Liraglutide

Abstract

Peptide-based therapeutics represent a rapidly expanding class of drugs. Endogenous peptides typically exhibit short elimination half-lives due to proteolytic cleavage and renal filtration. However, modifications such as amino acid substitutions and fatty-acid conjugation can significantly prolong their half-lives, enabling, for example, once weekly dosing. This study revisits the systemic pharmacokinetics of peptide drugs using classical pharmacokinetic principles and elucidates the scaling of peptide pharmacokinetics across species.

Abstract

Beyond the metabolic effects induced by long- and short-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, they modulate reward-related behaviors by acting on brain regions including lateral septum (LS) and neural pathways involving the nucleus tractus solitarii (NTS). While the short-acting GLP-1R agonist exendin-4 (Ex-4) reduces sexual behaviors in sexually naïve male mice, the effects of long- versus short-acting GLP-1R agonists on natural rewards, such as sexual and social behaviors, in females remain unexplored. In the current study, we investigate the effects of both long-acting (dulaglutide, liraglutide) and short-acting (Ex-4) GLP-1R agonists on sexual and social behaviors in sexually experienced female rats and mice. While the GLP-1R agonists decreased sexual behaviors in females, they appear to be drug- and species-specific. In female rats, Ex-4 reduced the time with the males, the number of mounts, intromissions, ejaculations, darts and hops, as well as the lordosis intensity. Female mice treated with liraglutide and dulaglutide display a reduction in time with male stimulatory mouse, and as a possible consequence, a lowered mounting and intromission duration, potentially involving increased noradrenaline levels in the NTS and altered glutamate, glutamine, and taurine levels in the LS. In the three-chamber test, dulaglutide decreased the social novelty, another behavior associated with reward/motivation. Moreover, the long-acting GLP-1R agonists increased sociability and the time to seek a novel object. These results highlight species-dependent and agonist-specific effects of GLP-1R activation on sexual and social function in females and expands our understanding of the broader role of GLP-1.

Abstract

Patients with concurrent obesity, type 2 diabetes, and depression experience high disease severity and prevalence. This triad of conditions compromises quality of life and treatment adherence, further exacerbating disease progression. Therapeutic strategies for such patients must address both glycemic control and psychological well-being. Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), offers benefits beyond glucose-lowering and weight reduction, with emerging evidence suggesting it may also alleviate depressive symptoms. Therefore, liraglutide represents a promising intervention for managing depression in patients with obesity and diabetes.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used in patients with chronic kidney disease (CKD), but existing evidence regarding their efficacy and safety remains inconsistent. To evaluate the cardiorenal outcomes and adverse effects of GLP-1 RAs in this population, we conducted a systematic review and meta-analysis of randomized controlled trials from PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science up to December 2024. Nine trials involving 21,717 patients, the vast majority of whom had T2DM, were included. GLP-1RAs treatment for CKD was associated with decreasing the incidence of major adverse kidney events (MAKE; RR, 0.84; 95% CI, 0.76-0.94) and major adverse cardiac and cerebrovascular events (MACE; RR, 0.84; 95% CI, 0.72-0.97), reducing all-cause mortality (RR, 0.83; 95% CI, 0.76-0.90) and albuminuria level (SMD, -1.22; 95% CI, -1.53 - 0.90). Gastrointestinal events associated with GLP-1 RA treatments including nausea (RR, 4.14; 95% CI, 2.70-6.33), vomiting (RR, 3.05; 95% CI, 1.88-4.97), diarrhea (RR, 2.65; 95% CI, 1.76-3.98), and dyspepsia (RR, 3.79; 95% CI, 1.02-14.12) have garnered significant attention. In conclusion, administration of GLP-1RAs treatment demonstrates excellent cardiorenal protective effects in CKD, primarily in patients with co-existing T2DM, though with notable gastrointestinal concerns.

Abstract

Fatty infiltration (FI) and muscle atrophy following rotator cuff (RC) tears are largely irreversible and are major determinants of poor surgical outcomes, increased re-tear risk, and long-term functional disability. No pharmacologic therapies have been validated to prevent or reverse these degenerative changes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including liraglutide, have demonstrated anti-adipogenic and tissue-preserving effects in other organ systems, suggesting potential application in RC-related muscle degeneration.

Abstract

This meta-analysis evaluates the safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RA) for the treatment of older adults with obesity compared to younger individuals.

