traditional pharmacological interventions, including GLP-1 receptor agonists (GLP-1 RAs), have demonstrated efficacy in glycemic control and weight management, a substantial unmet need persists for more comprehensive and profound metabolic improvements. This report undertakes an in-depth exploration of dual incretin receptor agonists, particularly those targeting both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. These novel agents harness the complementary physiological actions of both incretin hormones, offering a synergistic approach to glucose homeostasis, energy balance, and body weight regulation. We meticulously examine the intricate molecular and physiological mechanisms underpinning GLP-1 and GIP signaling pathways and their combined effects. A significant portion of this analysis is dedicated to the comprehensive review of clinical trial data, with a specific focus on the SURPASS program for tirzepatide, a pioneering GLP-1/GIP dual agonist. The SURPASS trials, encompassing diverse patient populations and comparative arms, have consistently demonstrated superior reductions in glycated hemoglobin (HbA1c) and body weight compared to established monotherapies and other incretin-based treatments. Furthermore, the report critically assesses the safety and tolerability profile of these agents, considering gastrointestinal adverse events and ongoing cardiovascular outcome studies. Finally, we delineate the transformative potential of dual agonists beyond T2DM, including their profound implications for obesity management, as evidenced by the SURMOUNT program, and their prospective roles in addressing other metabolic dysfunctions such as metabolic-associated fatty liver disease (MAFLD). This comprehensive review posits that dual incretin agonists are poised to revolutionize the holistic management of metabolic disorders, offering a paradigm shift towards more effective and pleiotropic therapeutic interventions.

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

1. Introduction

Type 2 Diabetes Mellitus (T2DM) is a chronic, progressive metabolic disorder characterized by defects in insulin secretion, insulin action, or both, leading to persistent hyperglycemia [1]. The global burden of T2DM is substantial and continues to rise, with estimates suggesting that hundreds of millions of individuals are affected worldwide [1]. This condition is a leading cause of morbidity and mortality, primarily due to its associated microvascular complications (retinopathy, nephropathy, neuropathy) and macrovascular complications (cardiovascular disease, stroke, peripheral artery disease), which significantly impair quality of life and impose immense healthcare costs [1].

Traditional therapeutic approaches for T2DM have historically focused on correcting hyperglycemia through various mechanisms, including enhancing insulin sensitivity (e.g., metformin, thiazolidinediones), stimulating insulin secretion (e.g., sulfonylureas, meglitinides), inhibiting glucose absorption (e.g., alpha-glucosidase inhibitors), or directly supplementing insulin. While these agents have improved glycemic outcomes, many patients struggle to achieve and maintain individualized glycemic targets, often experiencing progressive disease, weight gain, or an increased risk of hypoglycemia [1]. Moreover, many conventional therapies do not adequately address the multifaceted metabolic derangements inherent in T2DM, particularly the pervasive issue of obesity, which is a major driver and exacerbating factor of the disease.

The advent of incretin-based therapies marked a significant evolution in T2DM management. The incretin hormones, Glucagon-like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP), are gut-derived peptides released in response to nutrient ingestion, playing crucial roles in glucose homeostasis by potentiating glucose-dependent insulin secretion [2]. GLP-1 receptor agonists (GLP-1 RAs) such as exenatide, liraglutide, and semaglutide, have demonstrated considerable efficacy not only in improving glycemic control but also in promoting weight loss, reducing cardiovascular events, and exerting renal protective effects [2]. However, the therapeutic landscape continued to seek even more potent and comprehensive solutions, particularly for patients who exhibit suboptimal responses to GLP-1 RA monotherapy or require more substantial weight reduction.

This evolving understanding of incretin biology, coupled with the limitations of existing monotherapies, paved the way for the development of dual incretin receptor agonists. These innovative agents are designed to simultaneously activate both GLP-1 and GIP receptors, thereby leveraging the complementary and potentially synergistic actions of these two crucial gut hormones [2]. The rationale behind this dual agonism is rooted in the physiological understanding that both incretins contribute significantly to the ‘incretin effect’—the phenomenon where orally administered glucose elicits a greater insulin response than intravenously administered glucose, largely attributed to GLP-1 and GIP [2]. In patients with T2DM, the incretin effect is often diminished, with GIP receptor signaling frequently being impaired in the context of chronic hyperglycemia, while GLP-1 signaling may be relatively preserved or its effects more therapeutically accessible [1, 2].

The emergence of tirzepatide, a first-in-class dual GLP-1 and GIP receptor agonist, represents a pivotal advancement. Extensive clinical evaluation through the SURPASS program has showcased its superior efficacy in glycemic control and unprecedented weight reduction compared to existing therapies [3, 4]. This report aims to meticulously detail the underlying mechanisms of dual agonism, present a comprehensive review of the clinical evidence supporting their use, discuss their safety profile, and explore their far-reaching potential across a spectrum of metabolic disorders. The objective is to highlight how these agents are not merely incremental improvements but rather transformative interventions poised to reshape the therapeutic paradigm for T2DM and related metabolic conditions.

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

2. Mechanisms of Dual Agonists

To fully appreciate the therapeutic power of dual GLP-1 and GIP receptor agonists, a detailed understanding of the individual incretin hormones and their synergistic interaction is paramount. These gut-derived peptides are central to postprandial glucose regulation and energy balance, and their coordinated action is critical for metabolic health.

