What are the therapeutic candidates targeting GLP-1?

Introduction to GLP-1
Glucagon-like peptide-1 (GLP-1) is an incretin hormone mainly secreted by the L-cells located in the distal ileum and colon in response to nutrient ingestion. GLP-1 plays a central role in maintaining metabolic homeostasis by enhancing glucose-dependent insulin secretion, suppressing glucagon release, and slowing gastric emptying, which together contribute to postprandial glycemic control. Its ability to activate its cognate receptor, the GLP-1 receptor (GLP-1R), extends beyond the pancreas to several extrapancreatic tissues such as the brain, heart, kidney, and adipose tissue; this pleiotropy has revolutionized its application not only in diabetes management but also in obesity and cardiovascular risk reduction.

Role of GLP-1 in Metabolism
GLP-1 is instrumental in regulating plasma glucose levels following meals by stimulating insulin secretion in a glucose-dependent manner, thereby ensuring that insulin levels are raised only when circulating blood glucose is elevated. In addition to its classical insulinotropic effect, the hormone reduces hepatic glucose production and modulates nutrient absorption by delaying gastric motility, which ultimately enhances satiety and contributes to weight loss. Moreover, GLP-1 influences the health of pancreatic β-cells by reducing apoptosis and promoting cell proliferation, potentially slowing the progression of β-cell dysfunction observed in type 2 diabetes. As a result, the metabolic actions of GLP-1 provide a compelling rationale for its therapeutic intervention in both hyperglycemia and obesity, two conditions that are frequently intertwined.

Importance of GLP-1 in Therapeutic Development
The multifaceted role of GLP-1 in glucose homeostasis, weight regulation, and cardiovascular function has prompted extensive research into its signaling pathways. This understanding, coupled with its short in vivo half‐life (approximately 2 minutes due to rapid degradation by dipeptidyl peptidase‐4 (DPP-4)), has driven the development of GLP-1 receptor agonists with enhanced enzymatic stability, prolonged action, and improved pharmacokinetic properties. GLP-1’s relevance in therapeutic development is further underscored by its potential effects on extra-glycemic outcomes, such as reducing inflammation, ameliorating cardiovascular risk factors, and even providing neuroprotective effects, which broaden the potential clinical applications of drugs targeting its receptor.

Therapeutic Candidates Targeting GLP-1
The spectrum of therapeutic candidates targeting the GLP-1 axis can be broadly classified into current approved therapies and emerging therapeutic candidates. These candidates are designed to mimic or enhance the activity of endogenous GLP-1, overcoming its inherent limitations and exploiting its beneficial actions to treat diabetes, obesity, and associated comorbidities.

Current Approved Therapies
Several GLP-1 receptor agonists (GLP-1RAs) have received regulatory approval for the treatment of type 2 diabetes and, in some cases, obesity. Among these, the most established compounds include:

• Exenatide was the first GLP-1RA approved for type 2 diabetes, originally derived from the saliva of the Gila monster. It is available in a twice-daily formulation and as an extended-release once-weekly formulation (exenatide-LAR), which improves patient compliance by extending the duration of receptor activation.

• Lixisenatide is a short-acting GLP-1RA administered once daily that has demonstrated efficacy in reducing postprandial glucose excursions by delaying gastric emptying while providing modest weight loss benefits.

• Liraglutide, a human GLP-1 analog with a half-life of approximately 13 hours, is administered once daily. It not only lowers glycated hemoglobin (HbA1c) effectively but also induces significant weight loss and has been approved at higher doses for obesity management under the trade name Saxenda.

• Dulaglutide is engineered as a long-acting, once-weekly GLP-1RA with a modified structure that utilizes a human immunoglobulin fragment to prolong its plasma half-life. It has demonstrated robust glycemic control and weight reduction while improving cardiovascular outcomes in high-risk individuals.

• Semaglutide represents one of the most potent and long-acting GLP-1RAs available. It is unique in that it is approved both in an injectable once-weekly formulation (Ozempic) for type 2 diabetes and as an oral formulation (Rybelsus) for glycemic control. Semaglutide has shown impressive results in reducing HbA1c and body weight and has recently gained approval for obesity treatment (Wegovy).