Abstract

Recent research has challenged the viewpoint that pancreatic islets operate independently of surrounding exocrine tissues, revealing a bidirectional blood flow between the endocrine and exocrine pancreas. However, a methodology for simultaneous evaluation of pancreatic microhemodynamics and oxygen profiles remains elusive.

Abstract

Endothelial dysfunction is a hallmark of type 2 diabetes mellitus (T2DM) and a major contributor to cardiovascular complications. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemic control and cardiovascular outcomes, the mechanisms linking GLP-1RA therapy, gut microbiome modulation, and endothelial function remain incompletely understood. In this study, we investigated whether the GLP-1RA liraglutide improves endothelial dysfunction in T2DM through microbiome-associated mechanisms that support vascular homeostasis. Male db/db mice and non-diabetic controls were treated with liraglutide (300 μg/kg/day, intraperitoneally) or saline for two weeks. Vascular function was assessed in mesenteric resistance arteries using wire myography. Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose with or without liraglutide or the short chain fatty acid (SCFA), butyrate. Endothelial nitric oxide (NO) signaling was evaluated by eNOS (at Ser1177) phosphorylation and nitrite production. Gut microbiota composition was analyzed by 16S rRNA gene sequencing. Liraglutide significantly improved endothelium-dependent relaxation in db/db mice and restored high glucose-induced impairment of eNOS phosphorylation and NO production in HUVECs. In vivo, diabetes was associated with marked gut dysbiosis characterized by reduced alpha diversity and depletion of SCFA-producing taxa. Liraglutide treatment substantially restored microbial diversity and enriched beneficial genera, including Lachnospiraceae and Lactobacillus. Consistently, low-dose butyrate modestly enhanced NO production in endothelial cells. These findings support the concept of a GLP-1RA-microbiome-vascular axis, in which liraglutide-associated remodeling of the gut microbiota may contribute to improved endothelial NO signaling and vascular function in diabetes.

Abstract

Psoriasis and obesity often occur together, with up to 50% of patients with psoriasis being classified as obese. This increases systemic inflammation, cardiovascular risk, and disease severity while reducing the efficacy of biologic treatments. Despite this overlap, dermatology lacks obesity-specific guidance. This review evaluates lifestyle, pharmacological (glucagon-like peptide 1 receptor agonists [GLP-1 RAs] and tirzepatide) and surgical strategies, as well as clinic-level algorithms, to inform dermatological practice.

Abstract

Pulmonary delivery provides a noninvasive route for systemic administration of biologics, yet efficient lung deposition and permeation across pulmonary barriers remain major challenges. In this study, morphology-engineered zinc oxide (ZO) biointeractive carriers were fabricated and evaluated as inhalable carriers for liraglutide (LG). Three distinct morphologies were obtained: smooth spherical ZO-1 (5-7 μm), spiky sea-urchin-like ZO-2 (5-8 μm with elongated ~ 3.5 μm tips), and compact spiky ZO-3 (1-3 μm with short ~ 1.3 μm tips). Particle image velocimetry (PIV) revealed morphology-dependent aerodynamic behaviors, where ZO-3 exhibited turbulence-driven dispersion favoring distal lung deposition. At the cellular level, ZO-3 demonstrated enhanced mucus penetration and reduced macrophage uptake, maintaining prolonged contact with the epithelial surface. Following intratracheal administration, LG@ZO-3 achieved bioavailability of ~ 60% relative to subcutaneous injection in healthy rats and ~ 51% in diabetic rats, far exceeding the < 2% oral bioavailability of semaglutide. These results suggest that morphology-controlled modulation of aerodynamic and biological interactions can overcome multiple pulmonary barriers, offering a promising strategy for effective inhalable delivery of peptide therapeutics.

Abstract

To explore the relevant mechanisms and principles by which liraglutide alleviates sepsis-associated encephalopathy (SAE) through reducing neuronal injury, glial cell activation and mitochondrial dysfunction.

