Almanac A1C

The Spectrum of GLP-1 Agonists: From Short-Acting to Multi-Receptor Therapeutics—Integrating Precision Technologies for Proactive Metabolic Wellness Prevention

Posted

by

dr. Karunia Valeriani Japar

Table of Contents

Introduction: Shifting Paradigms in Metabolic Disease Prevention

The 21st century has witnessed an unprecedented rise in metabolic diseases, fundamentally altering the global health landscape and challenging traditional models of chronic disease management. Type 2 diabetes mellitus (T2DM), obesity, hypertension, metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular disease constitute a syndemic that accounted for 226 million disability-adjusted life years (DALYs) from hypertension alone and 75 million DALYs from T2DM in 2021. Over the past three decades, the burden of T2DM has increased at an accelerated annual rate of 0.42% (95% UI: 0.34–0.51), while obesity burden has risen by 0.26% annually (95% UI: 0.17–0.34), with the highest absolute burden concentrated in India, China, and the United States. Diabetes has emerged as the eighth leading cause of death globally, with 1.66 million deaths in 2021 and a 7.95% increase in age-standardized mortality since 1990, with T2DM accounting for 97.1% of diabetes-related deaths. More than 830 million people worldwide live with diabetes, yet over half remain untreated, underscoring profound gaps in early detection and access to care.

Traditional healthcare systems have operated predominantly within a reactive paradigm, intervening only after symptomatic disease has manifested and often after irreversible vascular, renal, or neurologic complications have emerged. This approach is both medically and economically unsustainable. The cost of managing advanced complications including dialysis, amputations, blindness, cardiovascular events, and hospitalizations far exceeds that of early prevention, with reactive diabetes care costing 7.4 times more than preventive care over a 10-year period (₹24,99,000 versus ₹3,38,000 in India). By the time prediabetes or overt diabetes is diagnosed, chronic vascular disease, inflammation, and insulin resistance, the true root causes of metabolic morbidity and mortality have already progressed for years. Treating diabetes as a late-stage disease rather than targeting the upstream drivers of insulin resistance represents a missed opportunity for meaningful risk reduction.

The paradigm is now shifting from reactive treatment to proactive, precision-based prevention. This transformation is driven by three converging forces: emerging pharmacotherapies with pleiotropic metabolic and cardiovascular benefits, technological advances enabling real-time metabolic monitoring and risk stratification, and evidence demonstrating the superior cost-effectiveness and clinical outcomes of early intervention. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for glycemic control in T2DM, have emerged as transformative agents with effects extending far beyond glucose lowering. Meta-analyses of cardiovascular outcome trials (CVOTs) involving over 67,000 patients demonstrate that GLP-1 RAs significantly reduce major adverse cardiovascular events (MACE) by 13% (OR 0.87, 95% CI: 0.81–0.93), cardiovascular death by 14% (OR 0.86, 95% CI: 0.79–0.94), and all-cause mortality by 13% (OR 0.87, 95% CI: 0.82–0.94). These benefits are thought to be largely independent of glucose-lowering effects and instead mediated through weight reduction, improved endothelial function, reduced inflammation, enhanced lipid profiles, and direct cardioprotective mechanisms.

Critically, the cardiovascular benefits of GLP-1 RAs are most pronounced in individuals with higher baseline body mass index (BMI) and older age, with each 1 kg/m² increase in BMI associated with a 9% additional MACE risk reduction and each additional year of age conferring a 3% incremental benefit. These findings challenge the perception of advanced age as a barrier to therapy and support prioritizing GLP-1 RAs in populations with elevated metabolic and age-related vulnerabilities—not merely for weight loss but as a comprehensive strategy to mitigate cardiovascular risk. The evolution of GLP-1 pharmacology has expanded from short-acting agents requiring multiple daily injections to long-acting formulations with once-weekly dosing, and now to dual and triple receptor agonists (tirzepatide, retatrutide) that augment weight loss (15–24% body weight reduction), improve hepatic steatosis resolution (>75%), and enhance cardiometabolic biomarkers beyond GLP-1 monotherapy.

Concurrently, artificial intelligence (AI) and digital health technologies are revolutionizing early detection, risk stratification, and personalized intervention for metabolic diseases. Transformer-based AI models applied to electronic health records demonstrate superior accuracy in predicting T2DM, MASLD, atherogenic dyslipidemia, and chronic kidney disease compared to classical machine learning models, enabling proactive identification of high-risk individuals before disease onset. Integration of continuous glucose monitoring (CGM) with machine learning algorithms enables metabolic subphenotyping, differentiating insulin-resistant from insulin-sensitive individuals based on glucose variability patterns and supports precision dietary recommendations, real-time glycemic feedback, and early detection of metabolic derangements undetectable by standard HbA1c or fasting glucose measurements. AI-driven bundled interventions combining CGM, behavioural coaching, and pharmacotherapy significantly improve HbA1c, body weight, and quality of life while reducing medication burden and healthcare costs.

The convergence of GLP-1 receptor agonism, multi-receptor agonist therapies, and AI-enabled metabolic monitoring represents a paradigm shift from reactive disease management to proactive metabolic wellness prevention. This new model emphasizes early risk stratification using novel biomarkers (alpha-hydroxybutyrate, linoleoyl-glycerophosphocholine, CGM-derived glucose variability), personalized pharmacologic selection based on metabolic phenotype and cardiovascular risk profile, and integration of lifestyle interventions (nutrition, resistance training, physical activity) to amplify treatment efficacy and preserve lean mass. Prevention has proven to be one of the most cost-effective strategies to achieve improved population health, with data-driven allocation of preventive care (e.g., metformin, lifestyle programs) yielding annual savings of $1.1 billion in the United States by preventing over 25% more diabetes cases compared to clinical risk score-based stratification.

True success in metabolic disease management must be measured not by achieving numeric glycemic targets but by preserving vascular integrity, preventing irreversible vascular injury, and addressing the root causes of insulin resistance, inflammation, and endothelial dysfunction. The goal is to prevent complications entirely rather than delay them, a shift that demands early screening incorporating vascular and metabolic biomarkers, multifactorial management addressing inflammation and oxidative stress, and personalized medicine tailored to genetic, metabolic, and environmental profiles. Redirecting healthcare resources toward vascular health and biomarker-based early intervention has the potential to dramatically reduce both the clinical and economic burden of metabolic diseases while enhancing equity and access to care.

For AI health-tech companies focused on preventing metabolic disease and promoting metabolic wellness, this paradigm shift presents unprecedented opportunities to deploy scalable, precision interventions integrating pharmacology (GLP-1 RAs, multi-agonists), biosensor technology (CGM, wearables), and AI-driven clinical decision support. By targeting insulin resistance and metabolic dysregulation in their earliest stages, before prediabetes, before overt cardiovascular disease, before irreversible complications. Health-tech platforms can redefine the trajectory of metabolic health at both individual and population scales, achieving improved outcomes, reduced costs, and sustainable wellness. The following sections explore the spectrum of GLP-1 agonists from short-acting to long-acting to multi-receptor formulations and their integration with technological innovations to enable precision metabolic wellness prevention in the era of proactive, patient-centered care.

Molecular Mechanisms Underlying GLP-1 Receptor Activation

Receptor Signaling and Physiological Effects

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the diverse metabolic, cardiovascular, and neuroprotective effects of endogenous GLP-1 and its pharmacological agonists. GLP-1R is widely distributed across multiple tissues, including pancreatic β-cells, α-cells, gastrointestinal tract, central nervous system (hypothalamus, hippocampus, neocortex, cerebellum), cardiovascular tissues (myocardium, vascular endothelium, smooth muscle), kidneys, lungs, and peripheral nerves. This broad tissue expression profile underscores the pleiotropic nature of GLP-1 signalling, extending far beyond glycemic control to encompass appetite regulation, cardiovascular protection, neuroprotection, and metabolic homeostasis [1,2,3,4,5].

