Comprehensive Review of the Incretin System and GLP-1-Based Therapies

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

Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) stand as pivotal incretin hormones, fundamental to the intricate regulation of glucose homeostasis and broader metabolic functions. This extensive report meticulously examines the physiological intricacies of these two primary incretins within the complex incretin system. It traces the profound historical evolution of GLP-1-based therapeutic strategies, from their initial discovery to the development of sophisticated receptor agonists. The report further delves into their expansive therapeutic utility across a spectrum of critical conditions, including Type 2 diabetes mellitus (T2DM), obesity, and established cardiovascular diseases, while also exploring emerging evidence for their significant neurological benefits. A detailed comparative analysis elucidates the distinctions among the diverse array of GLP-1 receptor agonists currently available. Furthermore, the report provides a forward-looking perspective on ongoing research into next-generation incretin-based drugs, such as dual and triple agonists, and innovative oral formulations, highlighting their transformative potential for future medical interventions and the advancement of metabolic disorder management.

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

1. Introduction

The human body possesses an exquisitely refined system for maintaining glucose homeostasis, a critical balance essential for cellular energy and overall physiological function. Central to this system is the incretin axis, a sophisticated endocrine loop originating in the gastrointestinal tract. The incretin system comprises a group of hormones released promptly into circulation in response to nutrient ingestion, primarily orchestrating an amplification of glucose-dependent insulin secretion from pancreatic beta cells. This phenomenon, known as the ‘incretin effect,’ is predominantly mediated by two key gut-derived peptides: Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP). Both hormones play indispensable roles in postprandial glucose metabolism, satiety regulation, and energy balance. The profound understanding of their physiological functions, coupled with the identification of impairments in the incretin effect in conditions such as Type 2 Diabetes Mellitus (T2DM), has paved the way for the revolutionary development of incretin-based therapies. This report aims to provide a comprehensive, in-depth analysis of the incretin system, the historical trajectory of GLP-1-based pharmacotherapies, their diverse therapeutic applications, the pharmacological distinctions between existing agents, and the promising frontier of next-generation incretin mimetics, underscoring their burgeoning impact on the treatment of various metabolic and neurodegenerative disorders.

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

2. The Incretin System: GLP-1 and GIP

2.1 Physiological Roles of GLP-1 and GIP

GLP-1 and GIP are integral components of the entero-insular axis, a feedback loop between the gut and the pancreatic islets. Their synthesis, release, and multifaceted actions extend far beyond glucose regulation, influencing numerous physiological systems.

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

GLP-1 is a 30- or 31-amino acid peptide derived from the post-translational processing of proglucagon. This processing is tissue-specific; in the pancreatic alpha cells, proglucagon is cleaved to yield glucagon, while in the enteroendocrine L cells predominantly located in the distal small intestine (ileum) and colon, it is processed into GLP-1 (7-36) amide and GLP-1 (7-37), as well as glucagon-like peptide-2 (GLP-2) and oxyntomodulin (en.wikipedia.org).

Secretion and Degradation: GLP-1 is secreted rapidly in response to nutrient intake, particularly carbohydrates and fats. Its release is biphasic: an initial rapid phase within minutes of food ingestion, likely due to neural signals and proximal gut factors, followed by a more sustained phase as nutrients reach the distal small intestine. Native GLP-1 has a very short circulating half-life, typically less than two minutes, due to rapid enzymatic degradation by the ubiquitous enzyme dipeptidyl peptidase-4 (DPP-4) (en.wikipedia.org). This rapid inactivation necessitates specific drug design strategies to prolong its therapeutic action.

Receptors and Target Organs: GLP-1 exerts its effects by binding to the highly specific GLP-1 receptor (GLP-1R), a G-protein coupled receptor expressed in a wide array of tissues throughout the body, reflecting its broad physiological impact. Key target organs include:

• Pancreas: The primary site of action for glycemic control. GLP-1 stimulates glucose-dependent insulin secretion from beta cells, meaning its insulinotropic effect is diminished as blood glucose levels fall, thereby reducing the risk of hypoglycemia. It achieves this by increasing intracellular cAMP levels, leading to enhanced insulin granule exocytosis. GLP-1 also promotes beta-cell proliferation, neogenesis, and protects existing beta cells from apoptosis, thus potentially preserving beta-cell mass and function. Concurrently, GLP-1 suppresses glucagon secretion from pancreatic alpha cells, particularly in hyperglycemic states, which further contributes to lower hepatic glucose production (en.wikipedia.org).
• Gastrointestinal Tract: GLP-1 delays gastric emptying, leading to a slower absorption of glucose into the bloodstream and a blunted postprandial glucose excursion. This effect also contributes to satiety and reduced food intake. It also decreases gastric acid secretion and motility.
• Brain: GLP-1 receptors are abundant in various brain regions involved in appetite control, reward, and cognition, including the hypothalamus, brainstem, and hippocampus. Activation of these receptors leads to increased satiety, reduced food intake, and a decrease in hedonic eating, contributing to weight loss. Emerging evidence also points to neuroprotective and cognitive-enhancing effects.
• Cardiovascular System: GLP-1R activation has direct and indirect cardioprotective effects. It can improve myocardial contractility, reduce inflammation and oxidative stress in the vasculature, lower blood pressure, and improve endothelial function. These effects are distinct from its glucose-lowering actions.
• Kidney: GLP-1R activation promotes natriuresis (sodium excretion), potentially contributing to blood pressure reduction and exhibiting direct renoprotective effects, including reductions in albuminuria.
• Adipose Tissue: While less direct, GLP-1 can influence adipose tissue metabolism and may improve insulin sensitivity.