Abstract

ObjectiveThis systematic review and meta-analysis evaluated the efficacy, acceptability, and tolerability of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in individuals with severe mental illness (SMI).MethodsPubMed, Embase, the Cochrane Library, Google Scholar, and ClinicalTrials.gov were searched on December 1, 2025, for randomized controlled trials (RCTs) of GLP-1RAs in participants with SMI. Primary outcomes were weight reduction, glycated hemoglobin (HbA1c) reduction, all-cause dropouts, and adverse-effect dropouts. Mean differences (MDs) and risk ratios (RRs) were estimated using a frequentist random-effects model.ResultsIncluded were 10 RCTs (N = 665) of exenatide, liraglutide, and semaglutide. Participants were those with schizophrenia, schizophrenia-spectrum disorders, or bipolar disorder with cardiometabolic risk. Compared with placebo/usual care, GLP-1RAs significantly reduced weight (MD = -6.17 kg, 95% CI: -9.10 to -3.25, I2 = 91.8%, 9 trials) and HbA1c (MD = -0.31%, 95% CI: -0.40 to -0.22, I2 = 51.3%, 8 trials). All-cause dropouts did not differ significantly between groups (RR = 0.98, 95% CI: 0.71 to 1.35, I2 = 28.5%, 10 trials), nor did adverse-effect dropouts (RR = 0.99, 95% CI: 0.35 to 2.77, I2 = 31.6%, 5 trials). Low-certainty evidence supports the tolerability and efficacy of GLP-1RAs for weight and HbA1c reduction. Moderate-certainty evidence also supports their acceptability.ConclusionLimited evidence suggests that GLP-1RAs may reduce body weight and slightly reduce HbA1c in individuals with SMI who have prediabetes or are overweight/obese. GLP-1RAs are likely acceptable and may be tolerated in this population.

Abstract

Alzheimer's disease (AD) is a neurodegenerative condition characterised by amyloid-β pathology, neuroinflammation, synaptic dysfunction and cognitive decline. Few pharmacological interventions are available, offering only symptomatic relief, and approval for a number of anti-amyloid biologics is limited, with concerns about safety, cost and efficacy. Here we investigated the effects of 8-10 weeks treatment with liraglutide, NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL], long-lasting analogues of gut hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and xenin-25, respectively, in the APP/PS1 mouse model of AD. Cognitive function was measured in novel object recognition (NOR) and Morris water maze (MWM) tasks and amyloid burden, gliosis, synapse density and neurogenesis were assessed in brains of APP/PS1 and wild-type mice. AD-associated gene expression analysis was performed to identify potential pathways targeted by treatment. Liraglutide and NAcGIP[Lys(37)PAL] improved cognitive performance in APP/PS1 mice and, along with Xenin-25[Lys(13)PAL], reduced amyloid-β burden in the brain. Liraglutide ameliorated gliosis and all three treatments restored synaptophysin levels. Additionally, Xenin-25[Lys(13)PAL] increased neurogenesis in the dentate gyrus. Numerous AD-associated genes were altered in the brain following treatments. Notably, Serpina3c was upregulated in brains of APP/PS1 mice treated with liraglutide, NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL], while Map2, Adam9, Lrp8, Casp3, Abca1 and App were downregulated. These results underscore the neuroprotective effects of liraglutide and suggest that NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL] possess neuroprotective properties. Further investigation of the precise nature of these effects may support development of multi-target therapeutics based on combinations of gut hormone analogues.

Abstract

Obesity is a complex, multifactorial disease that contributes to a broad range of cardiometabolic, reproductive, and psychological disorders. Representing a major global health challenge, obesity can be addressed by lifestyle modifications such as reduced calorie intake, physical activity, adequate sleep, and stress management to help achieve sustainable weight loss and improve metabolic health in the long term. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two naturally produced incretin hormones in the gastrointestinal tract. Incretin analogues were initially approved for type 2 diabetes mellitus but were later found to exhibit weight-reducing properties. Liraglutide, semaglutide, and tirzepatide are the three incretin analogues approved for obesity in non-diabetic patients. This narrative review presents detailed comparisons of the three approved incretin analogues for obesity, their cost-effectiveness, and trends in the clinical setting.