Upon ligand binding, GLP-1R undergoes a conformational change that activates heterotrimeric Gs proteins, which in turn stimulate adenylate cyclase to catalyze the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Elevated intracellular cAMP activates two major downstream effectors: protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac), also known as cAMP-regulated guanine nucleotide exchange factor II. In pancreatic β-cells, this canonical cAMP-PKA-Epac pathway enhances glucose-dependent insulin secretion through multiple mechanisms. PKA phosphorylates key proteins that facilitate exocytosis of insulin-containing vesicles, while Epac promotes mobilization of intracellular calcium (Ca²⁺) stores. Concurrently, GLP-1 signalling modulates ion channel activity, including closure of ATP-sensitive potassium (K_ATP) channels and opening of voltage-gated L-type calcium channels, leading to membrane depolarization and extracellular Ca²⁺ influx. The resultant increase in cytosolic Ca²⁺ concentration, together with elevated cAMP levels, synergistically promotes insulin granule exocytosis and glucose-stimulated insulin secretion (GSIS) [2,4,6].

Notably, recent evidence indicates that picomolar concentrations of GLP-1 (physiologically relevant levels) activate insulin secretion via a protein kinase C (PKC)-dependent, PKA-independent pathway, whereas nanomolar concentrations (conventionally used in experimental settings) predominantly activate the cAMP-PKA pathway. At picomolar concentrations, GLP-1 induces significant insulin secretion, membrane depolarization, increased L-type calcium currents, and membrane capacitance even in the presence of PKA inhibitors, suggesting the existence of a high-affinity GLP-1R binding site that couples to PKC signalling. This dual-pathway model, PKC-mediated at physiological picomolar levels and PKA-mediated at pharmacological nanomolar levels provides a more nuanced understanding of GLP-1R signalling dynamics and may explain the sustained efficacy of GLP-1 RAs across varying plasma concentrations [4,6,7].

Beyond acute insulinotropic effects, GLP-1R activation promotes β-cell proliferation, survival, and differentiation through multiple signaling cascades. GLP-1 stimulates β-cell replication and neogenesis in vitro and in vivo by inducing proteolytic maturation of betacellulin, a member of the epidermal growth factor (EGF) family, which transactivates the EGF receptor (EGFR) and activates phosphatidylinositol 3-kinase (PI3K) signalling. Downstream effectors of PI3K, including protein kinase B (Akt), protein kinase C-zeta (PKCζ), and p38 mitogen-activated protein kinase (p38 MAPK), co-ordinately regulate β-cell mass expansion. GLP-1 also enhances the expression and nuclear translocation of the transcription factor pancreatic and duodenal homeobox 1 (Pdx1), which is essential for insulin gene transcription, β-cell differentiation, and survival. Simultaneously, GLP-1 inhibits the fork head box protein O1 (FoxO1) transcription factor via nuclear exclusion mediated by Akt phosphorylation, thereby relieving a constraint on β-cell proliferation and Pdx1 expression [4,8].

GLP-1R activation exerts potent anti-apoptotic effects through both cAMP-PKA and PI3K-Akt pathways. PKA-mediated activation of the cAMP response element-binding protein (CREB) enhances expression of insulin receptor substrate 2 (IRS2), a key survival factor in β-cells. GLP-1 protects β-cells from glucotoxicity, lipotoxicity, and cytokine-induced apoptosis by activating Akt, reducing caspase-3 activation, and upregulating anti-apoptotic proteins. These proliferative and cytoprotective mechanisms contribute to the preservation and expansion of functional β-cell mass, a critical determinant of long-term glycemic control and diabetes prevention [4,8].

In α-cells, GLP-1R activation suppresses glucagon secretion in a glucose-dependent manner, thereby reducing hepatic glucose production and contributing to improved fasting glycemia. In the central nervous system, GLP-1R signalling in hypothalamic appetite-regulating centers promotes satiety, reduces food intake, and delays gastric emptying, effects that are mediated in part through interactions with aversive signalling pathways and vagal afferent nerves. In the cardiovascular system, GLP-1R activation enhances myocardial contractility, reduces oxidative stress, promotes vasodilation, and protects against ischemia-reperfusion injury through mechanisms involving nitric oxide production, reduced inflammation, and improved endothelial function. This broad spectrum of tissue-specific GLP-1R signalling pathways underscores the therapeutic versatility of GLP-1 receptor agonists in metabolic, cardiovascular, and neurodegenerative diseases [1,2,3,4,5,8].

Mechanisms of Pharmacokinetic Extension

Native GLP-1 is an incretin hormone secreted by enteroendocrine L-cells in response to nutrient ingestion, but its therapeutic utility is severely limited by its extremely short plasma half-life of approximately 1.5 to 2 minutes. This rapid degradation is primarily mediated by dipeptidyl peptidase-4 (DPP-4), which cleaves the N-terminal dipeptide (His-Ala) from GLP-1(7-36) amide or GLP-1(7-37), rendering the peptide biologically inactive. Additionally, rapid renal clearance contributes to the swift elimination of native GLP-1 from circulation. To overcome these pharmacokinetic limitations and enable clinically feasible dosing regimens, multiple molecular strategies have been developed to extend the half-life of GLP-1 receptor agonists, including amino acid substitutions conferring DPP-4 resistance, fatty acid acylation promoting albumin binding, fusion to immunoglobulin Fc fragments reducing renal clearance, and encapsulation in biodegradable polymer matrices enabling sustained release [4,9,10,11,12,13,14].

In summary, the pharmacokinetic extension strategies employed in contemporary GLP-1 RAs fatty acid acylation for albumin binding (liraglutide, semaglutide), Fc fusion to reduce renal clearance and exploit FcRn recycling (dulaglutide), amino acid substitutions conferring DPP-4 resistance (exenatide, albiglutide), and biodegradable polymer encapsulation for sustained release (exenatide ER) have collectively transformed GLP-1 therapy from an impractical peptide requiring continuous infusion into a versatile class of agents compatible with once-daily, once-weekly, and potentially longer dosing intervals. These molecular innovations underpin the clinical success of GLP-1 RAs and provide a foundation for next-generation multi-receptor agonists and ultra-long-acting formulations aimed at maximizing patient adherence, metabolic efficacy, and cardiovascular protection [10,11,12,13,14].

Pharmacokinetic and Clinical Profiles: Classification by Duration of Action

The GLP-1 RAs currently approved for clinical use can be systematically classified according to their duration of action, which is determined by pharmacokinetic properties including elimination half-life, time to peak plasma concentration (T_max), dosing frequency, and the molecular modification that confer metabolic stability. This classification distinguishes short-acting agents (exenatide twice-daily, lixisenatide), intermediate-acting agents (liraglutide), and long-acting formulations (semaglutide, dulaglutide, exenatide extended-release), each exhibiting distinct clinical efficacy profiles, mechanisms of glycemic control, and tolerability characteristics [13,14,15].

Short Acting GLP-1 Agonists: Exenatide Twice-Daily and Lixisenatide

Short-acting GLP-1 RAs are characterized by rapid absorption, short plasma half-lives, and pharmacodynamic effects that predominantly target postprandial glucose excursions rather than fasting glycemia. Exenatide immediate-release (EBID), the first GLP-1 RA approved for clinical use, is a 39-amino acid synthetic peptide derived from exendin-4, a naturally occurring compound isolated from the saliva of the Gila monster lizard (Heloderma suspectum). Exenatide shares approximately 53% amino acid sequence homology with native human GLP-1 but exhibits natural resistance to degradation by dipeptidyl peptidase-4 (DPP-4), conferring an elimination half-life of approximately 2.4 hours after subcutaneous administration. The pharmacokinetics of exenatide are dose-proportional, with maximum serum concentrations of 56 pg/mL and 85 pg/mL achieved at 2.1 hours following single subcutaneous doses of 2.5 µg and 5 µg, respectively. Exenatide is eliminated primarily through renal mechanisms, including glomerular filtration and subsequent proteolytic degradation, with an apparent clearance of approximately 9 L/h [16,17,18].