Each of these approved therapies has been optimized to overcome the rapid degradation of native GLP-1, achieving improved receptor occupancy and prolonged therapeutic effects that translate into better patient outcomes. Their successful use in clinical practice has established the GLP-1 axis as a critical target in metabolic disease management.

Emerging Therapeutic Candidates
Beyond the already approved therapies, researchers are exploring a wide array of novel candidates and modifications to further refine the therapeutic potential of GLP-1 targeting agents. These emerging strategies include:

• Dual and Triple Agonists:
Recent efforts have focused on creating single molecules that simultaneously target multiple receptors involved in energy homeostasis. For example, tirzepatide is a dual agonist that targets both GLP-1 and gastric inhibitory polypeptide (GIP) receptors. By stimulating these two incretin pathways concurrently, tirzepatide has demonstrated superior reductions in HbA1c and body weight compared to traditional GLP-1RAs in clinical studies. Additionally, there is ongoing research into triple agonists that combine GLP-1, GIP, and glucagon receptor activity. These multifunctional peptides aim to provide a balanced effect that enhances weight loss and metabolic control while potentially addressing dyslipidemia and other metabolic disturbances.

• Biased Agonists:
It has been observed that not all intracellular signaling events downstream of GLP-1R activation are equally beneficial. Biased agonists are designed to selectively promote the cAMP generation pathway while minimizing the recruitment of beta‐arrestin, which may be associated with receptor internalization and desensitization. This approach may yield agents that sustain insulinotropic action with reduced adverse events such as gastrointestinal discomfort.

• Long-Acting Fusion Proteins and Modified Peptides:
To address the short half-life of native GLP-1, several groups have developed fusion proteins that link modified GLP-1 peptides to carriers such as albumin or immunoglobulin fragments. For instance, AGLP-1/HSA and its linker-modified variant AGLP-1-L/HSA have been engineered to resist DPP-4 degradation and prolong circulation time, extending their glucose-lowering capacity to 24 hours or more. These constructs not only enhance half-life but also potentially improve stability and reduce the frequency of administration.

• Non-Peptide Small Molecule Agonists:
Although most current therapies are peptide-based, there is increasing interest in developing small molecule agonists that target GLP-1R. The advantage of small molecules lies in their potential for oral bioavailability and improved manufacturing scalability. Early-phase research is exploring candidates that mimic the key conformational characteristics of GLP-1 necessary for receptor activation, although these remain in the preclinical stage.

• Conjugates and Combination Therapies:
Therapeutic strategies are also evolving to include conjugates where GLP-1RAs are combined with other hormones or molecular moieties. Such combinations can include pairing GLP-1RAs with insulin in a fixed-ratio formulation (for example, IDegLira and Xultophy), which aims to harness complementary mechanisms of action to achieve superior glycemic control with reduced risk of hypoglycemia and weight gain. Moreover, researchers are investigating co-formulations that combine GLP-1 receptor agonism with agents that block GLP-1 degradation or target specific risk factors such as inflammation, thereby offering a more holistic addressing of the metabolic syndrome.

These emerging candidates reflect an ongoing commitment to refining the pharmacologic profile of GLP-1 targeted therapies, constantly striving for improved efficacy, safety, and patient adherence.

Mechanisms of Action
Understanding the mechanisms of action of therapeutic candidates targeting GLP-1 is central to appreciating their benefits, limitations, and potential for further development. Two primary mechanistic approaches are identified: one involving the classical receptor agonism and another encompassing alternative strategies for modulating the GLP-1 signaling pathway.

GLP-1 Receptor Agonists
The fundamental mechanism underlying the action of GLP-1 receptor agonists is the binding and activation of the GLP-1 receptor, a G-protein coupled receptor (GPCR) located on pancreatic β-cells as well as in several extra-pancreatic tissues. Upon receptor activation, there is a rapid increase in intracellular cyclic adenosine monophosphate (cAMP) which enhances glucose-dependent insulin secretion and suppresses glucagon release, thus efficiently lowering postprandial and fasting glucose levels. In the pancreatic islets, these effects help maintain or restore β-cell function and viability, contributing to the long-term management of type 2 diabetes.