Abstract

Oral administration of peptide-based drugs offers improved patient compliance compared to injectable formulations. However, this route is hindered by several physiological barriers like enzymatic degradation, poor intestinal permeability, and low absorption in the gastrointestinal tract. To address these challenges, a novel virus-mimicking nanocarrier was developed for the oral delivery of liraglutide. Hollow mesoporous silica nanoparticles (HMSN) were synthesized via a co-condensation method and subsequently functionalized with a positively charged cell-penetrating peptide (CPP; KLPVM) to facilitate transcellular transport, and with negatively charged hyaluronic acid (HA) to enhance mucus penetration and enable receptor-mediated targeting. Liraglutide was efficiently encapsulated within HMSN matrix, achieving an encapsulation efficiency of 96.16% and a drug loading of 19.23%. In vitro release studies showed pH-responsive behavior, with limited release under acidic gastric conditions (7%) and sustained release at near-neutral intestinal pH (77% over 12 h). Cellular uptake studies revealed enhanced internalization of the HMSN-CPP@HA (98.1%), predominantly via caveolae-mediated endocytosis. Ex vivo intestinal permeability studies further confirmed improved transmucosal transport, with permeability increasing from 34.4% for MSNs to 97.6% for HMSN-CPP@HA. Pharmacodynamic evaluation in streptozotocin-induced diabetic rat models showed that oral administration of liraglutide-loaded virus-mimicking HMSNs resulted in a 50.98% reduction in fasting blood glucose and a 14.6% decrease in body weight over 28-day period. These outcomes were comparable to those achieved via subcutaneous liraglutide administration (62.7% and 19.2% respectively). These findings suggest that HMSN-CPP@HA preserve the biological activity of liraglutide during gastrointestinal transit, enhance intestinal absorption, and mimic viral translocation mechanisms, representing a promising platform for non-invasive oral delivery of peptide drugs.

Abstract

Patients with diabetes and a history of major adverse limb events (MALEs) are at an increased risk of cardiovascular and limb-related complications; however, effective glucose-lowering therapies for secondary prevention in this population are limited.

Abstract

Aging and insulin resistance are intertwined factors in the development of metabolic diseases such as type 2 diabetes and cardiovascular disorders. Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown promising cardioprotective effects in preclinical and clinical studies of metabolic diseases. Yet, its action on insulin-resistant aged subjects is not clearly defined. This study aimed to investigate the effects of liraglutide on intracellular zinc levels, including its modulation of oxidative stress, mitochondrial function, and Endoplasmic Reticulum (ER) stress in a novel insulin-resistant senescent model. Insulin resistance and senescence were confirmed by reduced glucose uptake and increased β-Galactosidase Staining and increased p-H2A.X (Ser139) levels after 24 h of co-incubation with bovine serum albumin (BSA) conjugated palmitic acid (PA; 50 µM) and 278 mM D-galactose (D-Gal) in human AC16 cells. Our findings showed upregulated expression of ER and mitochondrial proteostasis markers in the early minutes of liraglutide treatment. In addition, chronic but not acute liraglutide treatment significantly increased intracellular zinc levels, accompanied by improved mitochondrial membrane potential and reduced reactive oxygen species in the insulin-resistant senescent model. Casein kinase 2 inhibition completely abolished liraglutide-induced zinc elevation and mitochondrial improvements in the chronic context, highlighting the role of casein kinase 2 in the subcellular signaling of liraglutide. These findings indicate that liraglutide alters intracellular zinc and modulates endoplasmic reticulum-mitochondria communication, giving insight into its therapeutic potential in metabolic cardiomyopathies linked to insulin resistance and aging.

Abstract

Background/Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exhibit neuroprotective properties in preclinical models of Alzheimer's disease (AD), reducing amyloid accumulation, neuroinflammation, and insulin resistance within the brain. However, clinical evidence regarding their cognitive effects in AD and mild cognitive impairment (MCI) remains inconclusive. To evaluate the effects of GLP-1 RAs on cognitive outcomes in patients with AD or MCI due to AD. Methods: A systematic review was conducted according to PRISMA 2020 and registered in PROSPERO (CRD420251143171). Although the original registry was broad, the identification of a small set of homogeneous randomized controlled trials (RCTs) during screening, prior to data extraction, allowed for a random-effects meta-analysis of cognitive outcomes. RCTs enrolling adults with clinically or biomarker-confirmed AD or MCI were included. Interventions comprised liraglutide or exenatide compared with placebo. Standardized mean differences (SMD) in global cognitive scores were pooled using a random-effects model (restricted maximum likelihood [REML] estimator with Hartung-Knapp adjustment). Results: Three randomized trials (n = 278 participants; 51% women; mean age 68 ± 7 years) met inclusion criteria. Treatment duration ranged from 26 weeks to 18 months. Pooled analysis revealed no significant effect of GLP-1 RAs on global cognition compared with placebo -0.21 (95% CI -0.81 to 0.38; I2 = 47%; τ2 = 3.77). Sensitivity analyses restricted to liraglutide or studies ≥ 12 months yielded similar results. Conclusions: Current randomized evidence does not support cognitive improvement with GLP-1 RAs in AD or MCI.