From a pharmacodynamic perspective, the short half-life of exenatide necessitates twice-daily administration, typically 15 minutes before breakfast and dinner, with injections separated by at least six hours. This dosing regimen produces pharmacologically effective plasma concentrations for approximately 5 to 7 hours following each injection, resulting in glucose-lowering effects that are most pronounced during the postprandial periods immediately following the administered doses. Exenatide significantly slows gastric emptying in a dose-dependent manner, which represents a major mechanism underlying its postprandial glucose-lowering effect. The delay in gastric emptying reduces the rate at which meal-derived glucose appears in the systemic circulation, thereby attenuating postprandial glycemic excursions. In contrast, the effect of exenatide twice-daily on fasting plasma glucose (FPG) is relatively modest compared to long-acting GLP-1 RAs, as the short half-life results in subtherapeutic plasma concentrations during the overnight fasting period [16,18,19,20,21,22,23,24,25].

Clinical trials have demonstrated that exenatide twice-daily reduces HbA1c by approximately 0.8 to 1.0% when added to metformin, sulfonylurea, or combination oral antidiabetic therapy. However, head-to-head comparisons with intermediate- and long-acting GLP-1 RAs have consistently demonstrated inferior glycemic efficacy for exenatide twice-daily. In the landmark LEAD-6 trial, liraglutide 1.8 mg once daily produced significantly greater HbA1c reductions than exenatide 10 µg twice daily (−1.12% versus −0.79%, estimated treatment difference −0.33%, 95% CI −0.47 to −0.18, P < 0.0001), with a higher proportion of patients achieving target HbA1c <7% (54% versus 43%, P= 0.0015). Fasting plasma glucose was also reduced significantly more with liraglutide (−1.61 mmol/L versus −0.60 mmol/L, P< 0.0001), reflecting the superior overnight glycemic coverage afforded by the longer-acting agent [18,26,27,28,29].

Lixisenatide, another short-acting GLP-1 RA, is a 44-amino acid synthetic peptide based on exendin-4 with C-terminal modification (addition of six lysine residues and deletion of one proline) to enhance DPP-4 resistance. Despite this modification, lixisenatide retains a short plasma half-life of approximately 2 to 4 hours following subcutaneous administration, with mean terminal half-lives ranging from 1.4 to 4.5 hours depending on antibody status and renal function. Lixisenatide is classified as a prandial, short-acting GLP-1 RA and is administered once daily, typically before the main meal of the day [20,30,31].

The predominant mechanism of glycemic control with lixisenatide is profound and sustained slowing of gastric emptying, which accounts for the majority of its postprandial glucose-lowering effect. Scintigraphic studies demonstrate that lixisenatide doses as low as 5 µg significantly delay gastric emptying, with maximum inhibition (>80% reduction) observed at the 20 µg dose. Importantly, this gastric emptying effect persists over prolonged treatment periods without significant tachyphylaxis, distinguishing short-acting GLP-1 RAs from long-acting agents. In an 8-week randomized trial using scintigraphy, lixisenatide induced substantial and sustained slowing of gastric emptying (ratio of adjusted geometric means for gastric retention AUC 0–120 minutes: 1.55, 95% CI 1.37–1.74, P< 0.001), associated with marked reductions in postprandial glycemia and systemic appearance of ingested glucose. The magnitude of postprandial glucose reduction correlated directly with the degree of gastric emptying delay, and patients with faster baseline gastric emptying derived the greatest benefit from lixisenatide therapy [20,24,30,32].

In contrast to its pronounced effects on postprandial glucose, lixisenatide exerts relatively modest effects on fasting plasma glucose, reflecting the short duration of pharmacologically active plasma concentrations. The dose–response relationship for lixisenatide demonstrates that reductions in postprandial glucose are maximal at 10 to 20 µg, with delays in gastric emptying continuing to increase at the 20 µg dose. Lixisenatide 20 µg once daily reduces HbA1c by approximately 0.7 to 0.9% in clinical trials, with more pronounced effects on postprandial glucose than fasting glucose [20,24,27,30].

The gastrointestinal tolerability of short-acting GLP-1 RAs is influenced by their pharmacokinetic profiles. Nausea, the most common adverse effect, tends to be more frequent during the initial weeks of therapy but often attenuates over time. In LEAD-6, nausea was less persistent with liraglutide than with exenatide twice-daily (3% versus 9% at week 26), and rates of minor hypoglycemia were significantly lower with liraglutide (1.93 versus 2.60 events per patient-year, rate ratio 0.55, 95% CI 0.34–0.88, ****P= 0.0131) [27,28].

Intermediate-Acting Agents: Liraglutide

Liraglutide represents the prototypical intermediate-acting GLP-1 RA, bridging the pharmacokinetic and clinical profiles of short-acting and long-acting formulations. Structurally, liraglutide is a human GLP-1 analog with 97% sequence homology to native GLP-1, featuring an arginine substitution at position 34 (Arg34) and attachment of a palmitic acid (C16 fatty acid) side chain via a γ-glutamyl linker to lysine 26 (Lys26). These modifications confer three key pharmacokinetic protraction mechanisms: (1) self-association into heptamers at the subcutaneous injection site, creating a depot that slows absorption; (2) reversible, high-affinity binding to serum albumin (>98% plasma protein binding), which protects liraglutide from enzymatic degradation and reduces renal clearance; and (3) enhanced stability against DPP-4 and neutral endopeptidase (NEP) degradation [11,33].

The resulting pharmacokinetic profile is characterized by slow absorption (T_max 8 to 12 hours), an elimination half-life of approximately 13 hours, and steady-state plasma concentrations that support once-daily subcutaneous administration. The apparent clearance following subcutaneous injection of liraglutide 3.0 mg is approximately 0.9 to 1.4 L/h, and the volume of distribution is approximately 13 to 25 L, depending on body weight. Liraglutide is not metabolized by any specific organ but is degraded through endogenous plasma protein catabolism pathways, with no single metabolic pathway accounting for more than a minor fraction of elimination. No clinically significant drug–drug interactions have been identified with liraglutide, and no dose adjustment is required for hepatic impairment, although caution is advised in severe hepatic dysfunction due to limited data [34,35].

The once-daily dosing regimen of liraglutide produces pharmacodynamic effects that address both fasting and postprandial hyperglycemia, although the predominant effect is on fasting plasma glucose due to sustained overnight GLP-1R activation. In the LEAD (Liraglutide Effect and Action in Diabetes) clinical trial program, liraglutide 1.2 mg and 1.8 mg once daily reduced HbA1c by 1.0 to 1.5% across a range of background therapies, with robust reductions in fasting plasma glucose (−1.5 to −2.0 mmol/L) and clinically meaningful weight loss (−2 to −3 kg over 26 to 52 weeks). The proportion of patients achieving HbA1c <7% ranged from 42 to 58%, depending on baseline characteristics and concomitant therapy [27,28,29].

Compared to short-acting GLP-1 RAs, liraglutide produces greater reductions in fasting plasma glucose and HbA1c but exhibits tachyphylaxis (desensitization) of its effect on gastric emptying with sustained use. Studies using acetaminophen absorption as a proxy for gastric emptying have demonstrated that liraglutide and placebo produce equivalent effects on gastric emptying after several weeks of treatment, whereas short-acting agents such as exenatide twice-daily and lixisenatide maintain significant gastric emptying delay. This tachyphylaxis limits the postprandial glucose-lowering efficacy of liraglutide compared to short-acting GLP-1 RAs, but is offset by superior fasting glucose control and overall HbA1c reduction [25,30,32,36].

In head-to-head comparisons with long-acting once-weekly GLP-1 RAs, liraglutide has demonstrated comparable or slightly superior glycemic efficacy in some trials. The DURATION-6 trial compared liraglutide 1.8 mg once daily with exenatide extended-release (EQW) 2.0 mg once weekly and found significantly greater HbA1c reduction with liraglutide (−1.48% versus −1.28%, P= 0.02) and superior weight loss (−3.57 kg versus −2.68 kg, P= 0.0005). However, the clinical significance of these differences is modest, and both agents represent effective therapeutic options for glycemic control [27,29].