2.1.2 Glucose-dependent Insulinotropic Polypeptide (GIP)

GIP is a 42-amino acid peptide hormone secreted by enteroendocrine K cells, which are primarily located in the duodenum and proximal jejunum (en.wikipedia.org). GIP was the first incretin hormone to be identified and was initially termed ‘gastric inhibitory polypeptide’ due to its perceived role in inhibiting gastric acid secretion, an effect now considered physiologically minor.

Secretion and Degradation: Similar to GLP-1, GIP secretion is stimulated rapidly by the presence of nutrients in the lumen, with a strong response to fat and glucose. It also undergoes rapid degradation by DPP-4, resulting in a similarly short circulating half-life.

Receptors and Target Organs: GIP exerts its effects via the GIP receptor (GIPR), another G-protein coupled receptor. GIPR is also widely distributed, though its precise tissue distribution and full physiological repertoire of effects differ from GLP-1R:

• Pancreas: GIP is a potent glucose-dependent insulin secretagogue, arguably even more potent than GLP-1 at physiological concentrations. It also contributes to beta-cell proliferation and survival. However, unlike GLP-1, GIP’s effect on glucagon secretion is more nuanced: it can stimulate glucagon secretion during hypoglycemic conditions but suppress it during hyperglycemia.
• Adipose Tissue: GIP has significant direct effects on adipocytes, promoting glucose uptake into fat cells, enhancing lipogenesis (fat storage), and inhibiting lipolysis (fat breakdown). This effect on fat storage differentiates GIP from GLP-1, as GIP’s role in weight management is complex; while it enhances insulin secretion, its pro-adipogenic effects need careful consideration, especially in obesity.
• Bone: GIP receptors are found on osteoblasts and osteoclasts, suggesting a role in bone metabolism, potentially promoting bone formation.
• Brain: GIP receptors are also present in the brain, with research suggesting potential neuroprotective roles and influences on memory and cognition, though these areas are less explored than for GLP-1.
• Other tissues: GIPR are found in the stomach, heart, and kidney, but their functional significance in these organs is generally considered less prominent than GLP-1R activation for therapeutic purposes related to obesity and cardiovascular outcomes.

2.2 Incretin Effect and Its Implications

The ‘incretin effect’ is a cornerstone concept in metabolic physiology. It describes the phenomenon where the insulin response to orally ingested glucose is significantly greater than the insulin response to an equivalent amount of intravenously administered glucose. This augmented insulin secretion, primarily mediated by GLP-1 and GIP, accounts for approximately 50-70% of the total postprandial insulin response in healthy individuals (pmc.ncbi.nlm.nih.gov). The discovery of this effect provided a crucial understanding of how the gut modulates pancreatic function.

Mechanisms of Diminished Incretin Effect in T2DM: A hallmark of Type 2 Diabetes Mellitus is a profoundly diminished incretin effect. This impairment contributes significantly to postprandial hyperglycemia. The underlying reasons are multifactorial:

• Impaired GLP-1 Secretion: While not universally observed, some individuals with T2DM exhibit reduced GLP-1 secretion in response to nutrient intake.
• GIP Resistance: A more consistent finding in T2DM is a reduced or blunted insulinotropic response to GIP, even when GIP levels are normal or elevated. This GIP resistance means that even though GIP is released, the beta cells do not respond adequately to its insulin-stimulating signal.
• Chronic Hyperglycemia: Prolonged exposure to high glucose levels can desensitize beta cells to incretin stimulation, further exacerbating the diminished incretin effect.

The clinical implications of a reduced incretin effect are significant. It leads to inadequate postprandial insulin secretion, contributing to sustained hyperglycemia after meals, a critical driver of chronic diabetic complications. This understanding underpinned the rationale for developing therapeutic strategies that either augment the action of endogenous incretins (DPP-4 inhibitors) or directly agonize incretin receptors (GLP-1 receptor agonists, dual agonists), thereby restoring or enhancing the incretin effect.

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

3. Historical Development of GLP-1-Based Therapies

The journey from the physiological identification of incretins to their clinical application has been a remarkable testament to modern pharmaceutical research, transforming the landscape of diabetes and obesity management.

3.1 Discovery and Early Research

The concept of a gut factor influencing insulin secretion dates back to the early 20th century. In 1902, Bayliss and Starling described secretin, the first hormone. Later, in 1964, Dupré and colleagues demonstrated that oral glucose elicited a greater insulin response than intravenous glucose, providing the first clear evidence of an ‘incretin effect.’ GIP was discovered in the 1970s. However, the identification of GLP-1 as a major physiological incretin and its potent insulinotropic capabilities solidified its central role.