Abstract

Women of reproductive age, especially those with polycystic ovarian syndrome (PCOS), often use glucagon-like peptide-1 receptor agonists (GLP-1RAs) to improve their metabolic functions. A growing body of evidence suggests that GLP-1R signaling may directly affect ovarian physiology, influencing granulosa cell proliferation, survival pathways, and steroidogenic production, in addition to its systemic metabolic effects. Nonetheless, there is a limited comprehension of the molecular mechanisms that regulate these activities and their correlation with menstrual function, reproductive potential, and assisted reproduction. This comprehensive review focuses on ovarian biology, granulosa cell signaling networks, steroidogenesis, and translational fertility outcomes, integrating clinical, in vivo, and in vitro information to elucidate the effects of GLP-1 receptor agonists on reproductive health. We conducted a thorough search of PubMed, Scopus, and Web of Science for randomized trials, prospective studies, animal models, and cellular experiments evaluating the effects of GLP-1RA on reproductive or ovarian outcomes, in accordance with PRISMA criteria. The retrieved data included metabolic changes, androgen levels, monthly regularity, ovarian structure, granulosa cell growth and death, FOXO1 signaling, FSH-cAMP-BMP pathway activity, and fertility or IVF results. Clinical trials shown that GLP-1 receptor agonists improve menstrual regularity, decrease body weight and central adiposity, increase sex hormone-binding globulin levels, and lower free testosterone in overweight and obese women with PCOS. Liraglutide, when combined with metformin, significantly improved IVF pregnancy rates, whereas exenatide increased natural conception rates. Mechanistic studies demonstrate that GLP-1R activation affects FOXO1 phosphorylation, hence promoting granulosa cell proliferation and anti-apoptotic processes. Incretin signaling altered steroidogenesis by reducing the levels of StAR, P450scc, and 3β-HSD, so inhibiting FSH-induced progesterone synthesis, while simultaneously enhancing BMP-Smad signaling. Animal studies demonstrated both beneficial (enhanced follicular growth, anti-apoptotic effects) and detrimental results (oxidative stress, granulosa cell death, uterine inflammation), indicating a context- and dose-dependent response. GLP-1 receptor agonists influence female reproductive biology by altering overall physiological processes and specifically impacting the ovaries via FOXO1 regulation, steroidogenic enzyme expression, and BMP-mediated FSH signaling. Preliminary clinical data indicate improved reproductive function in PCOS, as seen by increased pregnancy rates in both natural and IVF cycles; nevertheless, animal studies reveal a potential risk of ovarian and endometrial damage. These results highlight the need for controlled human research to clarify reproductive safety, molecular pathways, and optimum therapy timing, particularly in non-PCOS patients and IVF settings.

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have reshaped pharmacological management of type 2 diabetes, but emerging safety signals suggest a possible association with intestinal obstruction. Because many candidates for these agents already harbor risk factors for ileus and bowel obstruction, clarifying agent- and dose-specific gastrointestinal safety is clinically important. We aimed to re-evaluate the risk of intestinal obstruction across individual GLP-1 receptor agonists and SGLT2 inhibitors, with particular attention to dose stratification. We systematically searched eight databases through 21 January 2025 to identify randomized controlled trials (RCTs) comparing GLP-1 receptor agonists or SGLT2 inhibitors with placebo or active comparators in adults. The primary outcome was incident intestinal obstruction (small or large bowel). A frequentist random-effects network meta-analysis estimated odds ratios (ORs) with 95% confidence intervals (CIs) across drugs and dose tiers; Bayesian models and surface under the cumulative ranking (SUCRA) metrics were used for sensitivity analyses and treatment ranking. Risk of bias and certainty of evidence were assessed with standard Cochrane and GRADE-adapted tools. Fifty RCTs (47 publications; 192,359 participants) met inclusion criteria. Overall, canagliflozin use was associated with a higher incidence of intestinal obstruction than control therapies (OR 2.56, 95% CI 1.01-6.49), corresponding to an absolute risk difference of 0.15% and a number needed to harm of 658. High-dose canagliflozin (300 mg/day) showed the clearest signal (OR 3.42, 95% CI 1.08-10.76). In contrast, liraglutide was associated with a lower risk of intestinal obstruction (OR 0.44, 95% CI 0.24-0.81), with an absolute risk reduction of 0.34% and a number needed to treat of 295. No other GLP-1 receptor agonist or SGLT2 inhibitor demonstrated a statistically significant increase in obstruction risk. Frequentist and Bayesian analyses yielded concordant estimates and rankings. From a randomized-trial perspective, intestinal obstruction risk is not elevated for most GLP-1 receptor agonists and SGLT2 inhibitors. A dose-dependent safety signal was observed only for high-dose canagliflozin, whereas liraglutide may confer a protective effect. These findings refine gastrointestinal safety profiles for modern antidiabetic agents and may inform perioperative bowel management, drug selection, and dose optimization in patients at risk for ileus or adhesive obstruction.