2.1 GLP-1 and GIP Receptors: Individual Physiology and Pathophysiology

2.1.1 Glucagon-Like Peptide-1 (GLP-1)

GLP-1 is a 30-amino acid peptide hormone primarily secreted by enteroendocrine L-cells located in the distal ileum and colon, in response to nutrient ingestion, particularly carbohydrates and fats [2]. There are two biologically active forms: GLP-1(7-37) and GLP-1(7-36) amide, with the latter being more abundant [2]. GLP-1 is rapidly degraded in vivo by the enzyme dipeptidyl peptidase-4 (DPP-4), resulting in a short half-life of only 1-2 minutes [2].

The physiological actions of GLP-1 are mediated through the GLP-1 receptor (GLP-1R), a G protein-coupled receptor (GPCR) predominantly expressed on pancreatic beta-cells, but also found in alpha-cells, the brain (hypothalamus and brainstem), gastrointestinal tract, heart, kidney, and adipose tissue [2]. Activation of GLP-1R leads to the stimulation of adenylyl cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP) levels, which in turn activates protein kinase A (PKA) and exchange protein activated by cAMP 2 (EPAC2). These signaling cascades culminate in a range of effects:

• Glucose-dependent insulin secretion: GLP-1 significantly enhances insulin secretion from pancreatic beta-cells only in the presence of elevated glucose levels. This glucose-dependency mitigates the risk of hypoglycemia [2].
• Glucagon suppression: GLP-1 inhibits glucagon secretion from pancreatic alpha-cells, particularly in hyperglycemic conditions, further contributing to reduced hepatic glucose output [2].
• Gastric emptying: It slows gastric emptying, which helps to regulate postprandial glucose excursions by delaying nutrient absorption and promoting satiety [2].
• Satiety and appetite reduction: GLP-1 acts on GLP-1Rs in the brain to reduce appetite and food intake, leading to weight loss [2].
• Beta-cell protection: Preclinical and some clinical data suggest GLP-1 promotes beta-cell proliferation, neogenesis, and reduces apoptosis, thereby preserving beta-cell mass and function [2].

In T2DM, the GLP-1 response may be attenuated, but the GLP-1R remains largely functional, making GLP-1 RAs an effective therapeutic class [1, 2].

2.1.2 Glucose-Dependent Insulinotropic Polypeptide (GIP)

GIP is a 42-amino acid peptide hormone primarily secreted by enteroendocrine K-cells, located predominantly in the duodenum and proximal jejunum, also in response to nutrient intake, especially fats and carbohydrates [2]. Similar to GLP-1, GIP is rapidly inactivated by DPP-4, giving it a similarly short half-life [2].

The GIP receptor (GIPR) is also a GPCR, widely expressed on pancreatic beta-cells, adipose tissue, bone, brain, heart, and kidney [2]. Its activation also leads to increased intracellular cAMP, PKA, and EPAC2 signaling pathways, mediating several key actions:

• Glucose-dependent insulin secretion: GIP is a potent stimulator of insulin secretion from pancreatic beta-cells, also in a glucose-dependent manner [2]. In healthy individuals, GIP contributes significantly to the overall incretin effect, often more so than GLP-1 [2].
• Glucagon secretion: The effect of GIP on glucagon secretion is complex and context-dependent. In some settings, GIP can stimulate glucagon secretion, particularly when glucose levels are low, preventing hypoglycemia. However, in hyperglycemic states, it can indirectly suppress glucagon by stimulating insulin release [2].
• Adipogenesis and lipid metabolism: GIP has been shown to promote lipid deposition in adipose tissue, enhance fatty acid synthesis, and reduce lipolysis, contributing to fat storage. This effect, while potentially contributing to weight gain in certain contexts, is also crucial for efficient energy storage [2].
• Bone metabolism: GIPRs are present on osteoblasts and osteoclasts, and GIP has been implicated in bone formation and remodeling [2].

In T2DM, the GIP system exhibits a distinct pathophysiology. While GIP secretion from K-cells may be preserved or even elevated, the response of pancreatic beta-cells to GIP is significantly impaired or resistant, particularly in chronic hyperglycemic states [1, 2]. This ‘GIP resistance’ has historically led to GIP being considered a less viable therapeutic target than GLP-1. However, recent research suggests that pharmacological activation with potent GIPR agonists can overcome this resistance, especially when combined with GLP-1 agonism [1, 2].

2.2 Synergistic Effects of Dual Agonism

The fundamental premise of dual GLP-1 and GIP receptor agonism is that by simultaneously engaging both incretin pathways, a more comprehensive and robust metabolic benefit can be achieved compared to activating either pathway alone [1, 2]. This synergy operates at multiple physiological levels:

• Enhanced Glucose-Dependent Insulin Secretion: Both GLP-1 and GIP are potent stimulators of glucose-dependent insulin release. By activating both receptors, dual agonists leverage distinct but converging intracellular signaling pathways to maximize insulinotropic effects [1, 2]. Even if GIP sensitivity is reduced in T2DM, a sufficiently potent GIP agonist component, especially when paired with GLP-1, may restore or significantly enhance its insulinotropic action. This leads to superior postprandial glucose control and a more normalized beta-cell response.