Moreover, GLP-1 receptor agonists influence gastric motility, leading to delayed gastric emptying and reduced appetite. The central nervous system (CNS) effects that are mediated through GLP-1 receptors in the hypothalamus promote satiety and contribute significantly to weight loss, an effect that is particularly valuable in obesity treatment. In addition, many GLP-1 receptor agonists demonstrate extra-glycemic benefits, such as improved cardiovascular risk profiles, reduction in blood pressure, and renal protection due to their ability to modulate inflammatory responses and promote natriuresis. The degree of receptor binding and downstream signaling may vary depending on structural modifications, duration of action, and formulation, which explains the variation in clinical efficacy and side effect profiles among approved agents.

Other Mechanistic Approaches
Aside from direct receptor agonism, other mechanistic strategies are being explored to modulate the GLP-1 pathway:

• Biased Agonism:
Biased agonists are engineered to preferentially activate specific intracellular signaling pathways (primarily the cAMP/PKA pathway) while avoiding pathways that lead to receptor desensitization (such as beta‐arrestin recruitment). This promoter “bias” aims to sustain the desired insulinotropic effect without the rapid receptor internalization that may limit efficacy over time or contribute to adverse effects.

• Fusion Protein Technology:
As discussed under emerging therapeutic candidates, fusion proteins such as AGLP-1/HSA or AGLP-1-L/HSA are developed to circumvent the rapid proteolytic degradation of native GLP-1 by DPP-4. By fusing the active peptide to a larger protein carrier, these constructs extend the plasma half-life, ensuring prolonged receptor activation and consistent glycemic control. This approach also reduces the dosing frequency, which may improve patient adherence.

• Multi-receptor Agonism and Combination Therapies:
Combination therapies or molecules that act on multiple receptors concurrently, such as dual agonists (GLP-1/GIP) and triple agonists (GLP-1/GIP/glucagon), are designed to leverage the synergistic effects of multiple metabolic pathways. These therapies not only enhance insulin secretion and lower glucose but also promote weight loss and improve lipid metabolism, thus addressing several pathophysiological aspects of metabolic syndrome simultaneously.

• Small Molecule Approaches:
Although in early developmental stages, small molecule GLP-1 receptor agonists are being investigated. These non-peptide compounds, once optimized for affinity and selectivity, can potentially offer oral bioavailability and lower manufacturing costs compared to their peptide counterparts. Their development represents a shift towards more patient-friendly dosing forms while maintaining target specificity.

Each of these mechanistic approaches continues to evolve as our understanding of the GLP-1 receptor signaling cascade deepens, offering avenues for novel drug design, improved receptor occupancy, and long-lasting therapeutic effects.

Clinical Trials and Efficacy
The clinical evaluation of GLP-1 targeting drugs spans multiple phases, from early-phase studies assessing safety and pharmacokinetics to large-scale Phase 3 trials that evaluate long-term efficacy and cardiovascular outcomes. The body of clinical evidence supports not only robust glycemic control but also significant improvements in weight reduction and secondary benefits that influence cardiovascular and renal health.

Overview of Clinical Trial Phases
Clinical trials for GLP-1 receptor agonists have progressed through traditional phases. In early-phase trials (Phase 1 and Phase 2), the focus is on dose ranging, pharmacokinetics, receptor occupancy, and initial safety profiles. For example, the transition from short-acting exenatide to long-acting agents like liraglutide and semaglutide involved rigorous preclinical and early-phase studies to evaluate how structural modifications affected half-life and receptor binding.

Phase 3 studies have corroborated that long-acting agents significantly reduce HbA1c levels by approximately 1–1.6% and induce meaningful weight loss (often 5–15% of baseline body weight) over one-year treatment periods. In addition, the cardiovascular outcome trials (CVOTs) have established that several GLP-1 receptor agonists reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes, with liraglutide and semaglutide demonstrating both noninferiority and in some cases superiority over placebo in reducing cardiovascular risk. These large-scale trials have included tens of thousands of patients with diverse backgrounds, confirming the efficacy and safety of these candidates in a real‐world context.