Key breakthroughs occurred in the 1980s. In 1986, Professor Jens Juul Holst’s group in Denmark, alongside Dr. Joel Habener and his colleagues at Massachusetts General Hospital, independently characterized GLP-1 and its remarkable potency in stimulating insulin secretion and inhibiting glucagon secretion in a glucose-dependent manner (en.wikipedia.org). Their pioneering work revealed that GLP-1 was a far more potent insulin secretagogue than previously studied incretins. This foundational research laid the groundwork for investigating GLP-1’s potential as a therapeutic target for diabetes. The major challenge identified was the extremely short half-life of native GLP-1 in circulation due to rapid degradation by the enzyme DPP-4, making it unsuitable for direct therapeutic use.

3.2 Development of GLP-1 Receptor Agonists

The challenge of GLP-1’s rapid degradation by DPP-4 spurred intense research efforts to develop analogues or mimetics with extended half-lives suitable for pharmacological intervention. This quest led to the development of a new class of drugs: GLP-1 receptor agonists (GLP-1 RAs).

3.2.1 First-Generation GLP-1 Receptor Agonists

The initial breakthrough came from an unexpected source: the venom of the Gila monster (Heloderma suspectum). Researchers discovered exendin-4, a peptide found in the venom, which shared significant sequence homology with GLP-1 and activated the human GLP-1 receptor. Crucially, exendin-4 was resistant to degradation by DPP-4. This resistance stemmed from specific amino acid substitutions at the N-terminal end, which is the cleavage site for DPP-4.

• Exenatide: A synthetic version of exendin-4, exenatide (marketed as Byetta) became the first GLP-1 RA approved for clinical use in 2005 for T2DM. Its resistance to DPP-4 allowed for a half-life of approximately 2-4 hours, necessitating twice-daily subcutaneous injections. This was a significant advance, offering glucose-lowering effects, mild weight loss, and low risk of hypoglycemia (en.wikipedia.org). An extended-release (ER) formulation of exenatide (Bydureon), utilizing microsphere technology, was later developed, allowing for once-weekly administration by providing a sustained release of the drug over several days.

3.2.2 Second-Generation Long-Acting GLP-1 Receptor Agonists

Building on the success of exenatide, pharmaceutical companies sought to develop GLP-1 RAs with even longer half-lives to enable less frequent dosing, improve patient adherence, and potentially enhance efficacy and reduce side effects associated with peak drug concentrations. These next-generation agonists achieved prolonged action through various molecular modifications:

• Liraglutide: Approved in 2010 (marketed as Victoza for diabetes, Saxenda for obesity), liraglutide is a fatty-acylated GLP-1 analogue. A C16 fatty acid chain is attached to the lysine residue, allowing it to bind reversibly to albumin in the bloodstream. This binding protects it from DPP-4 degradation and slows its renal clearance, extending its half-life to approximately 13 hours, permitting once-daily subcutaneous injection (en.wikipedia.org).
• Dulaglutide: Approved in 2014 (marketed as Trulicity), dulaglutide is a modified GLP-1 analogue fused to an Fc fragment of a human immunoglobulin G4 (IgG4) antibody. The Fc fusion leads to a significantly extended half-life (around 5 days) due to increased molecular size, reduced renal clearance, and FcRn-mediated recycling, allowing for convenient once-weekly subcutaneous administration (en.wikipedia.org).
• Semaglutide: Approved in 2017 (marketed as Ozempic for diabetes, Wegovy for obesity), semaglutide represents a further refinement. It is an acylated GLP-1 analogue with two amino acid substitutions (alanine for glycine at position 8 and arginine for lysine at position 34) and a C18 diacid fatty chain linker attached to lysine at position 26. These modifications confer exceptional resistance to DPP-4 degradation and very strong albumin binding, resulting in a remarkably long half-life of approximately one week, enabling once-weekly subcutaneous injection (en.wikipedia.org). This extended half-life allows for more stable drug concentrations and highly effective glycemic control and weight loss. An oral formulation of semaglutide (Rybelsus) was later approved, representing a significant advancement in convenience.
• Lixisenatide: Approved in 2016 (marketed as Adlyxin/Lyxumia), lixisenatide is another short-acting GLP-1 analogue that has been modified from exendin-4. It is administered once daily. Its primary effects are on gastric emptying and postprandial glucose control.

The evolution of GLP-1 RAs reflects a continuous effort to improve pharmacokinetic profiles, enhance efficacy, and optimize convenience for patients. These advancements have solidified their position as cornerstone therapies in metabolic disease management.

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

4. Therapeutic Applications of GLP-1 Receptor Agonists

GLP-1 receptor agonists have emerged as versatile therapeutic agents, extending their utility beyond their initial indication for Type 2 Diabetes to encompass broader metabolic and cardiovascular benefits, with promising avenues in neurology and other conditions.