The tolerability profile of liraglutide is favorable, with nausea being the most common adverse effect (occurring in approximately 20 to 30% of patients during dose titration) but typically transient and diminishing with continued therapy. The recommended dose-escalation protocol (starting at 0.6 mg daily and increasing weekly by 0.6 mg increments to the target dose of 1.2 to 1.8 mg for diabetes or 3.0 mg for obesity) mitigates gastrointestinal intolerability and improves adherence. Liraglutide has a well-established cardiovascular safety profile, with the LEADER cardiovascular outcome trial demonstrating significant reductions in major adverse cardiovascular events (MACE), cardiovascular death, and all-cause mortality in patients with type 2 diabetes at high cardiovascular risk [27,33,37].

Long-Acting Formulations: Semaglutide, Dulaglutide, and Exenatide Extended-Release

Long-acting GLP-1 RAs are distinguished by elimination half-lives of 5 to 7 days, enabling once-weekly subcutaneous administration and providing sustained 24-hour GLP-1R activation throughout the dosing interval. This pharmacokinetic profile produces superior reductions in fasting plasma glucose compared to short- and intermediate-acting agents, with comparable or greater HbA1c lowering and weight loss [36,37,38,39].

Semaglutide is a human GLP-1 analog featuring three key structural modifications: (1) an alanine-to-α-aminoisobutyric acid (AIB) substitution at position 8, which confers complete resistance to DPP-4 degradation; (2) an arginine substitution at position 34; and (3) attachment of a C18 fatty diacid (octadecanedioic acid) side chain via a γ-glutamyl-2×oligoethylene glycol (γGlu-2×OEG) linker to lysine 26. The C18 diacid confers markedly higher albumin binding affinity (>99% plasma protein binding) compared to the C16 monocarboxylic acid used in liraglutide, resulting in a plasma half-life of approximately 7 days (165–184 hours) after subcutaneous administration. Steady-state plasma concentrations are achieved after 4 to 5 weeks of once-weekly dosing, with mean steady-state concentrations of 65 ng/mL (0.5 mg weekly) and 123 ng/mL (1.0 mg weekly). The prolonged half-life ensures that therapeutic plasma concentrations are maintained continuously throughout the dosing interval, providing sustained GLP-1R activation during both fasting and postprandial periods [11,40,41].

In the SUSTAIN clinical trial program, semaglutide 0.5 mg and 1.0 mg once weekly produced HbA1c reductions of 1.2 to 1.8% and weight loss of 4 to 6 kg over 30 to 56 weeks, with the majority of patients achieving HbA1c targets <7%. In the head-to-head SUSTAIN 3 trial, semaglutide 1.0 mg once weekly demonstrated superiority over exenatide extended-release 2.0 mg once weekly for HbA1c reduction (−1.5% versus −0.9%, estimated treatment difference −0.62%, 95% CI −0.80 to −0.44, P< 0.0001), weight loss (−5.6 kg versus −1.9 kg, estimated treatment difference −3.78 kg, 95% CI −4.58 to −2.98, P < 0.0001), and the proportion achieving HbA1c <7% (67% versus 40%, P < 0.0001). Fasting plasma glucose was also reduced significantly more with semaglutide (−2.8 mmol/L versus −2.0 mmol/L, P < 0.0001) [38,39,41].

Despite its long half-life, semaglutide continues to slow gastric emptying, although the magnitude of this effect may be attenuated compared to short-acting GLP-1 RAs due to receptor desensitization with continuous exposure. Gastrointestinal adverse events (nausea, vomiting, diarrhea) occurred in 41.8% of semaglutide-treated patients versus 33.3% with exenatide extended-release in SUSTAIN 3, but injection-site reactions were markedly less common with semaglutide (1.2% versus 22.0%). Semaglutide has demonstrated cardiovascular benefits in the SELECT and SUSTAIN-6 trials, including significant reductions in MACE, stroke, and cardiovascular death [32,37,39].

Dulaglutide is a GLP-1 RA fusion protein consisting of two identical disulfide-linked chains, each comprising a DPP-4-resistant GLP-1 analog (featuring alanine-to-glycine substitution at position 8) covalently linked to a modified human IgG4 Fc fragment via a 16-amino acid peptide linker. The assembled molecule has a molecular weight of approximately 63 kDa per monomer (total approximately 126 kDa), which significantly exceeds the glomerular filtration threshold and thereby reduces renal clearance. The IgG4 Fc fragment has been modified with amino acid substitutions (S228P, L235E) to reduce immunogenicity and prevent Fc receptor-mediated immune activation. Dulaglutide binds to the neonatal Fc receptor (FcRn), which mediates recycling from endosomes back to the circulation, further extending its plasma half-life [40,41,42].

The pharmacokinetic profile of dulaglutide is characterized by a half-life of approximately 4.7 to 5 days (90–120 hours), supporting once-weekly subcutaneous administration. Steady-state concentrations are achieved after approximately 2 to 4 weeks of weekly dosing. The large molecular size of dulaglutide also slows absorption from the subcutaneous injection site, contributing to its protracted pharmacokinetic profile. In the AWARD (Assessment of Weekly Administration of LY2189265 [Dulaglutide] in Diabetes) clinical trial program, dulaglutide 0.75 mg and 1.5 mg once weekly reduced HbA1c by 0.7 to 1.6% and body weight by 1.5 to 3.2 kg across various background therapies and comparator groups. Dulaglutide 1.5 mg demonstrated non-inferiority or superiority to liraglutide 1.8 mg once daily for HbA1c reduction in several trials, with comparable gastrointestinal tolerability [42].

Compared with daily insulin glargine, dulaglutide 1.5 mg once weekly produced greater HbA1c reductions (−1.08% versus −0.63% at 52 weeks), higher proportions of patients achieving HbA1c <7% (53% versus 31%), and significant weight loss (−1.87 kg versus +1.44 kg, P< 0.001), with a lower incidence of hypoglycemia. Fasting plasma glucose reductions were initially greater with dulaglutide but were ultimately greater with glargine at week 52 (−16 mg/dL versus −32 mg/dL), reflecting the insulin’s more direct effect on hepatic glucose production. Dulaglutide has an established cardiovascular safety profile, with the REWIND trial demonstrating significant reduction in MACE in patients with type 2 diabetes with and without established cardiovascular disease [37,42,43].

Exenatide Extended-Release (EQW), marketed as Bydureon, employs a biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microsphere formulation to achieve sustained release of exenatide over one week. Exenatide is encapsulated within PLGA microspheres (50:50 lactide:glycolide ratio) with a mean diameter of approximately 85 µm, which are suspended in an aqueous diluent and administered as a once-weekly subcutaneous injection. Following injection, exenatide release from PLGA microspheres exhibits a triphasic pharmacokinetic profile: (1) an initial burst release (0–48 hours) accounting for 1–2% of total drug exposure, resulting from exenatide on or near the microsphere surface; (2) a diffusion-controlled release phase (approximately 2 weeks) as exenatide diffuses through the intact polymer matrix; and (3) an erosion-controlled release phase (weeks 3–7) as hydrolysis of PLGA into lactic acid and glycolic acid results in matrix erosion and steady-state exenatide release [12,44].

Therapeutic plasma exenatide concentrations (>50 pg/mL) are achieved by week 2, with steady-state concentrations reached by weeks 6 to 8. The elimination half-life of exenatide from the depot formulation is approximately 2 weeks, reflecting the slow release from the microsphere matrix rather than the intrinsic elimination of exenatide itself (2.4 hours). In clinical trials, exenatide extended-release 2.0 mg once weekly reduced HbA1c by 1.3 to 1.9%, with robust reductions in fasting plasma glucose (−2.2 to −2.4 mmol/L) and postprandial glucose, and weight loss of approximately 2 to 4 kg. The magnitude of HbA1c reduction with exenatide extended-release is approximately twice that observed with exenatide twice-daily (−1.9% versus −0.9% in DURATION-1), reflecting the sustained 24-hour glycemic coverage provided by continuous exenatide exposure [12,18,26,29,39,45].