Abstract

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have advanced the treatment of type 2 diabetes mellitus (T2DM), yet their association with cancer risk remains subject of ongoing research. Chronic pancreatitis (CP) is a well-established risk factor for pancreatic cancer, yet the impact of GLP-1 RA therapy in this high-risk population is unknown. In this study, we aimed to evaluate the association between GLP-1 RA use and pancreatic cancer incidence among patients with CP, and among those with CP and T2DM. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. In the first analysis, adult patients with pre-existing CP were identified and stratified by use of a GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, lixisenatide, and albiglutide). Propensity score matching (PSM) was conducted between GLP1-RA users and non-users, matching for age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, and pancreatic cysts. Five-year incidence of pancreatic cancer was compared between GLP-1 RA users and non-users in the matched cohort between 2015 and 2025. We then restricted the cohort to patients with CP and T2DM and repeated this analysis. Results: We identified 89,596 patients with CP, including 3183 GLP-1 RA users and 86,413 non-users. After PSM, GLP-1 RA use was associated with a lower 5-year incidence of pancreatic cancer (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.30-0.80, p < 0.005). Similarly, amongst patients with CP and T2DM, GLP-1 RA use was associated with a lower 5-year incidence of pancreatic cancer (HR 0.53, 95% CI 0.31-0.91, p < 0.05). Conclusions: GLP-1 RA use was associated with a significantly reduced incidence of pancreatic cancer in all patients with CP, as well as the subpopulation with both CP and T2DM. Given the elevated cancer risk in CP, these findings suggest a potential beneficial effect of GLP-1RA use in this high-risk population. Prospective studies will be important to further analyze and confirm this potential benefit.

Abstract

Volume status management is a critical challenge in hemodialysis. Water transgression usually results from intractable polydipsia, for which there are no approved pharmacological treatments. Given the emerging evidence on the role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in modulating neurological pathways that regulate dipsogenic behavior and satiety, their use is proposed as an unprecedented therapeutic opportunity. A 66-year-old woman with end-stage renal disease (ESRD) secondary to glomerulonephritis was in a chronic hemodiafiltration program without residual diuresis. She started hemodialysis in 2017 and, in 2025, developed refractory hypervolemia driven by intractable polydipsia and interdialytic weight gain (IDWG) of 8% (6 L) on one occasion, and, on average, 5.72%. Management was severely limited by persistent baseline hypotension (90/60 mmHg) and episodes of intradialysis hemodynamic instability that prevented the achievement of dry weight. In this scenario, treatment with liraglutide (1.2 mg weekly) was initiated, resulting in a reduction in IDWG to 2.72% and a significant decrease in thirst (from 10/10 to 3/10 on an analog scale), which stabilized blood pressure and improved tolerance to the treatment. GLP-1RAs can act as potent dipsogenic modulators by modulating neural circuits of osmoreception in the central nervous system, independent of glycemic control. Although gastrointestinal effects require proactive management, the systemic enzymatic degradation of liraglutide positions it as a safe alternative in end-stage renal failure. Pharmacological modulation of the neuroendocrine axis of thirst represents a promising therapeutic frontier to transform the management of refractory hypervolemia and improve hemodynamic stability in patients with no residual diuresis without diabetes. The benefit of GLP-1RAs in this case, a non-diabetic patient on hemodialysis with refractory thirst, extends beyond traditional metabolic control. The clinical success of an intentionally chosen weekly liraglutide regimen indicates that the therapeutic goal was to influence the neuroendocrine system that manages thirst and satiety. This case emphasizes that non-adherence to fluid therapy during dialysis can be viewed as a treatable physiological imbalance rather than a behavioral issue. Although there are no standardized guidelines for weekly dosing, this proof of concept points to a potential new treatment approach. Using incretins as tools to regulate thirst deserves further research through controlled trials to verify their long-term effects on hemodynamic stability and quality of life in patients with ESRD.