4.1 Type 2 Diabetes Mellitus

GLP-1 RAs are a cornerstone in the management of T2DM due to their multifaceted mechanisms of action that address several pathophysiological defects of the disease. Their efficacy in lowering blood glucose, promoting weight loss, and demonstrating cardiovascular safety and benefit has positioned them prominently in international treatment guidelines.

Mechanisms of Efficacy:

• Glucose-Dependent Insulin Secretion: As incretin mimetics, GLP-1 RAs potently stimulate insulin release from pancreatic beta cells in a glucose-dependent manner. This means that as blood glucose levels decrease, the insulinotropic effect of GLP-1 RAs diminishes, significantly lowering the risk of hypoglycemia when used as monotherapy or in combination with medications that do not directly stimulate insulin secretion (e.g., metformin, SGLT2 inhibitors). This is a critical safety advantage over sulfonylureas or exogenous insulin (en.wikipedia.org).
• Glucagon Suppression: In individuals with T2DM, glucagon secretion from pancreatic alpha cells is often dysregulated, leading to excessive hepatic glucose production. GLP-1 RAs effectively suppress glucagon secretion, particularly after meals and in hyperglycemic states, thereby reducing glucose output from the liver and contributing to improved glycemic control.
• Delayed Gastric Emptying: By slowing the rate at which food leaves the stomach, GLP-1 RAs mitigate the postprandial glucose surge, leading to a flatter and more sustained absorption of nutrients and preventing rapid spikes in blood glucose after meals. This effect also contributes to satiety.
• Beta-Cell Preservation and Function: Preclinical and some clinical data suggest that GLP-1 RAs may exert beneficial effects on pancreatic beta cells, promoting their proliferation, inhibiting apoptosis, and improving their overall function. This potential for beta-cell preservation is highly significant in a progressive disease like T2DM.
• Weight Loss: Through central mechanisms affecting appetite and satiety, and peripheral effects on gastric emptying, GLP-1 RAs consistently lead to dose-dependent weight reduction in patients with T2DM, a crucial benefit given the high prevalence of overweight and obesity in this population.

Clinical Efficacy: Clinical trials have consistently demonstrated significant reductions in HbA1c (a measure of average blood glucose over 2-3 months) with GLP-1 RAs, often ranging from 1.0% to 1.8% depending on the specific agent, dose, and patient characteristics. For instance, semaglutide has shown some of the most robust HbA1c reductions among the class (en.wikipedia.org). These agents are often used as second-line therapy after metformin, or as part of combination regimens to achieve glycemic targets and address associated comorbidities.

4.2 Obesity

Beyond their glucose-lowering effects, GLP-1 RAs have emerged as highly effective agents for chronic weight management, particularly in individuals with overweight or obesity, with or without T2DM. Their mechanism of action for weight loss is primarily centrally mediated.

Mechanisms of Efficacy:

• Appetite Suppression and Satiety Enhancement: GLP-1 receptors are highly expressed in key brain regions involved in appetite regulation, such as the hypothalamus (e.g., pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) neurons) and the brainstem. Activation of these receptors promotes feelings of fullness (satiety) and reduces hunger and cravings, leading to a decrease in overall caloric intake. They also influence reward pathways, reducing the hedonic desire for food.
• Delayed Gastric Emptying: As mentioned, this peripheral effect contributes to a prolonged feeling of fullness, further supporting reduced food intake.
• Energy Expenditure: While less pronounced, some data suggest GLP-1 RAs might have a minor positive effect on energy expenditure.

Clinical Evidence: The efficacy of GLP-1 RAs for weight loss has been rigorously demonstrated in large-scale clinical trial programs. For example, the STEP (Semaglutide Treatment Effect in People with Obesity) program for semaglutide (marketed as Wegovy for obesity) showed substantial and clinically meaningful weight loss. In STEP 1, participants receiving semaglutide 2.4 mg weekly achieved an average total body weight loss of approximately 15-17% over 68 weeks, significantly superior to placebo. This magnitude of weight loss is often comparable to that seen with bariatric surgery and significantly higher than previous pharmacological agents for obesity (en.wikipedia.org). Liraglutide (Saxenda) was also approved for obesity management, demonstrating average weight losses of 5-10%.

Their approval for obesity management represents a significant advancement, offering a powerful tool to address a global health crisis that contributes to numerous comorbidities, including T2DM, cardiovascular disease, non-alcoholic fatty liver disease, and sleep apnea.

4.3 Cardiovascular Diseases

One of the most impactful discoveries regarding GLP-1 RAs has been their demonstrated cardiovascular (CV) benefits, leading to a paradigm shift in diabetes management guidelines. Early concerns about potential CV risks associated with new diabetes medications led regulatory bodies to mandate large-scale cardiovascular outcome trials (CVOTs). These trials not only demonstrated CV safety but, remarkably, showed significant CV benefits for several GLP-1 RAs.