A consistent finding across clinical trials is that long-acting GLP-1 RAs produce greater reductions in fasting plasma glucose compared to short-acting agents, while short-acting agents more potently attenuate postprandial glucose excursions due to their preserved effect on gastric emptying. Meta-analyses confirm that long-acting GLP-1 RAs achieve greater overall HbA1c reductions (estimated treatment difference −0.55% to −0.62%), greater fasting plasma glucose reductions (−0.7 to −0.84 mmol/L), and greater weight loss (−1.4 to −3.8 kg) compared to short-acting agents, with improved gastrointestinal tolerability and adherence due to reduced dosing frequency. The differential mechanisms of glycemic control fasting glucose reduction via sustained insulinotropic and glucagonostatic effects versus postprandial glucose reduction via gastric emptying delay, inform the clinical selection of GLP-1 RAs based on individual patient characteristics, glycemic phenotype, and treatment goals [25,30,36,39].

In summary, the classification of GLP-1 RAs by duration of action reflects fundamental pharmacokinetic differences that translate into distinct clinical efficacy and tolerability profiles. Short-acting agents (exenatide twice-daily, lixisenatide) are characterized by rapid absorption, short half-lives (2–4 hours), preserved gastric emptying effects, and predominant postprandial glucose lowering. Intermediate-acting liraglutide, with a 13-hour half-life and once-daily dosing, provides balanced fasting and postprandial glycemic control but exhibits tachyphylaxis for gastric emptying. Long-acting agents (semaglutide, dulaglutide, exenatide extended-release), with half-lives of 5–7 days and once-weekly dosing, deliver superior fasting glucose and HbA1c reductions, enhanced convenience and adherence, and established cardiovascular benefits, positioning them as preferred options for comprehensive metabolic disease prevention in many clinical scenarios [25,27,36].

Beyond GLP-1: Dual and Triple Receptor Agonism

The evolution of incretin-based pharmacotherapy has progressed from single GLP-1 receptor agonism to multi-receptor targeting strategies that simultaneously engage complementary metabolic pathways. Tirzepatide and retatrutide represent dual and triple agonist approaches that substantially amplify therapeutic efficacy for weight loss, glycemic control, and cardiometabolic disease prevention [46,47].

Tirzepatide: GIP/GLP-1 Dual Agonism

Tirzepatide is a dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist, characterized by imbalanced agonism favouring GIPR over GLP-1R. This balanced dual incretin effect exploits synergistic metabolic pathways: GLP-1R activation slows gastric emptying and promotes satiety, while GIPR activation enhances lipid metabolism and adipocyte function. Tirzepatide’s plasma half-life is approximately 5 days, permitting once-weekly administration [13,46,48].

In the SURPASS clinical trial program, tirzepatide 5 mg, 10 mg, and 15 mg once weekly reduced HbA1c by 2.0 to 2.4%, with 85 to 90% of patients achieving HbA1c <7%. In head-to-head comparisons (SURPASS-2), tirzepatide demonstrated superiority over semaglutide 1 mg for both HbA1c reduction and weight loss. In the SURMOUNT obesity trials, tirzepatide achieved weight reductions of 15.0% to 20.9% (doses 5–15 mg), substantially exceeding GLP-1 monotherapy results [13].

Mechanistically, tirzepatide increases adiponectin levels, improves β-cell function (HOMA2-B increased 93–163%), and enhances glucose-dependent insulin secretion while suppressing glucagon in hyperglycemic states. These dual incretin effects produce robust glycemic control and weight loss superior to GLP-1 agonists alone [49].

Retatrutide: GIP/GLP-1/Glucagon Triple Agonism

Retatrutide represents the next evolutionary advancement as a triple agonist engaging GIP, GLP-1, and glucagon receptors (GCGR), adding glucagon-mediated hepatic fatty acid oxidation and energy expenditure to the dual incretin effects. Retatrutide has a half-life of approximately 6 days, enabling once-weekly dosing [47,50,51].

In phase 2 obesity trials, retatrutide achieved weight reductions of 22.8% to 24.2%, exceeding tirzepatide efficacy. Most striking are the effects on liver fat in metabolic dysfunction-associated steatotic liver disease (MASLD): at 24 weeks, liver fat reductions reached −81.4% to −82.4% (8 and 12 mg doses), with 79% to 86% of participants achieving normal liver fat levels (<5%). These represent the largest liver fat reductions reported for any pharmacological agent, substantially exceeding the ~47% reduction with tirzepatide and ~50% with semaglutide [50,52].

The glucagon receptor component directly stimulates hepatic fatty acid oxidation and reduces hepatic lipogenesis, contributing to liver fat reduction beyond that attributable to weight loss alone. Retatrutide improved insulin resistance markers (fasting insulin, C-peptide, and HOMA2-IR reduced by up to 50% or more), reduced triglycerides >40%, increased adiponectin, and elevated β-hydroxybutyrate 2- to 3-fold, a biomarker of fatty acid oxidation. Biomarkers of hepatocyte apoptosis (cytokeratin-18) and hepatic fibrogenesis (pro-C3) were significantly reduced, suggesting hepatoprotective benefits [50].

In summary, retatrutide’s triple agonism achieves unprecedented weight loss (~24%) and liver fat reduction (>80%), positioning it as a transformative agent for metabolic disease and MASLD prevention. Tirzepatide’s dual GIP/GLP-1 agonism provides superior efficacy compared to GLP-1 monotherapy but lesser hepatic fat reduction than retatrutide.

Cardiovascular and Mortality Outcomes: Evidence from Cardiovascular Outcome Trials

Large-scale cardiovascular outcome trials (CVOTs) have established glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as a cornerstone for reducing major adverse cardiovascular events (MACE) in patients with type 2 diabetes and elevated metabolic risk. Across meta-analyses of ten randomized trials including over 67,000 participants, GLP-1 RAs consistently produce a 12–14% relative reduction in the risk of MACE, a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke versus placebo (OR ~0.87–0.88, high-certainty evidence). These benefits extend to reductions in cardiovascular death (14%) and all-cause mortality (13%), with additional protection against fatal and nonfatal stroke, coronary revascularization, and heart failure hospitalizations [53,54].

Subgroup and meta-regression analyses confirm that the magnitude of cardiovascular risk reduction is sensitive to patient characteristics. The benefit of GLP-1 RA therapy is more pronounced in those with higher baseline body mass index (BMI) and older age. For each 1 kg/m² increase in BMI, there is a further 9% reduction in MACE risk, and with each additional year of age, risk is reduced by 3%, findings that underline the importance of targeting therapy to those at greatest cardiometabolic vulnerability. Importantly, these cardiovascular and mortality benefits are observed regardless of drug structure, diabetes duration, background medications, or presence of established cardiovascular disease, and they extend to kidney outcomes, lowering progression rates and hospitalizations [37,53].

Sensitivity analyses and trial-level subgroup findings are robust, with consistent effect sizes and no single trial unduly influencing the results. Safety analyses show no excess risk of severe hypoglycaemia, pancreatitis, pancreatic cancer, or retinopathy [53].

In summary, GLP-1 receptor agonists provide substantial, clinically meaningful reductions in cardiovascular and all-cause mortality, with greatest gains in those with higher BMI and older age, and should be prioritized in metabolic disease prevention strategies in at-risk populations.

Technological Integration: Digital Heath and Continuous Monitoring

Continuous glucose monitoring (CGM) technology enables highly granular, real-time profiling of glucose dynamics, surpassing traditional metrics such as fasting glucose or HbA1c in detecting early dysglycemia and metabolic heterogeneity. Recent studies show that CGM, combined with standardized oral glucose tolerance tests (OGTTs), can accurately distinguish metabolic subphenotypes related to muscle insulin resistance and β-cell deficiency using machine learning approaches, achieving diagnostic sensitivity superior to conventional biomarkers (AUC 88–84%). This enables precise risk stratification and personalized prevention strategies in diabetes and metabolic disease [55].

The clinical utility of CGM is dramatically enhanced by artificial intelligence (AI)-driven systems. AI algorithms can extract complex features from high-frequency CGM data, predict glycemic excursions and meal responses, and generate early warnings before standard glucose thresholds are abnormal. Integrated CGM and AI platforms provide automated feedback, personalized lifestyle and medication recommendations, and clinical decision support which improves risk identification, enables tailored interventions, and empowers continuous patient engagement and remote care. Together, CGM and AI represent a paradigm shift toward precision metabolic monitoring and management, offering actionable insights for individualized clinical decision-making and population health [56].