Moreover, the advent of combination products, such as fixed‐ratio formulations that combine basal insulin with a GLP‐1 receptor agonist (e.g., IDegLira and Xultophy), has also been supported by clinical trials that demonstrate improved glycemic control with reduced risk of hypoglycemia and weight gain compared to insulin up‐titration alone. Such trials have further delineated the position of GLP-1 therapies within treatment algorithms, affirming their role as valuable components not only in dual but also in triple therapy regimens.

Key Clinical Trial Results
Key trial outcomes for current approved GLP-1 receptor agonists illustrate their impact from multiple perspectives. For instance:

• Exenatide (both in its twice-daily and once-weekly formulations) has consistently lowered postprandial glucose levels and induced weight loss by approximately 2–4 kg in clinical trials, with significant improvements in HbA1c.

• Liraglutide has demonstrated reductions in HbA1c of around 1–1.5% and weight losses averaging 3–4 kg in randomized controlled trials. Its superior performance in head-to-head comparisons with DPP-4 inhibitors has reinforced its role in patients where weight loss is a priority.

• Dulaglutide, as a once-weekly injection, has shown comparable HbA1c reductions and weight benefits, while offering the convenience of less frequent dosing, which has garnered positive patient adherence data.

• Semaglutide, available in both once-weekly subcutaneous and daily oral formulations, has achieved striking outcomes with HbA1c reductions of up to 1.6% and substantial weight loss (often exceeding 6 kg or more), alongside favorable cardiovascular outcomes in large outcome trials.

Additionally, emerging multifunctional candidates such as tirzepatide have reported even greater efficacy, with a mean additional reduction in HbA1c of approximately 0.45% and significant weight loss (a differential of up to 5.5 kg compared with standard GLP-1RAs) in Phase 3 trials, indicating a potential paradigm shift in treatment strategies for metabolic diseases.

Overall, the results from clinical trials come from robust data sets with rigorous design and long follow-up periods, ensuring that the therapeutic candidates not only deliver glycemic improvements but also address the broader spectrum of metabolic and cardiovascular complications associated with type 2 diabetes.

Future Directions and Challenges
Despite the remarkable success of GLP-1 receptor agonists in clinical practice, ongoing research is directed toward further optimizing these agents and addressing challenges that remain in their broad application, including patient compliance, adverse effects, and potential for expanded indications.

Innovative Therapeutic Strategies
Innovative strategies for the next generation of GLP-1 targeting drugs are multifaceted in scope. One promising innovation is the development of biased agonists that selectively activate beneficial signaling pathways, as mentioned earlier, which may minimize side effects such as gastrointestinal discomfort while preserving potent insulinotropic activity. This approach leverages molecular insights to fine-tune receptor activity and could yield a new class of drugs with improved tolerability and sustained efficacy.

In addition, dual and triple agonists that combine GLP-1 receptor agonism with stimulation of other receptors (such as GIP and glucagon receptors) are poised to shift the treatment paradigm by addressing multiple metabolic defects simultaneously. These multifunctional agents not only lower blood glucose more effectively than single-mechanism drugs but also induce greater weight loss and may have additional cardiovascular and hepatic benefits, providing a comprehensive treatment for metabolic syndrome and related disorders.

Another innovative approach is the application of fusion protein technology; by linking GLP-1 peptides with long-circulating proteins or carriers, researchers have developed candidates with significantly prolonged half-lives (e.g., AGLP-1/HSA fusion constructs), reducing dosing frequency and improving patient adherence. Such modifications also permit alternative routes of administration, potentially culminating in orally available formulations that would further revolutionize treatment convenience.

The exploration of small molecule agonists that target the GLP-1 receptor is yet another promising field, offering the potential for fully oral medications that could overcome the limitations inherent with peptide drugs. Although these candidates are mostly in early preclinical development, they represent an exciting frontier in drug discovery that could complement or eventually supplant existing therapies.