• Superior Glycemic Control: The combined effects of enhanced insulin secretion, potent glucagon suppression (primarily via GLP-1, and contextually via GIP), and slowed gastric emptying contribute to a more profound reduction in both fasting and postprandial glucose levels and, consequently, HbA1c [1, 2]. The dual action effectively addresses multiple facets of hyperglycemia simultaneously.

• Profound Weight Reduction: This is one of the most striking advantages of dual agonists. While GLP-1 RAs are known for their weight loss effects (primarily via central appetite suppression and delayed gastric emptying), the addition of GIP agonism appears to significantly augment this benefit [1, 2]. The mechanisms contributing to enhanced weight loss are multifaceted:

  • Increased Satiety and Reduced Food Intake: Both incretins act on central nervous system receptors (hypothalamus, brainstem) to reduce appetite and increase satiety signals. The synergistic effect here likely leads to a greater reduction in caloric intake [1, 2].
  • Improved Energy Expenditure/Metabolism: While GLP-1 RAs primarily influence intake, GIP’s role in adipose tissue metabolism is complex. Early hypotheses suggested GIP’s role in fat storage might counteract weight loss. However, evidence with dual agonists indicates that in the presence of GLP-1 agonism, GIP may modulate fat metabolism in a way that contributes to energy expenditure or more favorable fat distribution, or perhaps by enhancing nutrient partitioning [1, 2]. The precise interaction in human adipose tissue under dual agonism is an active area of research, but the clinical data unequivocally show superior weight loss.
  • Synergistic Gut-Brain Axis Modulation: The interaction between GLP-1 and GIP on the vagal nerve and within different brain regions (e.g., area postrema, nucleus tractus solitarius) involved in appetite regulation is likely crucial for the profound anorexigenic effects [1, 2].

• Addressing Incretin Resistance: A key advantage of dual agonism is its potential to overcome the ‘incretin resistance’ observed in T2DM. By providing a supraphysiological level of both GLP-1 and GIP agonism, the therapy may circumvent or reverse the impaired GIP sensitivity that characterizes the disease, restoring a more robust incretin effect than GLP-1 agonism alone [1, 2].

In essence, dual agonists exploit the full physiological spectrum of the incretin system. By engaging both receptors, they offer a more holistic approach to metabolic dysregulation, targeting not only glucose control but also the underlying issues of body weight and energy balance with unprecedented efficacy. This represents a significant advancement over monotherapy with either GLP-1 RAs or GIP RAs alone, positioning dual agonists as a potentially transformative therapeutic class [1, 2].

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

3. Clinical Efficacy of Dual Agonists

The clinical development of dual incretin receptor agonists has rapidly progressed, with tirzepatide emerging as the flagship compound demonstrating remarkable efficacy across multiple pivotal trials. This section will delve into the extensive clinical data, primarily from the SURPASS program for tirzepatide, and briefly discuss other compounds in development.

3.1 Tirzepatide: A Case Study in Dual Agonism

Tirzepatide (Mounjaro®) is a once-weekly, injectable dual GLP-1 and GIP receptor agonist developed by Eli Lilly and Company. It is a synthetic peptide engineered with a C20 fatty diacid moiety that enables albumin binding, significantly extending its half-life to approximately five days, allowing for convenient once-weekly administration [1]. Preclinical studies indicated that tirzepatide exhibits balanced agonism at both GLP-1R and GIPR, meaning it activates both receptors with similar potencies, a feature believed to be crucial for its synergistic effects [1, 2]. Its development program, notably the SURPASS and SURMOUNT clinical trials, has established its superior efficacy in T2DM and obesity management.

3.1.1 The SURPASS Program: A Comprehensive Clinical Evaluation

The SURPASS program is a series of global Phase 3 clinical trials designed to evaluate the efficacy and safety of tirzepatide as a monotherapy and in combination with various background medications in adults with T2DM. The program compared tirzepatide at different doses (5 mg, 10 mg, and 15 mg once weekly) against placebo or other active comparators, including GLP-1 RAs and different types of insulin [3, 4, 13].

3.1.1.1 SURPASS-1: Monotherapy Efficacy

• Objective: To evaluate the efficacy and safety of tirzepatide monotherapy compared to placebo in patients with T2DM inadequately controlled with diet and exercise alone [3, 13].
• Design: This was a 40-week, randomized, double-blind, placebo-controlled trial involving 478 patients naive to injectable glucose-lowering therapy. Patients were randomized to receive tirzepatide 5 mg, 10 mg, 15 mg, or placebo once weekly [3, 13].
• Key Findings:
  • HbA1c Reduction: All three doses of tirzepatide demonstrated significant and dose-dependent reductions in HbA1c from baseline. The mean HbA1c reductions were -1.87% for 5 mg, -1.89% for 10 mg, and -2.07% for 15 mg, compared to +0.04% for placebo (all p < 0.001 vs. placebo) [3, 13]. A substantial proportion of patients achieved an HbA1c < 7% (81.8% to 92.2% across tirzepatide doses) and < 6.5% (51.7% to 68.3%) [3, 13].
  • Body Weight Reduction: Significant dose-dependent body weight reductions were also observed. Patients on tirzepatide achieved mean weight reductions of -7.0 kg (5 mg), -7.8 kg (10 mg), and -9.5 kg (15 mg), compared to +0.7 kg for placebo (all p < 0.001 vs. placebo). A notable proportion of patients achieved at least 10% weight loss (27.2% to 47.8%) [3, 13].
  • Safety: The safety profile was consistent with incretin-based therapies, with gastrointestinal adverse events (nausea, diarrhea, vomiting) being the most common, generally mild-to-moderate and transient [3, 13].

