Overview
Last updated
Last updated
Glucagon-like peptide-1 (GLP-1) is a hormone produced in the gut (distal ileum and colon) in response to food intake (Sun et al. 2017). It plays a pivotal role in regulating energy balance and metabolism by exerting systemic effects across multiple organs and tissues (Figure 1). These effects make GLP-1 central to metabolic health and a key therapeutic target for metabolic disorders.
Key physiological functions of GLP-1 include:
Glycemic regulation: GLP-1 plays a central role in glycemic control by influencing the pancreas. It stimulates insulin secretion and biosynthesis while suppressing glucagon secretion, thereby reducing blood glucose levels. Additionally, GLP-1 promotes β-cell proliferation and inhibits β-cell apoptosis, contributing to sustained insulin production. These actions help prevent large fluctuations in blood glucose levels after food intake (Sun et al. 2017).
Modulating digestion: GLP-1 slows gastric emptying and reduces acid secretion in the stomach, effectively lowering the rate at which glucose enters the bloodstream after food intake. By delaying nutrient absorption, it prevents postprandial blood glucose spikes. Furthermore, GLP-1 enhances gut motility and promotes intestinal growth, which supports overall digestive efficiency (Bodnaruc et al. 2016).
Controlling appetite: GLP-1 influences appetite regulation by acting on the brain. It reduces food and water intake by promoting satiety and enhancing neuroprotection. These effects are mediated through central nervous system pathways that suppress hunger signals. This satiety-promoting action is also linked to the neurogenic and protective roles of GLP-1 in the brain (Shah and Vella 2014).
By its chemical structure, GLP-1 is a peptide of 30 or 31 amino acids, with its active domain starting at position 7 (Figure 2). This domain binds to receptors on target organs, triggering signaling pathways involved in glucose metabolism, appetite control, and digestion. However, GLP-1’s short half-life (1–2 minutes) due to enzymatic degradation by dipeptidyl peptidase-4 (DPP-4) limits its sustained action. DPP-4 cleaves the peptide at position 9 (Figure 2), rendering it inactive and necessitating continuous secretion to maintain its effects.
While GLP-1 plays a vital role in regulating blood glucose levels, digestion, and appetite, its physiological effectiveness can be compromised in individuals with metabolic disorders such as type 2 diabetes and obesity. In these conditions, the production or action of GLP-1 is often insufficient to meet the body’s increased metabolic demands. Moreover, the hormone’s short half-life (1–2 minutes), caused by enzymatic degradation by DPP-4, limits its ability to exert sustained physiological effects, particularly in individuals who require prolonged glucose regulation and appetite control (Drucker 2024).
To address the limitations of native GLP-1 and provide support for individuals with metabolic disorders, researchers have developed GLP-1 receptor agonists (GLP-1 RAs), which are synthetic compounds designed to closely mimic the structure and function of native GLP-1. These agonists bind to GLP-1 receptors on target tissues, replicating the hormone’s beneficial physiological effects. However, unlike native GLP-1, GLP-1 RAs incorporate structural modifications that render them resistant to DPP-4 degradation. These enhancements significantly extend their half-life, allowing them to remain active for several hours to days, and in some cases up to a week. As a result, GLP-1 RAs provide sustained support for glucose homeostasis, appetite control, and weight management. They are an essential therapeutic option for individuals with type 2 diabetes or obesity, offering improved glycemic control, reduced risk of complications, and better quality of life.
There are different types of GLP-1 receptor agonists (GLP-1 RAs), each incorporating specific structural modifications to enhance therapeutic efficacy (Figure 3). These modifications improve DPP-4 resistance, extend half-life, and optimize receptor activation. The key GLP-1 RAs include:
Exenatide derives from exendin-4 and features substituted amino acids (magenta) that confer resistance to DPP-4 degradation. Key amino acids critical for receptor potency (gold) are preserved, ensuring effective receptor activation. However, due to its close structural similarity to native GLP-1, Exenatide has a short half-life, necessitating more frequent administration, and is therefore classified as a short-acting GLP-1 RA.
Semaglutide incorporates non-natural amino acids like Aib (magenta) and a C-18 fatty acid chain (pink), which facilitates albumin binding and significantly prolongs its half-life. These modifications extend the half-life of Semaglutide, enabling once-weekly administration and classifying it as a long-acting GLP-1 RA effective for type 2 diabetes and obesity while preserving key receptor-binding amino acids.
Dulaglutide utilizes an IgG4 Fc fragment (green) linked via spacers (blue) to increase molecular size and prevent renal clearance. This design greatly extends its duration of action, enabling weekly dosing. Key amino acids for receptor activation are preserved, ensuring potency while enhancing pharmacokinetic stability. As a long-acting GLP-1 RA, Dulaglutide offers sustained therapeutic benefits with improved convenience.
Several GLP-1 receptor agonists have been developed into commercially available therapies, each designed to address specific clinical needs (Table 1). These therapies differ in their structural modifications, dosing regimens, and modes of administration, providing a wide range of options for managing type 2 diabetes and obesity. Such differences allow for tailored treatment strategies that improve glycemic control, promote weight loss, and enhance patient adherence.