Adherence, Barriers, and Innovation in Drug Delivery

Medication adherence with GLP-1 receptor agonists is strongly influenced by dosing frequency and route of administration. Meta-analyses and real-world studies show that once-weekly injectable GLP-1RAs (e.g., semaglutide, dulaglutide, exenatide extended-release) achieve significantly better adherence and persistence than once-daily regimens (e.g., liraglutide, exenatide twice-daily). The risk of non-adherence with daily injections is 11% higher compared to weekly dosing, a finding attributed to reduced treatment burden and increased patient convenience. Adherence rates with once-weekly regimens often exceed 88%, with higher proportion of patients reaching clinically effective coverage versus daily therapies [57,58].

Barriers to optimal use persist, notably therapeutic inertia, perceived injection aversion, and complexity of dosing devices, all factors that may delay uptake or increase discontinuation. Many patients express a strong preference for oral or buccal formulations, citing convenience, reduced discomfort, and social acceptability as drivers, which have led to innovative development in drug delivery approaches. Oral GLP-1 analogues use protective barriers, permeation enhancers, and enzymatic stability technologies to maintain peptide bioavailability despite hostile gastrointestinal environments. Buccal tablets and films utilizing mucoadhesive polymers and permeation enhancers can achieve therapeutic peptide delivery via the oral mucosa, offering patient-friendly alternatives [59,60].

Depot and extended-release injectable formulations further ease adherence by enabling once-monthly or less frequent dosing via biodegradable microspheres or in situ gel systems that provide sustained therapeutic drug release after a single administration. These advancements collectively improve patient experience, minimize barriers to initiation and persistence, and optimize long-term outcomes in both obesity and type 2 diabetes therapy. Ongoing innovation in delivery platforms, especially oral and buccal routes, continues to expand options for personalized, patient-centered GLP-1 therapy [61].

Clinical and Preventive Implications for AI Health-Tech Companies

Advances in GLP-1 therapeutics and digital health platforms have profound implications for AI-driven health tech companies seeking to prevent metabolic disease at scale. Primary prevention in at-risk populations is now achievable through AI-driven risk assessment, early detection using biomarkers and continuous glucose monitoring, and personalized lifestyle interventions. AI-powered platforms have demonstrated efficacy comparable to human-led diabetes prevention program (DPP) interventions, enabling tailored coaching, risk stratification, and remote engagement for populations with obesity, prediabetes, or metabolic syndrome. Digital phenotyping and AI analysis allow segmentation by metabolic subphenotype, supporting optimized, cost-effective allocation of GLP-1 therapy and ancillary preventive resources [55,62].

Secondary Prevention and Cardiorenal Protection are equally enhanced. GLP-1 receptor agonists not only reduce the risk of major cardiovascular events but confer renal benefits, lower hepatic steatosis, and support weight loss-driven reversal of cardiometabolic risk factors including hypertension and dyslipidemia. AI health tech can facilitate ongoing monitoring of cardiovascular, kidney, and metabolic parameters, automate dose titration and side effect management, and deliver data-driven outreach to support medication adherence and timely intervention for individuals at highest risk. Generative AI models can further streamline clinical and administrative workflows for GLP-1 management, driving improved health outcomes while reducing provider burden [63,64].

Future directions: Innovation and Personalized Medicine

Next-Generation Multi-Agonists and Extended-Duration Formulations

Recent advances have propelled the development of next-generation multi-agonists such as dual (GIP/GLP-1) and triple (GIP/GLP-1/glucagon) receptor agonists. These agents deliver enhanced metabolic and hepatic benefits, including greater weight loss and liver fat reduction, primarily due to synergistic effects and optimized receptor targeting. Chemical modifications, like extended fatty acid acylation (C18, C20), have enabled once-weekly or even longer dosing, improving convenience, adherence, and efficacy beyond current GLP-1 therapies [65].

Precision Medicine Through Metabolic Subphenotyping

Precision approaches driven by high-resolution continuous glucose monitoring (CGM) and machine learning enable early identification of metabolic subphenotypes, distinguishing muscle insulin resistance from β-cell dysfunction, for tailored intervention. AI models leveraging dynamic glucose responses can offer superior risk stratification over conventional biomarkers, supporting personalized preventive treatment and efficient resource allocation [55].

Challenges and Research Gaps

Despite these advances, several key challenges remain. Research gaps include optimizing dosing strategies for long-term safety, minimizing muscle mass loss during weight reduction, monitoring for rare side effects, and ensuring equitable access to these novel agents amid high costs. Further studies are needed to clarify patient selection, outcomes across diverse populations, and integration of new delivery systems. Robust real-world evidence and longer follow-up are critical to fully define the impact, safety, and sustainability of these innovations [66].

Conclusion

The landscape of metabolic disease prevention is entering an era defined by precision medicine, technological innovation, and integrated care. Advances in GLP-1 receptor agonist, from tailored short, intermediate, and long-acting agents to powerful new multi-agonist therapies, provide sustained improvements in glycemic control, weight management, and risk reduction for cardiovascular and renal disease across diverse populations.

Crucially, these pharmacologic innovations are now synergized by digital health platforms, artificial intelligence, and continuous monitoring tools. AI-driven diagnostics, metabolic phenotyping via continuous glucose monitoring, and real-time behavioural feedback fundamentally alter early detection, patient engagement, and therapy optimization. As a result, prevention programs can shift from a reactive, complication-focused paradigm to a proactive model that targets insulin resistance, inflammation, and vascular health before overt disease manifests.

Real-world evidence underscores the importance of adherence, with reduced dosing frequency, patient-friendly delivery systems, and the emergence of oral and depot formulations improving persistence and clinical outcomes. For AI health tech companies, this convergence offers new avenues for scalable, personalized interventions, risk stratification, and population level impact.

Nonetheless, challenges remain in ensuring equitable access, long-term safety, and personalized treatment allocation, while minimizing rare side effects and preserving muscle mass during aggressive weight loss. Addressing these gaps will require ongoing research robust real-world data, and multidisciplinary collaboration.

Ultimately, precision metabolic wellness is no longer an aspirational goal but an actionable reality, achieved through the seamless integration of advanced pharmacology and technology tailored to individual risk profiles, and delivered within a holistic, patient-centred framework. This transformation promises lasting improvements in population health, clinical outcomes, and the management of metabolic disease at scale.