3.1.1.2 SURPASS-2: Head-to-Head with Semaglutide

• Objective: To compare the efficacy and safety of tirzepatide against semaglutide (1 mg once weekly), a potent GLP-1 RA, as an add-on to metformin in patients with T2DM [4, 13].
• Design: This was a 40-week, open-label, randomized trial involving 1,879 patients. Patients were randomized to tirzepatide 5 mg, 10 mg, 15 mg, or semaglutide 1 mg (the maximum approved dose at the time for T2DM) once weekly, all added to stable metformin therapy [4, 13].
• Key Findings:
  • HbA1c Reduction: Tirzepatide demonstrated superior HbA1c reductions across all doses compared to semaglutide. Mean reductions were -2.01% (5 mg), -2.24% (10 mg), and -2.30% (15 mg) for tirzepatide, versus -1.86% for semaglutide (all tirzepatide doses p < 0.001 for superiority) [4, 13]. A significantly higher proportion of patients on tirzepatide achieved HbA1c < 7% and < 6.5% compared to semaglutide [4, 13].
  • Body Weight Reduction: Tirzepatide also achieved significantly greater body weight reductions. Mean weight losses were -7.6 kg (5 mg), -9.3 kg (10 mg), and -11.2 kg (15 mg) for tirzepatide, compared to -5.7 kg for semaglutide (all tirzepatide doses p < 0.001 for superiority) [4, 13]. Up to 54.3% of patients on the highest tirzepatide dose achieved at least 10% weight loss, compared to 28.1% on semaglutide [4, 13].
  • Safety: The incidence of gastrointestinal adverse events was similar between tirzepatide and semaglutide, though some individual events like nausea were numerically higher with tirzepatide at higher doses but transient [4, 13].

3.1.1.3 SURPASS-3: Comparison with Insulin Degludec

• Objective: To compare the efficacy and safety of tirzepatide against insulin degludec (a long-acting basal insulin), as an add-on to metformin with or without an SGLT2 inhibitor in patients with T2DM [13].
• Design: This was a 52-week, open-label, randomized trial involving 1,444 patients already on stable metformin, with or without an SGLT2 inhibitor. Patients were randomized to tirzepatide 5 mg, 10 mg, 15 mg, or titrated insulin degludec once weekly/daily [13].
• Key Findings:
  • HbA1c Reduction: All tirzepatide doses demonstrated superior HbA1c reductions compared to insulin degludec. Mean reductions were -1.93% (5 mg), -2.12% (10 mg), and -2.27% (15 mg) for tirzepatide, versus -1.34% for insulin degludec (all tirzepatide doses p < 0.001 for superiority) [13].
  • Body Weight Reduction: Tirzepatide led to significant weight loss, whereas insulin degludec was associated with modest weight gain. Mean weight changes were -7.5 kg (5 mg), -10.7 kg (10 mg), and -12.9 kg (15 mg) for tirzepatide, versus +1.7 kg for insulin degludec (all p < 0.001 for superiority) [13].
  • Hypoglycemia: Tirzepatide was associated with a significantly lower risk of hypoglycemia compared to insulin degludec [13].

3.1.1.4 SURPASS-4: In Patients with Increased Cardiovascular Risk

• Objective: To compare the efficacy and safety of tirzepatide against insulin glargine (another long-acting basal insulin) in patients with T2DM and increased cardiovascular (CV) risk already on 1-3 oral antihyperglycemic medications [13].
• Design: This was a 104-week, open-label, randomized trial (with a minimum of 52 weeks primary outcome) involving 2,000 patients with T2DM and established CV disease or high CV risk. Patients were randomized to tirzepatide 5 mg, 10 mg, 15 mg, or titrated insulin glargine once weekly/daily [13].
• Key Findings:
  • HbA1c Reduction: Tirzepatide demonstrated superior HbA1c reductions compared to insulin glargine across all doses. Mean reductions were -1.95% (5 mg), -2.16% (10 mg), and -2.43% (15 mg) for tirzepatide, versus -1.44% for insulin glargine (all tirzepatide doses p < 0.001 for superiority) [13].
  • Body Weight Reduction: Tirzepatide significantly reduced body weight, while insulin glargine resulted in modest weight gain. Mean weight changes were -6.9 kg (5 mg), -10.2 kg (10 mg), and -11.7 kg (15 mg) for tirzepatide, versus +1.9 kg for insulin glargine (all p < 0.001 for superiority) [13].
  • Safety: Hypoglycemia was significantly less frequent with tirzepatide than with insulin glargine [13]. The trial also assessed a major adverse cardiovascular event (MACE) composite endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke), demonstrating non-inferiority for tirzepatide versus insulin glargine [13].