Combination products, such as fixed-ratio preparations with insulin, are already making inroads into clinical practice, and future research may explore even more complex multi-agent regimens. For example, the design of co-formulations that integrate GLP-1 receptor agonists with agents that act on the renin-angiotensin system or anti-inflammatory drugs could offer synergistic benefits in terms of cardiovascular and renal protection.

Challenges in GLP-1 Targeting
Despite these potential advancements, several challenges remain with therapies targeting GLP-1. One of the most significant hurdles is the occurrence of gastrointestinal adverse effects (nausea, vomiting, and diarrhea), which are frequently reported with GLP-1RAs and can limit patient adherence, despite dose-titration strategies aimed at mitigating these effects.
Furthermore, the cost of these therapies – particularly the injectable formulations – is a major barrier to widespread use. High drug prices can restrict access and negatively affect long-term treatment adherence, emphasizing the need for more cost-effective manufacturing processes and possibly the development of orally bioavailable agents.

Another challenge is the variable patient response seen with GLP-1 targeting drugs. Differences in receptor expression, genetic polymorphisms, and the progressive nature of β-cell dysfunction in type 2 diabetes may mean that not all patients experience the same level of benefit. Identifying biomarkers that can predict response and tailoring therapy accordingly is a priority for future research.

Moreover, while our current understanding of GLP-1 receptor signaling has led to tremendous therapeutic successes, further elucidation of the complex intracellular cascades is required. This includes a deeper comprehension of how different structural modifications influence receptor binding, signal transduction, and subsequent biological outcomes. Addressing these gaps could lead to the creation of next-generation molecules with finely tuned efficacy and safety profiles.

Finally, the transition of GLP-1 therapies into non-diabetic indications such as obesity, cardiovascular diseases, neurodegenerative conditions, and even certain cancers is accompanied by regulatory, clinical, and economic challenges. Limited long-term data on safety in non-diabetic populations and potential off-target effects raise questions that need to be thoroughly addressed in future trials.

Conclusion
In summary, therapeutic candidates targeting GLP-1 range from current approved agents—including exenatide, lixisenatide, liraglutide, dulaglutide, and semaglutide—to emerging compounds such as dual agonists (e.g., tirzepatide), biased agonists, fusion proteins, small molecule agonists, and innovative combination therapies. From a general perspective, GLP-1 is a critical hormone in regulating metabolic homeostasis, and leveraging its actions has transformed the management of type 2 diabetes and obesity. On a specific level, the approved therapies have demonstrated robust efficacy in lowering HbA1c, promoting weight loss, and improving cardiovascular outcomes, while the emerging candidates strive to enhance these benefits through novel modifications and multi-receptor strategies. More broadly, the mechanistic insights into the receptor signaling pathways have driven creative therapeutic innovations while also delineating areas for improvement such as reducing gastrointestinal side effects and extending drug half-life.

Clinical trial data across multiple phases have validated the efficacy and safety of GLP-1RAs and combination products, thereby cementing their role in the therapeutic armamentarium for metabolic diseases. Future directions in this field are aimed at overcoming challenges related to cost, patient adherence, and individual variability through personalized medicine strategies, innovative molecular designs, and the exploration of multifunctional pharmacologic agents. These efforts promise to further expand the application of GLP-1 based therapies beyond traditional diabetes care to a variety of conditions associated with metabolic dysfunction.

In conclusion, the therapeutic landscape targeting GLP-1 is both rich and dynamic. Current approved therapies have already improved clinical outcomes substantially, and ongoing research is expanding these benefits by addressing the limitations of existing agents. The emerging candidates—ranging from multi-agonists and biased tool compounds to novel fusion proteins and small molecule agonists—offer the potential for more effective, safer, and patient-friendly treatments. Ultimately, while challenges remain in optimizing receptor engagement, minimizing adverse effects, and ensuring cost-effective access, the future of GLP-1 targeting therapeutics is promising and holds the potential for transformational improvements in the management of diabetes, obesity, and beyond.