Abstract

To explore the association of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on heart rate (HR) in overweight or obese patients without diabetes.

Abstract

Secondary spinal cord injury (SCI) involves neuroinflammatory mechanisms such as microglial pyroptosis, which aggravates neural impairment via NLRP3 inflammasome activation. Although liraglutide (Lr) is commonly used for managing blood glucose, it also exhibits anti-inflammatory effects. Previous studies from our group have shown that glucagon-like peptide-1 receptor (GLP-1R) activation in microglia attenuates neuroinflammation and promotes functional recovery after SCI, the precise mechanism linking GLP-1R to the inhibition of pyroptosis remained unclear. Here, we report that high-dose Lr (independent of its metabolic effects) significantly improves functional and histological outcomes in a murine SCI model, and these benefits are abolished in GLP-1R-/- mice. In vitro, RNA sequencing, combined with pharmacological and genetic approaches, revealed that Lr, via the PI3K/Akt/transcription factor EB (TFEB) axis, by upregulates Fanconi anemia complementation group C (FANCC) to suppress pyroptosis. Crucially, FANCC knockdown both elevated p38 phosphorylation and blocked the anti-pyroptotic effect of Lr, thereby establishing FANCC as an essential downstream mediator. This signaling cascade culminates in the inhibition of p38-dependent NLRP3 inflammasome activation. Collectively, our work defines a novel GLP-1R/PI3K/Akt/TFEB/FANCC/p38 pathway through which Lr alleviates secondary SCI, identifying FANCC as a pivotal neuroprotective node and supporting the translational potential of GLP-1R modulation in SCI.

Abstract

Bone grafting materials are widely used in the treatment of critical-sized bone defects, and pharmacological agents with the potential to enhance their regenerative potential have been of great interest. The purpose of this study was to investigate the effect of the glucagon-like peptide-1 receptor agonist Liraglutide on bone regeneration when combined with different grafting materials.

Abstract

Carotid intima-media thickness (cIMT), amyloid-β1-40 (Aβ1-40), and oxidative stress are markers of vascular aging and cardiovascular risk. We compared the effects of insulin, glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and their combination on the aforementioned markers in type 2 diabetes (T2DM). We prospectively studied 183 metformin-treated T2DM patients, propensity-score-matched to 12-mo treatment with insulin, liraglutide, empagliflozin, or liraglutide plus empagliflozin. Six-segment cIMT and plaque-equivalent lesions (cIMT ≥ 1.5 mm) were assessed at baseline, 6, and 12 mo; plasma Aβ1-40 and malondialdehyde (MDA) were measured. All regimens were associated with reductions in cIMT and Aβ1-40 at 12 mo (P < 0.05). MDA decreased overall with the largest reduction in GLP-1RA-based regimens. Compared with insulin, liraglutide, empagliflozin, and their combination achieved greater reductions in cIMT (-8.2, -5.6, and -10.7% vs. -1.7%, P < 0.05) and in Aβ1-40 (-52.1, -40.3, and -50.7% vs. -30.7%, P < 0.05). Patients achieving cIMT < 1.5 mm at 12 mo was the highest with combination therapy (75%), followed by liraglutide (67%) and empagliflozin (54%) versus insulin (40%; P < 0.05). Patients who regressed <1.5 mm showed greater reduction in Aβ1-40 than those with ≥1.5 mm (-56.2% vs. -25.1%, P = 0.028). Liraglutide, empagliflozin, and their combination induced greater reduction of cIMT (-8.2, -5.6, and -10.7% vs. -1.7%) and Aβ1-40 (-52.1, -40.3, and -50.7% vs. -30.7%; P < 0.05) compared with insulin. cIMT regression was associated with Aβ1-40 and MDA reductions (P < 0.05). In T2DM patients, GLP-1RA and SGLT-2i-particularly in combination-were associated with improvements in carotid atherosclerotic burden, amyloid-related vascular injury, and oxidative stress.NEW & NOTEWORTHY We investigated the effect of insulin, glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and their combination on carotid intima-media thickness (cIMT) and amyloid-β1-40 (Aβ1-40) in diabetes. Twelve-month treatment with GLP-1RA, SGLT-2i, and their combination confers significant reductions in cIMT and Aβ1-40 compared with insulin. cIMT regression was associated with Aβ1-40 and malondialdehyde reductions. Our findings support that newer antidiabetic agents can favorably modify structural and biochemical markers of atherosclerosis.