3.1.1.5 SURPASS-5: Add-on to Basal Insulin

• Objective: To evaluate tirzepatide as an add-on therapy to insulin glargine (with or without metformin) in patients with T2DM inadequately controlled on basal insulin [13].
• Design: This was a 40-week, randomized, double-blind, placebo-controlled trial involving 475 patients. Patients were randomized to tirzepatide 5 mg, 10 mg, 15 mg, or placebo, all added to stable insulin glargine (with or without metformin) [13].
• Key Findings:
  • HbA1c Reduction: Tirzepatide significantly improved HbA1c compared to placebo. Mean reductions were -2.11% (5 mg), -2.40% (10 mg), and -2.54% (15 mg) for tirzepatide, versus -0.96% for placebo (all p < 0.001 vs. placebo) [13].
  • Body Weight Reduction: Tirzepatide also led to significant body weight reductions. Mean weight changes were -5.4 kg (5 mg), -7.5 kg (10 mg), and -8.8 kg (15 mg) for tirzepatide, versus +1.6 kg for placebo (all p < 0.001 vs. placebo) [13].
  • Insulin Dosing: Patients on tirzepatide experienced reductions in their total daily insulin glargine dose, while those on placebo required an increase [13].

Collectively, the SURPASS program consistently demonstrated that tirzepatide provides superior glycemic control and weight reduction across a broad spectrum of T2DM patients, often surpassing the efficacy of current standard-of-care agents, including potent GLP-1 RAs and insulin regimens [3, 4, 13]. The magnitude of HbA1c reduction and weight loss observed with tirzepatide is unprecedented for a single agent in T2DM, underscoring the powerful synergistic effects of dual GLP-1/GIP receptor agonism.

3.2 Other Dual and Poly-Agonists in Development

The success of tirzepatide has spurred intense research and development in the field of incretin-based poly-agonists. Several other compounds are currently in various stages of clinical development, targeting not only GLP-1 and GIP but also other gut hormones like glucagon [10, 11, 12].

3.2.1 GLP-1/GIP Dual Agonists

• VK2735 (Viking Therapeutics): This is another dual GLP-1 and GIP receptor agonist that has shown promising results in early-stage clinical trials for obesity and T2DM. Phase 1 results indicated dose-dependent weight loss and good tolerability. It is being evaluated for both subcutaneous and oral formulations, with continued development for weight management [6, 11].
• Mazdutide (Innovent Biologics/Eli Lilly): An investigational GLP-1/GIP dual agonist primarily developed for the Chinese market. It has completed Phase 3 trials for weight loss in adults with obesity and for T2DM, showing significant reductions in body weight and HbA1c [11].

3.2.2 GLP-1/Glucagon Dual Agonists

These agents aim to combine the insulinotropic and anorexigenic effects of GLP-1 with the metabolic benefits of glucagon agonism, particularly glucagon’s role in energy expenditure and lipolysis. Glucagon, while typically known for raising glucose, when administered pharmacologically in specific contexts, can increase energy expenditure and induce significant weight loss by activating glucagon receptors in the liver and adipose tissue [10, 11].

• Survodutide (BI 456906, Boehringer Ingelheim/Zealand Pharma): This is a potent, long-acting GLP-1/glucagon dual agonist. It has shown impressive results in Phase 2 trials for obesity and MAFLD/NASH. In a Phase 2 trial for MAFLD, survodutide achieved a significantly higher proportion of patients with histological improvement of NASH without worsening of fibrosis compared to placebo. It is currently in Phase 3 trials for obesity and MAFLD/NASH [9, 11].
• Efinopegdutide (MK-6024, Merck/Hanmi Pharmaceutical): Initially developed as a GLP-1/glucagon dual agonist, it showed promise in MAFLD. However, its development for T2DM and obesity indications was discontinued by Merck, although Hanmi Pharmaceutical continues its development [5, 11].

3.2.3 GLP-1/GIP/Glucagon Triple Agonists

These represent the next frontier, aiming to integrate the benefits of all three major incretin/gut hormone pathways. The hypothesis is that targeting three distinct but complementary mechanisms will lead to even more profound metabolic improvements [10, 11, 12].

• Retatrutide (LY3437943, Eli Lilly): A groundbreaking GLP-1/GIP/glucagon triple agonist. Early clinical trials (Phase 2) have shown unprecedented levels of weight loss, with patients achieving over 24% mean weight reduction at the highest dose after 48 weeks in individuals with obesity [10, 12]. It also demonstrated significant improvements in HbA1c and lipid profiles in patients with T2DM. Retatrutide is currently in Phase 3 development for obesity and T2DM [10, 12].
• CT-388 (Carmot Therapeutics, acquired by Roche): Another promising GLP-1/GIP/glucagon receptor triple agonist in clinical development, initially showing significant weight loss and glycemic control in early trials. Roche’s acquisition highlights the strategic importance of this class of drugs [7, 11].
• CT-868 (Carmot Therapeutics): A dual GLP-1/GIP receptor agonist from the same company, also in early development for obesity and T2DM [8].