Key Cardiovascular Outcome Trials:

• LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results): The first CVOT to demonstrate CV benefit for a GLP-1 RA. Liraglutide significantly reduced the risk of major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke, in patients with T2DM and high CV risk.
• SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes): Semaglutide also showed a significant reduction in MACE in patients with T2DM and established CV disease or high CV risk (en.wikipedia.org). PIONEER 6 later demonstrated similar CV benefits for oral semaglutide.
• REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes): Dulaglutide demonstrated a significant reduction in MACE, importantly, even in a broader population of T2DM patients, many of whom had CV risk factors but not established CV disease.
• Other trials like EXSCEL (exenatide ER) and Harmony Outcomes (albiglutide, which was later discontinued for commercial reasons) generally confirmed CV safety and, in some cases, benefit.

Proposed Cardioprotective Mechanisms: The CV benefits of GLP-1 RAs extend beyond their glucose-lowering and weight-loss effects and are thought to involve several direct and indirect mechanisms:

• Blood Pressure Reduction: GLP-1 RAs typically lead to modest reductions in systolic and diastolic blood pressure, partly due to natriuresis and direct vascular effects.
• Improved Lipid Profiles: While not primary lipid-lowering agents, some GLP-1 RAs can induce minor improvements in lipid parameters.
• Direct Vascular Effects: GLP-1 receptors are expressed on endothelial cells and vascular smooth muscle cells. Activation can improve endothelial function, reduce inflammation, and inhibit atherosclerosis progression.
• Myocardial Effects: GLP-1 RAs may directly improve myocardial glucose uptake and utilization, enhance cardiac contractility, and reduce myocardial ischemia-reperfusion injury. They also reduce systemic inflammation, a key driver of atherosclerosis.
• Weight Loss and Metabolic Improvement: The significant weight loss and overall metabolic improvements (e.g., insulin sensitivity) contribute indirectly to reduced cardiovascular risk.

This robust evidence for cardiovascular benefits has led to preferential recommendations for GLP-1 RAs in T2DM patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease in major clinical guidelines.

4.4 Neurological Benefits

Emerging research indicates that GLP-1 RAs may possess significant neuroprotective and neurotrophic properties, opening promising avenues for their application in neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). This area of research is still in its early stages of clinical translation but holds substantial potential.

Mechanisms of Neuroprotection: The widespread expression of GLP-1 receptors in the central nervous system, particularly in regions vital for learning, memory, and motor control (e.g., hippocampus, substantia nigra), supports their direct neurological actions. Proposed neuroprotective mechanisms include (en.wikipedia.org):

• Anti-inflammatory Effects: Neuroinflammation is a critical component of neurodegenerative diseases. GLP-1 RAs can reduce microglial activation and cytokine production in the brain.
• Anti-Apoptotic Effects: They can protect neurons from various insults, including oxidative stress and excitotoxicity, by reducing programmed cell death.
• Neurogenesis and Synaptogenesis: GLP-1 RAs may promote the birth of new neurons (neurogenesis) and the formation of new synapses (synaptogenesis), which are crucial for brain plasticity and function.
• Improved Mitochondrial Function: They can enhance mitochondrial health and energy metabolism within neurons, which is often compromised in neurodegeneration.
• Reduction of Protein Aggregation: In AD, GLP-1 RAs may reduce the formation of amyloid-beta plaques and tau tangles. In PD, they may reduce alpha-synuclein aggregation, which are hallmark pathologies of these diseases.
• Insulin Signaling in the Brain: GLP-1 RAs improve insulin sensitivity in the brain, addressing the ‘brain insulin resistance’ often observed in AD.

Preclinical and Clinical Evidence: Preclinical studies in animal models of AD and PD have shown promising results, including improved cognitive function, reduced neuronal loss, and attenuated pathology following GLP-1 RA treatment. For example, studies with exenatide and liraglutide have demonstrated these effects.

Translational research is now moving into human clinical trials. Several small-scale clinical trials have explored the use of exenatide and liraglutide in PD and AD patients, showing some encouraging signals in terms of slowing disease progression or improving cognitive function, but larger, definitive trials are still needed to confirm these findings and establish efficacy. This field represents a significant area of active research.

4.5 Other Emerging Therapeutic Areas

The broad physiological effects of GLP-1 RAs suggest potential utility in other conditions:

• Non-alcoholic Fatty Liver Disease (NAFLD) / Non-alcoholic Steatohepatitis (NASH): Given the strong association between obesity, T2DM, and NAFLD/NASH, the weight loss and metabolic improvements offered by GLP-1 RAs are highly beneficial. Studies have shown improvements in liver fat content, inflammation, and fibrosis markers in patients treated with GLP-1 RAs, with some agents demonstrating resolution of NASH without worsening of fibrosis.
• Chronic Kidney Disease (CKD): The cardiovascular outcome trials for GLP-1 RAs also demonstrated renoprotective effects, including a reduction in the decline of estimated glomerular filtration rate (eGFR) and a decrease in albuminuria, making them valuable in the management of diabetic kidney disease.
• Polycystic Ovary Syndrome (PCOS): PCOS is often associated with insulin resistance and obesity. GLP-1 RAs can address these underlying issues, potentially improving metabolic parameters and hormonal imbalances in women with PCOS.