References

  1. Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, et al. Glucagon-like peptide-1 receptor: Mechanisms and advances in therapy [Internet]. Nature Publishing Group; 2024 [cited 2025 Nov 25]. Available from: https://www.nature.com/articles/s41392-024-01931-z
  2. Graaf C de, Donnelly D, Wootten D, Lau J, Sexton PM, Miller LJ, et al. Glucagon-like peptide-1 and its class B G protein-coupled receptors: A long march to therapeutic successes [Internet]. U.S. National Library of Medicine; 2016 [cited 2025 Nov 25]. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC5050443/
  3. Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, et al. GLP-1 receptor agonists: Beyond their pancreatic effects. Frontiers in Endocrinology. 2021 Aug 23;12. doi:10.3389/fendo.2021.721135
  4. Buteau J. GLP-1 signaling and the regulation of pancreatic β-cells mass/function. Avances en Diabetología. 2011 Jan;27(1):3–8. doi:10.1016/s1134-3230(11)70002-3
  5. Song R, Qian H, Wang Y, Li Q, Li D, Chen J, et al. Research progress on the cardiovascular protective effect of glucagon-like peptide-1 receptor agonists. Journal of Diabetes Research. 2022 Apr 8;2022:1–8. doi:10.1155/2022/4554996
  6. Shigeto M, Kaku K. Are both protein kinase a‐ and protein kinase c‐dependent pathways involved in glucagon‐like peptide‐1 action on pancreatic insulin secretion? Journal of Diabetes Investigation. 2014 Apr 2;5(4):347–8. doi:10.1111/jdi.12225
  7. A; SAGN. Therapeutic stimulation of GLP-1 and GIP protein with DPP-4 inhibitors for type-2 diabetes treatment [Internet]. U.S. National Library of Medicine; [cited 2025 Nov 25]. Available from: https://pubmed.ncbi.nlm.nih.gov/26473146/
  8. Sharma A, Paliwal G, Upadhyay N, Tiwari A. Retracted article: Therapeutic stimulation of GLP-1 and GIP protein with DPP-4 inhibitors for type-2 diabetes treatment. Journal of Diabetes & Metabolic Disorders. 2015 Mar 19;14(1). doi:10.1186/s40200-015-0143-4
  9. Gupta V. Glucagon-like peptide-1 analogues: An overview. Indian Journal of Endocrinology and Metabolism. 2013;17(3):413. doi:10.4103/2230-8210.111625
  10. Collins L. Glucagon-like peptide-1 receptor agonists [Internet]. U.S. National Library of Medicine; 2024 [cited 2025 Nov 25]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551568/
  11. Knudsen LB, Lau J. The discovery and development of liraglutide and semaglutide [Internet]. Frontiers; 2025 [cited 2025 Nov 25]. Available from: https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00155/full
  12. DeYoung MB, MacConell L, Sarin V, Trautmann M, Herbert P. Encapsulation of exenatide in poly-(D,L-Lactide-Co-Glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technology & Therapeutics. 2011 Nov;13(11):1145–54. doi:10.1089/dia.2011.0050
  13. Min JS, Jo SJ, Lee S, Kim DY, Kim DH, Lee CB, et al. A comprehensive review on the pharmacokinetics and drug−drug interac: DDDT [Internet]. Dove Press; 2025 [cited 2025 Nov 25]. Available from: https://www.dovepress.com/a-comprehensive-review-on-the-pharmacokinetics-and-drugdrug-interactio-peer-reviewed-fulltext-article-DDDT
  14. Latif W. Compare and contrast the glucagon-like peptide-1 receptor agonists (GLP1RAS) [Internet]. U.S. National Library of Medicine; 2024 [cited 2025 Nov 25]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK572151/
  15. Uccellatore A, Genovese S, Dicembrini I, Mannucci E, Ceriello A. Comparison Review of short-acting and long-acting glucagon-like peptide-1 receptor agonists. Diabetes Therapy. 2015 Aug 14;6(3):239–56. doi:10.1007/s13300-015-0127-x
  16. Cirincione B, Mager DE. Population pharmacokinetics of exenatide. British Journal of Clinical Pharmacology. 2016 Nov 16;83(3):517–26. doi:10.1111/bcp.13135
  17. Knop FK, Brønden A, Vilsbøll T. Exenatide: Pharmacokinetics, clinical use, and Future Directions. Expert Opinion on Pharmacotherapy. 2017 Mar 22;18(6):555–71. doi:10.1080/14656566.2017.1282463
  18. Kim D, MacConell L, Zhuang D, Kothare PA, Trautmann M, Fineman M, et al. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care. 2007 Jun 1;30(6):1487–93. doi:10.2337/dc06-2375
  19. Schwartz SL, Ratner RE, Kim DD, Qu Y, Fechner LL, Lenox SM, et al. Effect of exenatide on 24-hour blood glucose profile compared with placebo in patients with type 2 diabetes: A randomized, double-blind, two-arm, parallel-group, placebo-controlled, 2-week study. Clinical Therapeutics. 2008 May;30(5):858–67. doi:10.1016/j.clinthera.2008.05.004
  20. Becker RH, Stechl J, Steinstraesser A, Golor G, Pellissier F. Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects. Diabetes/Metabolism Research and Reviews. 2015 Apr 23;31(6):610–8. doi:10.1002/dmrr.2647
  21. [Internet]. [cited 2025 Nov 25]. Available from: https://diabetesjournals.org/care/article/43/9/2303/35949/Efficacy-and-Safety-of-Short-and-Long-Acting
  22. Press D. Dove Medical Press – open access publisher of Medical Journals [Internet]. [cited 2025 Nov 25]. Available from: https://www.dovepress.com/
  23. [Internet]. [cited 2025 Nov 25]. Available from: https://diabetesjournals.org/care/article/43/8/1813/35580/Effects-of-Sustained-Treatment-With-Lixisenatide
  24. Werner U. Effects of the GLP-1 receptor agonist lixisenatide on postprandial glucose and gastric emptying – preclinical evidence. Journal of Diabetes and its Complications. 2014 Jan;28(1):110–4. doi:10.1016/j.jdiacomp.2013.06.003
  25. Guo X-H. The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: Experience with exenatide. Current Medical Research and Opinion. 2015 Nov 11;32(1):61–76. doi:10.1185/03007995.2015.1103214
  26. Zhang L, Zhang M, Zhang Y, Tong N. Efficacy and safety of dulaglutide in patients with type 2 diabetes: A meta-analysis and systematic review [Internet]. Nature Publishing Group; 2016 [cited 2025 Nov 25]. Available from: https://www.nature.com/articles/srep18904
  27. Trujillo JM, Nuffer W, Smith BA. GLP-1 receptor agonists: An updated review of head-to-head clinical studies. Therapeutic Advances in Endocrinology and Metabolism. 2021 Jan;12. doi:10.1177/2042018821997320
  28. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: A 26-week randomised, parallel-group, multinational, open-label trial (lead-6). The Lancet. 2009 Jul;374(9683):39–47. doi:10.1016/s0140-6736(09)60659-0
  29. Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists. Diabetes Care. 2011 Apr 22;34(Supplement_2). doi:10.2337/dc11-s231
  30. Rayner CK, Watson LE, Phillips LK, Lange K, Bound MJ, Grivell J, et al. Effects of sustained treatment with lixisenatide on gastric emptying and postprandial glucose metabolism in type 2 diabetes: A randomized controlled trial. Diabetes Care. 2020 May 29;43(8):1813–21. doi:10.2337/dc20-0190
  31. Barnett A. Lixisenatide: Evidence for its potential use in the treatment of type 2 diabetes. Core Evidence. 2011 Sept;67. doi:10.2147/ce.s15525
  32. Jalleh RJ, Plummer MP, Marathe CS, Umapathysivam MM, Quast DR, Rayner CK, et al. Clinical consequences of delayed gastric emptying with GLP-1 receptor agonists and Tirzepatide. The Journal of Clinical Endocrinology & Metabolism. 2024 Oct 17;110(1):1–15. doi:10.1210/clinem/dgae719
  33. Cerillo JL. Liraglutide [Internet]. U.S. National Library of Medicine; 2024 [cited 2025 Nov 25]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK608007/
  34. Alruwaili H, Dehestani B, le Roux CW. Clinical impact of liraglutide as a treatment of obesity. Clinical Pharmacology: Advances and Applications. 2021 Mar;Volume 13:53–60. doi:10.2147/cpaa.s276085
  35. Flint A, Nazzal K, Jagielski P, Hindsberger C, Zdravkovic M. Influence of hepatic impairment on pharmacokinetics of the human GLP‐1 analogue, liraglutide. British Journal of Clinical Pharmacology. 2010 Nov 11;70(6):807–14. doi:10.1111/j.1365-2125.2010.03762.x