The pipeline of poly-agonists signifies a vigorous pursuit of increasingly potent and pleiotropic agents capable of addressing the complex pathophysiology of metabolic diseases. The rationale for targeting multiple pathways simultaneously is to maximize the therapeutic benefit by synergistically influencing glucose homeostasis, energy expenditure, and appetite regulation, ultimately leading to superior outcomes in terms of glycemic control and substantial weight loss [10, 11, 12].

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

4. Safety and Tolerability

As with any potent pharmacological agent, a thorough understanding of the safety and tolerability profile of dual incretin receptor agonists is crucial for their clinical utility. The SURPASS program, alongside other clinical trials, has provided extensive data on the adverse event landscape of tirzepatide, and these findings are largely consistent with the broader class of incretin-based therapies, particularly GLP-1 RAs.

4.1 Gastrointestinal Side Effects

The most commonly reported adverse events associated with dual agonists, mirroring GLP-1 RAs, are gastrointestinal (GI) in nature [1, 2]. These include:

• Nausea: Reported as the most frequent GI side effect. In the SURPASS program, the incidence of nausea was generally higher with tirzepatide compared to placebo or insulin comparators, and often dose-dependent. For instance, in SURPASS-1, nausea occurred in 12-22% of tirzepatide recipients versus 2% for placebo. In SURPASS-2, the incidence was comparable to semaglutide (17.9-22.6% for tirzepatide vs. 18.2% for semaglutide) [3, 4, 13].
• Vomiting: Also commonly observed, with incidences ranging from 6-10% in tirzepatide groups in SURPASS trials, compared to 1-2% for placebo [3, 4, 13].
• Diarrhea: Similar to nausea and vomiting, diarrhea was reported by 11-14% of tirzepatide patients in SURPASS-1, compared to 3% for placebo [3, 4, 13].
• Constipation: Less frequent than diarrhea, but still a notable GI side effect, typically occurring in 3-6% of patients [3, 4, 13].

These GI side effects are typically mild-to-moderate in severity, transient, and tend to occur more frequently during the initial dose escalation phase. They often diminish over time as patients adapt to the medication [1, 2]. Strategies to mitigate these effects include gradual dose titration (as employed in the clinical trials) and advice on dietary modifications (e.g., smaller, more frequent meals, avoiding fatty foods). Discontinuation rates due to adverse events, while numerically higher than placebo, were generally acceptable and similar to other potent GLP-1 RAs [3, 4, 13].

4.2 Hypoglycemia

Consistent with their glucose-dependent mechanism of action, dual GLP-1/GIP agonists, when used as monotherapy or in combination with metformin, carry a low intrinsic risk of hypoglycemia [1, 2]. However, the risk increases when these agents are co-administered with insulin secretagogues (e.g., sulfonylureas) or insulin. In the SURPASS-3, SURPASS-4, and SURPASS-5 trials, which involved comparisons or co-administration with insulin, the incidence of severe or clinically significant hypoglycemia was significantly lower with tirzepatide compared to insulin comparators, highlighting its favorable safety profile in this regard [13]. Patients initiating dual agonists in combination with sulfonylureas or insulin may require a reduction in the dose of these concomitant medications to minimize hypoglycemia risk [1, 2].

4.3 Pancreatitis and Thyroid C-cell Tumors

Concerns regarding pancreatitis and medullary thyroid carcinoma (MTC) are class effects associated with GLP-1 RAs, stemming from preclinical studies in rodents [1, 2].

• Pancreatitis: While rare, acute pancreatitis has been reported with GLP-1 RAs. In the SURPASS program, the incidence of pancreatitis was low and comparable between tirzepatide, placebo, and active comparators, with no clear signal of increased risk [1, 2]. Nevertheless, dual agonists are contraindicated in patients with a history of pancreatitis, and patients should be monitored for symptoms (persistent severe abdominal pain) [1, 2].
• Thyroid C-cell Tumors/MTC: Rodent studies with GLP-1 RAs have shown a dose-dependent increase in thyroid C-cell tumors (adenomas and carcinomas). It is unknown whether tirzepatide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance of rodent C-cell tumors has not been definitively established [1, 2]. Tirzepatide is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [1, 2]. Patients should be counseled on the potential risk and to report symptoms such as a mass in the neck, dysphagia, dyspnea, or persistent hoarseness [1, 2]. Routine monitoring of serum calcitonin or thyroid ultrasound is generally not recommended.

4.4 Cardiovascular Considerations

The cardiovascular safety of new glucose-lowering medications is a paramount concern, mandated by regulatory bodies since the early 2000s. GLP-1 RAs have demonstrated significant cardiovascular benefits in dedicated cardiovascular outcome trials (CVOTs). For tirzepatide, the SURPASS-4 trial provided initial insights into its CV profile in a high-risk population, demonstrating non-inferiority for MACE compared to insulin glargine [13].

• SURPASS-CVOT: A dedicated, large-scale, randomized, placebo-controlled cardiovascular outcomes trial (SURPASS-CVOT, NCT04255433) is currently underway to definitively assess the cardiovascular safety and potential cardiovascular benefit of tirzepatide in patients with T2DM and established cardiovascular disease. This trial is comparing tirzepatide to dulaglutide (another GLP-1 RA known for its CV benefits). The primary endpoint is the first occurrence of a 3-point MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). The results of SURPASS-CVOT are eagerly awaited and will provide definitive evidence regarding the long-term cardiovascular impact of tirzepatide [1, 2]. Given the substantial reductions in body weight, HbA1c, blood pressure, and improvements in lipid profiles seen with tirzepatide, a favorable cardiovascular outcome is anticipated, potentially surpassing that of GLP-1 RAs due to its more profound metabolic effects [1, 2].