These expanding therapeutic applications underscore the versatility and significant clinical impact of GLP-1 receptor agonists across a wide spectrum of cardiometabolic and potentially neurodegenerative disorders.

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

5. Differences Among GLP-1 Receptor Agonists

While all GLP-1 receptor agonists share the common mechanism of activating the GLP-1 receptor, they exhibit notable differences in their pharmacokinetic profiles, efficacy, and side effect landscapes. These distinctions influence their clinical utility, dosing frequency, and patient suitability.

5.1 Pharmacokinetic Variations

The primary differentiating factor among GLP-1 RAs is their duration of action, which dictates their administration frequency. This is a direct consequence of their molecular design and how they overcome the rapid degradation of native GLP-1.

• Short-Acting Agents:

  • Exenatide (Byetta): Derived from exendin-4, it has a half-life of approximately 2-4 hours, necessitating twice-daily subcutaneous injections. Its main effect is to reduce postprandial glucose excursions by slowing gastric emptying and stimulating early insulin release.
  • Lixisenatide (Adlyxin/Lyxumia): Also a synthetic exendin-4 analogue, with a similar short half-life, requiring once-daily injection before the first meal. It primarily targets postprandial glucose and has a more modest effect on HbA1c and weight compared to longer-acting agents.

• Long-Acting Agents: These agents are designed to resist DPP-4 degradation and/or have reduced renal clearance, allowing for less frequent dosing.

  • Liraglutide (Victoza/Saxenda): An acylated GLP-1 analogue with a C16 fatty acid chain that promotes albumin binding and resistance to DPP-4. Its half-life is approximately 13 hours, allowing for once-daily subcutaneous administration. It provides more sustained glucose control and greater weight loss than the short-acting agents (en.wikipedia.org).
  • Exenatide extended-release (ER) (Bydureon): This formulation encapsulates exenatide within biodegradable microspheres. The drug is slowly released over time, achieving a sustained therapeutic concentration that allows for once-weekly subcutaneous injection. This improved convenience over the twice-daily formulation can enhance patient adherence.
  • Dulaglutide (Trulicity): A GLP-1 analogue fused to an Fc portion of human IgG4. This fusion significantly increases its molecular size and allows it to bind to albumin, extending its half-life to approximately 5 days. This enables convenient once-weekly subcutaneous administration and provides robust glycemic control and weight loss (en.wikipedia.org).
  • Semaglutide (Ozempic/Wegovy): Highly modified GLP-1 analogue with strong albumin binding and high resistance to DPP-4. It boasts the longest half-life in the class, approximately 7 days, allowing for once-weekly subcutaneous injection. This leads to very stable drug levels, which contribute to its potent effects on HbA1c, weight loss, and cardiovascular outcomes (en.wikipedia.org).

These pharmacokinetic differences directly impact dosing frequency, which can significantly influence patient adherence and preferences. Weekly injections are generally preferred over daily ones, improving convenience and potentially long-term treatment persistence.

5.2 Efficacy and Side Effect Profiles

While all GLP-1 RAs are effective in lowering blood glucose and promoting weight loss, there are differences in the magnitude of these effects and their associated side effect profiles.

5.2.1 Glycemic Efficacy and Weight Loss

Generally, the longer-acting GLP-1 RAs, particularly dulaglutide and semaglutide, tend to achieve greater reductions in HbA1c and more substantial weight loss compared to the shorter-acting agents or daily liraglutide. For instance, studies have shown that semaglutide often results in the highest HbA1c reduction (e.g., 1.5-1.8%) and the most significant weight loss (e.g., 10-15% for diabetes indication, up to 15-20% for obesity indication) within the class, particularly at higher doses approved for weight management (en.wikipedia.org). This is likely due to their more sustained receptor activation and higher drug exposure over time.

5.2.2 Side Effect Profiles

The side effect profiles are largely similar across the class, with gastrointestinal (GI) adverse events being the most common. However, their incidence and severity can vary.

• Gastrointestinal Issues: Nausea, vomiting, diarrhea, and constipation are frequently reported, especially during treatment initiation and dose escalation. These symptoms are often transient and tend to diminish over time as patients adapt to the medication. The slow titration of dosage, particularly for the longer-acting agents, is a common strategy to mitigate these GI side effects. The mechanism is thought to be related to delayed gastric emptying and central effects on the brainstem’s chemoreceptor trigger zone.
• Hypoglycemia: The risk of hypoglycemia with GLP-1 RAs as monotherapy is very low due to their glucose-dependent mechanism of action. However, the risk increases when co-administered with sulfonylureas or insulin, necessitating dose adjustments of these concomitant medications.
• Injection Site Reactions: Mild injection site reactions (e.g., redness, itching, swelling) can occur with subcutaneous formulations but are generally infrequent and mild.
• Pancreatitis: Acute pancreatitis has been reported in post-marketing surveillance, and a causal link has been debated. While GLP-1 RAs are generally considered safe, they are contraindicated in patients with a history of pancreatitis, and vigilance is recommended.
• Thyroid C-cell Tumors (Medullary Thyroid Carcinoma – MTC): Rodent studies showed an increased incidence of thyroid C-cell tumors (MTC) with GLP-1 RAs. However, this finding has not been replicated in human clinical trials or epidemiological studies, and the clinical relevance for humans is considered very low. Nonetheless, GLP-1 RAs are contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
• Gallbladder-related events: An increased risk of cholelithiasis (gallstones) and cholecystitis (gallbladder inflammation) has been observed, particularly with rapid and significant weight loss, which is a known risk factor for these conditions.