Abstract

Obesity is associated with impaired physical fitness, including physical functional performance and cardiorespiratory fitness, which affect health-related quality of life and mortality.

Abstract

Type 2 diabetes mellitus is a major global health concern. Liraglutide, a glucagon-like peptide-1 receptor agonist, is widely used for glycemic control and weight loss. While generally safe, its misuse, particularly overdose, poses severe risks that are poorly documented. This case report aims to describe the clinical course and management of a life-threatening diabetic ketoacidosis (DKA) induced by a massive liraglutide overdose, highlighting the critical importance of patient education and adherence to prescribing guidelines.

Abstract

Gastric inhibitory polypeptide (GIP)/Glucagon-like peptide-1 (GLP-1) receptor agonists are increasingly prescribed for the management of obesity and type 2 diabetes, yet research pertinent to their effects on muscle health is limited. Considering the central role of muscle strength as a sarcopenia component, this article summarizes emerging evidence on insulin-based therapies and muscle strength. Short-to-mid-term trials of semaglutide or liraglutide in adults with obesity have shown statistically preserved handgrip strength despite reductions in lean soft tissue mass, suggesting that muscle strength may not decline proportionally to weight loss. Likewise, tirzepatide combined with resistance and aerobic training in young men may not confer additional strength benefits beyond exercise alone. In contrast, longitudinal and retrospective research in older adults with type 2 diabetes have reported reductions in handgrip strength and accelerated sarcopenia with prolonged semaglutide use, raising concerns about potentially detrimental effects on neuromuscular health. Collectively, these findings indicate that lean soft tissue loss is not a reliable predictor of muscle strength change following GIP/GLP-1 agonists. While shorter term studies suggest relative preservation, longer term data in older adults point to possible risk of muscle strength decline. Future randomized, double-blinded trials with adequate sample sizes and longer follow-ups are warranted, particularly in older populations who are at an increased risk of sarcopenia. Their findings could support the integration of muscle strength outcomes into clinical monitoring and trial design to ensure that GIP/GLP-1 agonist-based strategies may not compromise muscle strength in these populations during weight loss.

Abstract

Prefilled syringes (PFSs) serve as primary containers for therapeutic peptides and proteins in combination drug products. Silicone oil, a lubricant in PFSs to facilitate plunger movement during injection, and the headspace from syringe fillings, have been reported to induce protein aggregation and particle formation as a result of the associated interfacial stress. However, their impact on the stability of peptide drugs is underexplored. In this study, we employed biophysical techniques, including size exclusion chromatography (SEC), circular dichroism (CD) spectroscopy, and thioflavin T fluorescence (ThT), to investigate aggregate formation, secondary structural changes, and fibrillation following physical stress on liraglutide in the presence of varying silicone oil concentrations, headspace, and agitation strength. In contrast to the minimal structural changes or formation of higher-molecular-weight aggregates observed under mild agitation or limited headspace, enhanced headspace and agitation promote fibrillation of liraglutide. Furthermore, we utilized advanced techniques to probe silicone-oil-liraglutide interactions and interfacial stress, including high-resolution label-free stimulated Raman scattering (SRS) for chemical imaging and nuclear magnetic resonance (NMR) spectroscopy for structural characterization. We observed, for the first time, the peptide adsorption on the silicone oil surface at submicrometer resolution by SRS. 1H NMR showed line broadening and signal loss, consistent with peptide aggregation or surface adsorption, but no chemical shift changes, supporting the absence of strong, specific interactions. Therefore, our data suggest that the dual air-water and silicone-oil-water interfacial stress, rather than either alone, plays a significant role in liraglutide aggregation. These findings emphasize the interactive roles of several stress parameters, including silicone oil concentration, silicone oil interface, headspace, and agitation strength, on the stability of peptide combination drug products, and highlight the critical role of interfacial stress-induced biophysical instability.