4.5 Other Safety Considerations

• Acute Kidney Injury: In patients with severe adverse GI reactions leading to fluid loss, there is a potential for acute kidney injury. Patients should be advised on hydration, especially during initiation or dose escalation [1, 2].
• Gallbladder-related adverse events: Like other rapid and substantial weight-loss agents, dual agonists may increase the risk of cholelithiasis and cholecystitis [1, 2].
• Injection site reactions: Localized reactions such as erythema, pruritus, or swelling at the injection site are typically mild and transient.

In summary, the safety profile of dual GLP-1/GIP receptor agonists, exemplified by tirzepatide, is generally consistent with the well-established safety profile of GLP-1 RAs. The most common adverse events are gastrointestinal and typically manageable. Critical safety considerations such as pancreatitis and thyroid C-cell tumors warrant careful consideration and patient counseling. The ongoing SURPASS-CVOT will provide comprehensive data on the long-term cardiovascular safety and efficacy, further solidifying the role of these agents in clinical practice.

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

5. Future Perspectives

The profound efficacy of dual incretin receptor agonists, particularly tirzepatide, in achieving superior glycemic control and unprecedented weight reduction, positions them as transformative agents with potential applications extending far beyond the current scope of T2DM management. The future holds immense promise for these compounds, exploring their role in obesity as a primary disease, their utility in other metabolic disorders, and their integration into personalized medicine strategies.

5.1 Potential for Obesity Management: The SURMOUNT Program

Obesity is a global pandemic, recognized as a chronic, relapsing disease that significantly increases the risk of T2DM, cardiovascular disease, certain cancers, and numerous other health complications. Despite its widespread prevalence and serious health implications, effective long-term pharmacological treatments for obesity have historically been limited [11, 12]. The remarkable weight loss observed with tirzepatide in the SURPASS trials prompted a dedicated clinical development program for obesity, known as SURMOUNT.

5.1.1 SURMOUNT-1: Tirzepatide for Obesity in Non-Diabetic Individuals

• Objective: To evaluate the efficacy and safety of tirzepatide in adults with obesity or overweight (with at least one weight-related comorbidity, excluding T2DM) [11, 12].
• Design: This was a 72-week, randomized, double-blind, placebo-controlled trial involving 2,539 adults with a BMI ≥ 30 kg/m² or ≥ 27 kg/m² with at least one weight-related comorbidity. Participants were randomized to receive tirzepatide 5 mg, 10 mg, 15 mg, or placebo once weekly [11, 12].
• Key Findings:
  • Weight Loss: Tirzepatide demonstrated unprecedented and substantial body weight reductions. The mean weight reduction from baseline was -15.0% (5 mg), -19.5% (10 mg), and -20.9% (15 mg), compared to -3.1% for placebo [11, 12]. A remarkable proportion of participants achieved at least 20% weight loss: 36.2% with 10 mg and 50.0% with 15 mg of tirzepatide, compared to 1.7% with placebo. For the highest dose, nearly half of the participants lost over 20% of their body weight, a level of weight loss previously only seen with bariatric surgery [11, 12].
  • Metabolic Improvements: Tirzepatide also led to significant improvements in various cardiometabolic risk factors, including blood pressure, lipid levels, and inflammatory markers, even in the absence of T2DM [11, 12].
  • Safety: The safety profile was consistent with the SURPASS program, with dose-dependent GI adverse events being the most common, generally mild-to-moderate and transient [11, 12].

5.1.2 SURMOUNT-2 and Beyond

SURMOUNT-2 specifically evaluated tirzepatide for weight loss in adults with obesity or overweight who also have T2DM. This trial similarly demonstrated significant weight loss and glycemic control, reinforcing the dual benefits of tirzepatide in this population [11, 12]. Other SURMOUNT trials are ongoing, including long-term extension studies and studies assessing weight maintenance. The results from the SURMOUNT program unequivocally establish dual GLP-1/GIP agonists as highly effective pharmacological interventions for obesity, potentially offering a new standard of care and shifting the paradigm of obesity treatment from lifestyle modifications alone to comprehensive medical management, often delaying or even preventing the onset of T2DM in at-risk individuals [11, 12].

5.2 Expansion to Other Metabolic Disorders

The pleiotropic effects of GLP-1 and GIP signaling suggest that dual agonists could have therapeutic utility beyond T2DM and obesity, extending to a broader range of metabolic and associated conditions.

5.2.1 Metabolic-Associated Fatty Liver Disease (MAFLD) and Non-alcoholic Steatohepatitis (NASH)

MAFLD, particularly its more severe form, non-alcoholic steatohepatitis (NASH), is a significant health concern, closely linked to obesity, insulin resistance, and T2DM. Dual agonists’ mechanisms of action offer several pathways for potential benefit:

• Insulin Sensitivity Improvement: Enhanced insulin sensitivity can reduce hepatic fat accumulation.
• Weight Loss: Direct reduction in body fat, including visceral and hepatic fat, is a primary driver of MAFLD improvement.
• Anti-inflammatory Effects: GLP-1 and GIP may have direct anti-inflammatory effects in the liver.
• Lipid Metabolism Modulation: Dual agonists improve dyslipidemia, which is common in MAFLD [11, 12].