The choice among GLP-1 RAs often depends on factors such as desired glycemic and weight loss efficacy, patient preference for injection frequency, specific cardiovascular or renal comorbidities, and individual tolerability to side effects.

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

6. Next-Generation Incretin-Based Therapies

The success of GLP-1 RAs has spurred intense research into even more potent and comprehensive incretin-based therapies. This has led to the development of dual and triple agonists, novel oral formulations, and combination strategies that aim to further optimize metabolic control and expand therapeutic benefits.

6.1 Dual Agonists (Co-Agonists)

Dual agonists represent a significant evolutionary step, targeting more than one incretin receptor to achieve synergistic therapeutic effects. The most prominent example is the unimolecular GIP/GLP-1 receptor co-agonist.

6.1.1 Tirzepatide (Mounjaro)

Tirzepatide is a novel, once-weekly injectable unimolecular co-agonist that activates both the GIP and GLP-1 receptors. The rationale behind its development is to harness the complementary actions of both incretins. While GLP-1 primarily acts on satiety and gastric emptying, GIP is a potent insulin secretagogue and also plays a role in adipose tissue metabolism. By co-agonizing both receptors, tirzepatide aims to achieve superior efficacy in glycemic control and weight reduction.

Mechanism of Action: Tirzepatide is an engineered peptide that contains amino acid sequences allowing it to bind to and activate both the GIPR and GLP-1R with high affinity. Its structure is modified to resist DPP-4 degradation and has a long half-life, enabling once-weekly administration.

Clinical Efficacy: The SURPASS (Semaglutide vs. Unimolecular Dual GIP/GLP-1 RA for Type 2 Diabetes Treatment) clinical trial program has demonstrated remarkable efficacy for tirzepatide in T2DM. In these head-to-head trials against comparator drugs, including semaglutide, tirzepatide consistently showed superior reductions in HbA1c and significantly greater weight loss. For example, in SURPASS-2, tirzepatide demonstrated superior HbA1c and weight reductions compared to semaglutide. In SURPASS-1 to SURPASS-5, tirzepatide led to HbA1c reductions of up to 2.5% and body weight reductions of up to 12.7 kg (~13% total body weight loss) over 40-52 weeks, demonstrating its profound metabolic effects. The SURMOUNT clinical trial program for obesity (in non-diabetic individuals) has shown even more substantial weight loss, with average total body weight reductions exceeding 20% at the highest dose.

Rationale for Dual Agonism: The superior efficacy of tirzepatide is attributed to the synergistic actions of GIP and GLP-1. GIP contributes significantly to insulin secretion and may counteract GLP-1’s pro-nausea effects in some contexts, potentially improving tolerability. The GIP component may also contribute to the unique adipose tissue effects and metabolic improvements observed.

6.1.2 Triple Agonists

Further research is exploring ‘triple agonists’ that target GLP-1, GIP, and glucagon receptors. Glucagon, while a counter-regulatory hormone to insulin, also has beneficial metabolic effects, such as increasing energy expenditure and lipolysis when its receptor is appropriately activated. An example in development is retatrutide, which targets all three receptors. Early clinical data suggest even greater weight loss and metabolic improvements compared to dual agonists, but careful balancing of glucagon agonism is crucial to avoid unwanted glycemic effects.

6.2 Oral Formulations

Addressing patient preference and convenience, the development of oral incretin-based therapies represents a significant advancement, reducing the burden associated with injectable medications.

6.2.1 Oral Semaglutide (Rybelsus)

Oral semaglutide was the first oral GLP-1 RA approved for T2DM management. The challenge of oral peptide delivery lies in their susceptibility to degradation by gastric enzymes and poor absorption across the gastrointestinal mucosa. Novo Nordisk developed a co-formulation with an absorption enhancer called sodium N-[8-(2-hydroxybenzoyl)aminocaprylate] (SNAC).

Mechanism of Oral Delivery: SNAC facilitates the absorption of semaglutide across the gastric lining by protecting the peptide from enzymatic degradation and increasing its local solubility and permeability. While its bioavailability is still relatively low (around 1%) compared to subcutaneous administration, the high potency of semaglutide allows it to achieve therapeutic concentrations.

Benefits and Limitations: Oral semaglutide offers the significant advantage of patient convenience, which can improve adherence, especially for individuals averse to injections. However, it requires strict dosing instructions: it must be taken on an empty stomach with a small amount of water (no more than 120 mL) at least 30 minutes before the first food, drink, or other oral medications. Failure to adhere to these instructions can significantly impair absorption. Despite these requirements, it provides a valuable alternative for many patients (en.wikipedia.org).