  36. Huthmacher JA, Meier JJ, Nauck MA. Efficacy and safety of short- and long-acting glucagon-like peptide 1 receptor agonists on a background of basal insulin in type 2 diabetes: A meta-analysis. Diabetes Care. 2020 Aug 11;43(9):2303–12. doi:10.2337/dc20-0498
  37. Kalayci A, Januzzi JL, Mitsunami M, Tanboga IH, Karabay CY, Gibson CM. Clinical features modifying the cardiovascular benefits of GLP-1 receptor agonists: A systematic review and meta-analysis. European Heart Journal – Cardiovascular Pharmacotherapy. 2025 Aug 31;11(6):552–61. doi:10.1093/ehjcvp/pvaf037
  38. Yao H, Zhang A, Li D, Wu Y, Wang C-Z, Wan J-Y, et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: Systematic review and network meta-analysis [Internet]. British Medical Journal Publishing Group; 2024 [cited 2025 Nov 25]. Available from: https://doi.org/10.1136/bmj-2023-076410
  39. Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, et al. Efficacy and safety of once-weekly semaglutide versus exenatide er in subjects with type 2 diabetes (sustain 3): A 56-week, open-label, Randomized Clinical Trial. Diabetes Care. 2017 Dec 15;41(2):258–66. doi:10.2337/dc17-0417
  40. Alorfi NM, Algarni AS. Clinical impact of semaglutide, a glucagon-like peptide-1 receptor agonist, on obesity management: A Review. Clinical Pharmacology: Advances and Applications. 2022 Aug;Volume 14:61–7. doi:10.2147/cpaa.s374741
  41. Mahapatra MK, Karuppasamy M, Sahoo BM. SEMAGLUTIDE, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes. Reviews in Endocrine and Metabolic Disorders. 2022 Jan 7;23(3):521–39. doi:10.1007/s11154-021-09699-1
  42. Dungan KM, Weitgasser R, Perez Manghi F, Pintilei E, Fahrbach JL, Jiang HH, et al. A 24‐week study to evaluate the efficacy and safety of once‐weekly dulaglutide added on to glimepiride in type 2 diabetes ( award ‐8). Diabetes, Obesity and Metabolism. 2016 Feb 19;18(5):475–82. doi:10.1111/dom.12634
  43. Giorgino F, Benroubi M, Sun J-H, Zimmermann AG, Pechtner V. Efficacy and safety of once-weekly Dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin and Glimepiride (award-2). Diabetes Care. 2015 Jun 18;38(12):2241–9. doi:10.2337/dc14-1625
  44. Ge Y, Hu Z, Chen J, Qin Y, Wu F, Jin T. Exenatide microspheres for monthly controlled-release aided by magnesium hydroxide. Pharmaceutics. 2021 May 30;13(6):816. doi:10.3390/pharmaceutics13060816
  45. Li Y, Vaughan KL, Tweedie D, Jung J, Kim HK, Choi H-I, et al. Pharmacokinetics of exenatide in nonhuman primates following its administration in the form of sustained-release PT320 and bydureon [Internet]. Nature Publishing Group; 2019 [cited 2025 Nov 25]. Available from: https://www.nature.com/articles/s41598-019-53356-2
  46. Willard FS, Douros JD, Gabe MBN, Showalter AD, Wainscott DB, Suter TM, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist [Internet]. American Society for Clinical Investigation; 2020 [cited 2025 Nov 25]. Available from: https://insight.jci.org/articles/view/140532/version/1
  47. a V;Koutsopoulos G;Fragoulis C;Dimitriadis K;Tsioufis K; Retatrutide-a game changer in obesity pharmacotherapy [Internet]. U.S. National Library of Medicine; [cited 2025 Nov 25]. Available from: https://pubmed.ncbi.nlm.nih.gov/40563436/
  48. El K, Douros JD, Willard FS, Novikoff A, Sargsyan A, Perez-Tilve D, et al. The incretin co-agonist TIRZEPATIDE requires GIPR for hormone secretion from human islets [Internet]. Nature Publishing Group; 2023 [cited 2025 Nov 25]. Available from: https://www.nature.com/articles/s42255-023-00811-0
  49. Farzam K. Tirzepatide [Internet]. U.S. National Library of Medicine; 2024 [cited 2025 Nov 25]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK585056/
  50. Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: A randomized phase 2A trial [Internet]. Nature Publishing Group; 2024 [cited 2025 Nov 25]. Available from: https://www.nature.com/articles/s41591-024-03018-2
  51. [Internet]. [cited 2025 Nov 25]. Available from: https://www.researchgate.net/publication/351163114_httpswwwsciencedirectcomsciencearticleabspiiS1051200421000968
  52. Buy reta GLP-3 + CJC-1295 no DAC + ipamorelin: GH Research Stack [Internet]. 2025 [cited 2025 Nov 25]. Available from: https://bioedgeresearchlabs.com/product/buy-reta-glp3-12mg-cjc-1295-no-dac-10mg-ipamorelin-10mg/
  53. Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. The Lancet Diabetes & Endocrinology. 2019 Oct;7(10):776–85. doi:10.1016/s2213-8587(19)30249-9
  54. [Internet]. [cited 2025 Nov 25]. Available from: https://diabetesjournals.org/care/article-abstract/48/5/846/158048/Cardiovascular-and-Kidney-Outcomes-and-Mortality?redirectedFrom=fulltext
  55. Metwally AA, Perelman D, Park H, Wu Y, Jha A, Sharp S, et al. Prediction of metabolic subphenotypes of type 2 diabetes via continuous glucose monitoring and machine learning [Internet]. Nature Publishing Group; 2024 [cited 2025 Nov 25]. Available from: https://www.nature.com/articles/s41551-024-01311-6
  56. Ji C, Jiang T, Liu L, Zhang J, You L. Continuous glucose monitoring combined with Artificial Intelligence: Redefining the pathway for Prediabetes Management [Internet]. Frontiers; 2025 [cited 2025 Nov 25]. Available from: https://doi.org/10.3389/fendo.2025.1571362
  57. Kostev K, Ouwens M, Grandy S, Johnsson KM, Qiao Q. Adherence to GLP-1 receptor agonist therapy administered by once-daily or once-weekly injection in patients with type 2 diabetes in Germany. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2016 Jun;Volume 9:201–5. doi:10.2147/dmso.s99732
  58. Weeda ER, Muraoka AK, Brock MD, Cannon JM. Medication adherence to injectable glucagon‐like peptide‐1 (GLP‐1) receptor agonists dosed once weekly VS once daily in patients with type 2 diabetes: A meta‐analysis. International Journal of Clinical Practice. 2021 Feb 16;75(9). doi:10.1111/ijcp.14060
  59. López MB, Babkowski MC, Ruiz RC, Cuenca AC, Fernández MG, Paz HD de, et al. Barriers and strategies to optimize the use of glucagon-like peptide 1 receptor agonists in people with type 2 diabetes and high cardiovascular risk or established cardiovascular disease: A Delphi consensus in Spain – advances in therapy [Internet]. Springer Healthcare; 2024 [cited 2025 Nov 25]. Available from: https://link.springer.com/article/10.1007/s12325-024-02938-2
  60. Öngoren B, Kara A, Serrano DR, Lalatsa A. Novel enabling strategies for Oral Peptide Delivery. International Journal of Pharmaceutics. 2025 Aug;681:125888. doi:10.1016/j.ijpharm.2025.125888
  61. Marino D. Formulation development – innovative drug delivery approaches for GLP-1 agonists: Enhancing medication adherence & treatment outcomes [Internet]. 2025 [cited 2025 Nov 25]. Available from: https://drug-dev.com/formulation-development-innovative-drug-delivery-approaches-for-glp-1-agonists-enhancing-medication-adherence-treatment-outcomes/
  62. Clarós A, Ciudin A, Muria J, Llull L, Mola JÀ, Pons M, et al. A model based on artificial intelligence for the prediction, prevention and patient-centred approach for non-communicable diseases related to metabolic syndrome. European Journal of Public Health. 2025 Jul 3;35(4):642–9. doi:10.1093/eurpub/ckaf098
  63. Stevens ER, Elmaleh-Sachs A, Lofton H, Mann DM. Lightening the load: Generative AI to mitigate the burden of the new era of Obesity Medical therapy. JMIR Diabetes. 2024 Nov 14;9. doi:10.2196/58680
  64. Apperloo EM, Heerspink HJ, van Raalte DH, Muskiet MH. GLP-1-based therapeutics for cardiorenal protection in metabolic diseases. Nephrology Dialysis Transplantation. 2025 Jun 25; doi:10.1093/ndt/gfaf110
  65. Knerr PJ, Mowery SA, Douros JD, Premdjee B, Hjøllund KR, He Y, et al. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Molecular Metabolism. 2022 Sept;63:101533. doi:10.1016/j.molmet.2022.101533
  66. Scragg J, Koutoukidis DA, Dirksen C, Heitmann BL, Jebb SA. The societal implications of using glucagon-like peptide-1 receptor agonists for the treatment of obesity. Med. 2025 Sept;6(9):100805. doi:10.1016/j.medj.2025.100805