Some therapies, like Ozempic, are optimized for once-weekly administration, ensuring prolonged glucose regulation and convenience for patients. Others, such as Rybelsus, provide an oral formulation, offering a non-injectable alternative that is particularly appealing for individuals who prefer pills over injections. For weight management, Wegovy delivers higher doses of semaglutide, maximizing its effects on appetite suppression and weight reduction. Short-acting agents, such as Byetta, are effective for addressing postprandial glucose spikes, while long-acting therapies like Trulicity offer extended half-life and convenient weekly dosing.
The availability of multiple therapies reflects a deliberate effort to address diverse patient profiles and treatment goals. By varying their duration of action, delivery methods, and therapeutic focus, these medications not only extend the physiological benefits of GLP-1 receptor activation but also cater to the practical considerations of everyday use.
The efficacy of GLP-1 receptor agonists has been demonstrated in several pivotal clinical trials. These studies highlight the profound impact of semaglutide and dulaglutide on weight management, glycemic control, and cardiovascular outcomes, supporting their approval and widespread use under brand names like Wegovy, Ozempic, and Trulicity.
The STEP 1 trial evaluated the efficacy of once-weekly semaglutide (2.4 mg) for weight management in adults with obesity or overweight. Over 68 weeks, 1,961 participants were randomized to receive semaglutide or placebo alongside structured lifestyle interventions. The study reported a 14.9% reduction in mean body weight in the semaglutide group, compared to only 2.4% in the placebo group (Figure 4 a). Additionally, 86.4% of participants in the semaglutide group achieved weight loss greater than 5%, compared to only 31.5% in the placebo group (Figure 4 b).
These results underscore the substantial weight-loss benefits of semaglutide, paving the way for its commercialization as Wegovy for obesity management.
The REWIND trial examined the efficacy of the long-acting GLP-1 RA dulaglutide (1.5 mg, administered weekly) in reducing cardiovascular risk among adults with type 2 diabetes and either established cardiovascular disease or cardiovascular risk factors. The trial included 9,901 participants who were followed for a median of 5.4 years. The study found that 12.0% of participants in the dulaglutide group experienced major adverse cardiovascular events (MACE), compared to 14.0% in the placebo group, representing a 12% relative risk reduction (hazard ratio: 0.88, 95% CI: 0.79–0.99) (Figure 5 a). Furthermore, dulaglutide demonstrated robust glycemic control, with fewer participants requiring additional medications during the study (Figure 5 b). These findings paved the way for the approval and widespread use of dulaglutide under the brand name Trulicity, making it a cornerstone therapy in managing diabetes and reducing cardiovascular risk.
The REWIND trial established dulaglutide’s dual efficacy in glycemic management and cardiovascular risk reduction, solidifying its role in diabetes care and its approval under the brand name Trulicity.
Studies on animals with species-specific GLP-1 characteristics provide valuable insights that can significantly enhance the development and optimization of GLP-1-based therapies. While human studies remain the gold standard, animal models offer unique opportunities to explore the diverse regulatory mechanisms of GLP-1 secretion and action under controlled conditions. For instance, rodents, which are commonly used in GLP-1 research, have contributed substantially to understanding its role in glucose homeostasis and β-cell function (Model et al. 2022). However, expanding research to include species like dogs and cats reveals critical differences that can inform more targeted therapies (Table 2).
In dogs, the stimulation of GLP-1 release by high-fat diets rather than carbohydrates, as well as the involvement of GIP-driven paracrine signaling, underscores the potential for therapies tailored to lipid metabolism and alternative pathways of GLP-1 secretion (Model et al. 2022). Similarly, studies in cats, where amino acids are the primary trigger for GLP-1 secretion, provide insights into amino acid-focused dietary interventions or therapeutic approaches for metabolic conditions (Table 2). These interspecies differences allow researchers to identify novel regulatory mechanisms and evaluate the effects of GLP-1 receptor agonists across varied metabolic contexts.
By leveraging these findings, researchers can refine GLP-1 therapies to better address patient-specific metabolic profiles, including those with lipid-driven or amino acid-sensitive metabolic disorders. Animal studies also provide crucial preclinical data on the safety, efficacy, and pharmacokinetics of GLP-1 receptor agonists, accelerating the translation of these therapies into clinical practice and potentially expanding their applications beyond diabetes and obesity to other metabolic and gastrointestinal diseases.
The rapid growth of GLP-1-based therapies is driven by the increasing prevalence of type 2 diabetes and obesity, two of the most pressing global health challenges. These conditions are fueled by demographic and lifestyle changes, including aging populations, sedentary behaviors, and poor dietary habits, creating a rising demand for effective and sustainable treatment options. GLP-1 receptor agonists address this demand with their dual efficacy in glycemic control and weight management, making them a cornerstone therapy for these metabolic disorders. Furthermore, advancements in drug delivery, such as once-weekly injections and oral formulations, have enhanced patient adherence and accessibility. Reflecting these drivers, the market for GLP-1-based therapies is projected to grow at a compound annual growth rate (CAGR) of 12.1%, reaching approximately 40 billion USD in 2028 and 70 billion USD in 2033 (Figure 6)
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