As mentioned earlier, compounds like survodutide (GLP-1/glucagon dual agonist) have shown promising results in Phase 2 trials for NASH, demonstrating histological improvement without worsening of fibrosis [9, 11]. The profound weight loss and metabolic improvements seen with GLP-1/GIP agonists like tirzepatide suggest they will also be highly effective for MAFLD/NASH, and dedicated trials are underway or planned.

5.2.2 Cardiovascular Disease

While SURPASS-CVOT will provide definitive data on MACE outcomes for tirzepatide, the comprehensive improvements in cardiovascular risk factors (HbA1c, body weight, blood pressure, lipid profile) strongly indicate a beneficial impact on cardiovascular health [1, 2]. Future research may explore the use of dual agonists in populations at high cardiovascular risk even without T2DM, leveraging their potent weight loss and metabolic benefits for primary or secondary prevention of cardiovascular events.

5.2.3 Polycystic Ovary Syndrome (PCOS)

PCOS is a common endocrine disorder affecting women, characterized by hyperandrogenism, ovulatory dysfunction, and often insulin resistance and obesity. Given the profound effects of dual agonists on insulin sensitivity and weight loss, they could offer significant therapeutic benefits for women with PCOS, addressing key pathophysiological drivers of the condition. Clinical trials evaluating this potential are warranted.

5.2.4 Chronic Kidney Disease (CKD)

GLP-1 RAs have demonstrated renoprotective effects in patients with T2DM and CKD, independent of glycemic control. The improved glycemic control, blood pressure, and weight loss associated with dual agonists suggest a similar, and potentially enhanced, renoprotective profile [1, 2]. Further research will clarify the specific benefits and mechanisms of dual agonists in various stages of CKD.

5.3 Combination Therapies and Personalized Medicine

As the armamentarium of metabolic therapies expands, future strategies may involve combinations of dual agonists with other novel agents, such as SGLT2 inhibitors or other emerging therapies, to achieve even more comprehensive metabolic control. The concept of personalized medicine, where treatment regimens are tailored based on individual patient characteristics, genetic predispositions, and responses to therapy, will also become increasingly relevant. Biomarkers or genetic markers might help predict which patients respond best to dual agonism versus other incretin-based therapies or entirely different drug classes.

The pipeline of triple agonists (GLP-1/GIP/glucagon) like retatrutide further illustrates the relentless pursuit of maximized metabolic efficacy [10, 12]. These agents are poised to push the boundaries of pharmacological weight loss and metabolic control even further, potentially offering non-surgical solutions for severe obesity and refractory T2DM. The ongoing research into these poly-agonists will provide critical insights into the optimal balance of receptor activation for various metabolic goals and patient populations.

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

6. Conclusion

The landscape of metabolic disorder management has been significantly advanced by the advent of dual incretin receptor agonists, primarily exemplified by tirzepatide. These agents represent a paradigm shift from traditional monotherapeutic approaches to a multifaceted strategy that simultaneously targets the complementary physiological pathways of GLP-1 and GIP. By leveraging the synergistic actions of these two crucial gut hormones, dual agonists achieve superior efficacy in both glycemic control and body weight reduction, addressing core pathophysiological defects inherent in Type 2 Diabetes Mellitus and obesity.

The extensive clinical trial data from the SURPASS program for tirzepatide have consistently demonstrated its unparalleled ability to reduce HbA1c and body weight, often surpassing the performance of established GLP-1 receptor agonists and insulin regimens across diverse patient populations. This remarkable efficacy positions tirzepatide as a leading therapeutic option for T2DM, offering a more holistic approach to disease management.

Furthermore, the profound weight loss observed with tirzepatide in the dedicated SURMOUNT program has opened new avenues for the pharmacological treatment of obesity as a primary disease, potentially offering a non-surgical intervention with efficacy levels previously thought unattainable through medication alone. This has significant implications for reducing the global burden of obesity and its myriad comorbidities.

While the safety profile of dual agonists is largely consistent with the well-established GLP-1 RA class, characterized predominantly by transient gastrointestinal adverse events, ongoing cardiovascular outcome trials (e.g., SURPASS-CVOT) will provide definitive long-term cardiovascular safety and efficacy data. The potential for these agents to extend their therapeutic reach to other metabolic disorders, such as MAFLD/NASH, PCOS, and chronic kidney disease, underscores their broad pleiotropic benefits and transformative potential.

In conclusion, dual GLP-1 and GIP receptor agonists represent a significant milestone in metabolic medicine. Their ability to deliver superior glycemic control and substantial, clinically meaningful weight loss offers a powerful tool for clinicians to effectively manage the complex and interconnected nature of T2DM and obesity. As research continues to explore even more advanced poly-agonists, the future of metabolic management promises increasingly effective, comprehensive, and potentially personalized therapeutic strategies, paving the way for improved patient outcomes and a reduction in the global burden of these chronic diseases.

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

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