Research is ongoing to develop other oral incretin mimetics and improve the oral bioavailability of peptide drugs.

6.3 Combination Therapies

As the understanding of T2DM pathophysiology deepens, combination therapies that target multiple pathways are gaining prominence. Combining GLP-1 RAs with other anti-diabetic agents can offer synergistic benefits and more comprehensive metabolic control.

6.3.1 GLP-1 RAs with SGLT2 Inhibitors

One of the most promising combination strategies involves co-administering GLP-1 RAs with sodium-glucose cotransporter-2 (SGLT2) inhibitors. SGLT2 inhibitors work by increasing glucose excretion in the urine, independent of insulin action. This combination leverages complementary mechanisms:

• GLP-1 RAs: Enhance insulin secretion, suppress glucagon, delay gastric emptying, promote weight loss.
• SGLT2 inhibitors: Reduce renal glucose reabsorption, leading to glucosuria, modest weight loss, and blood pressure reduction.

Synergistic Benefits: Clinical studies have shown that this combination leads to superior glycemic control, greater weight loss, and enhanced cardiovascular and renal protection compared to either agent alone. Both drug classes have demonstrated impressive benefits in reducing major adverse cardiovascular events and improving renal outcomes, making their combination particularly attractive for patients with T2DM and existing cardiovascular disease or chronic kidney disease.

6.3.2 GLP-1 RAs with Basal Insulin

Fixed-ratio co-formulations of GLP-1 RAs with basal insulin (e.g., insulin degludec/liraglutide as Xultophy; insulin glargine/lixisenatide as Soliqua) have been developed. This combination aims to optimize glycemic control while mitigating some of the drawbacks of insulin monotherapy:

• GLP-1 RA component: Helps with weight management (counteracting insulin-induced weight gain), reduces hypoglycemia risk (due to glucose-dependent action), and addresses postprandial glucose excursions.
• Basal insulin component: Provides foundational glycemic control by suppressing hepatic glucose production and facilitating glucose uptake into peripheral tissues.

This combination offers a simplified injection regimen (once daily) and can achieve excellent glycemic control with less weight gain and lower risk of hypoglycemia compared to intensifying insulin therapy alone.

6.4 Other Innovative Approaches

Research continues into other novel approaches, including sustained-release implants, gene therapies to induce endogenous GLP-1 production, and the development of small-molecule GLP-1R agonists, which might offer oral bioavailability without the need for absorption enhancers. These innovations aim to provide even more effective, convenient, and patient-tailored treatments in the future.

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

7. Conclusion

The incretin system, anchored by the pivotal hormones GLP-1 and GIP, represents a fundamental regulatory axis in glucose homeostasis and broader metabolic health. The profound understanding of its physiological mechanisms, coupled with the recognition of its dysfunction in metabolic disorders, has catalyzed a revolution in therapeutic development. The journey from the early characterization of GLP-1 and GIP to the creation of potent, long-acting GLP-1 receptor agonists has fundamentally reshaped the management of Type 2 Diabetes Mellitus and obesity.

GLP-1 receptor agonists have moved beyond mere glycemic control to demonstrate robust efficacy in achieving significant and sustained weight loss, critically impacting the global obesity epidemic. Furthermore, compelling evidence from large-scale cardiovascular outcome trials has established their unequivocal cardiovascular protective effects, including reductions in major adverse cardiovascular events, making them indispensable in the comprehensive care of patients with diabetes and cardiovascular comorbidities. Emerging research, while still in its nascent stages, points towards tantalizing neuroprotective benefits, suggesting a potential role in ameliorating neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases, alongside other promising applications in areas like non-alcoholic fatty liver disease and chronic kidney disease.

The field continues to advance at an unprecedented pace. Next-generation incretin-based therapies, particularly dual agonists like tirzepatide targeting both GLP-1 and GIP receptors, are demonstrating superior efficacy in both glycemic control and weight reduction compared to existing monotherapies, heralding a new era of highly potent metabolic drugs. The development of convenient oral formulations, such as oral semaglutide, addresses critical aspects of patient adherence and preference, broadening access to these life-changing medications. Moreover, strategic combination therapies with other agents like SGLT2 inhibitors are unlocking synergistic benefits, offering more comprehensive metabolic control and multi-organ protection.

In conclusion, the sustained scientific inquiry into the incretin system has yielded a class of drugs that not only effectively manage metabolic disorders but also profoundly influence patient outcomes across multiple organ systems. The ongoing research into next-generation incretin-based therapies, encompassing multi-agonism, novel delivery methods, and rational combination strategies, promises a future with even more effective, safer, and personalized treatment options, fundamentally transforming the landscape of chronic disease management and offering renewed hope for millions worldwide.

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

References

• en.wikipedia.org
• pmc.ncbi.nlm.nih.gov
• en.wikipedia.org
• en.wikipedia.org
• en.wikipedia.org