GLP-1 receptor/glucagon-like peptide-1 receptor
Liraglutide is a glucagon-like peptide-1 (GLP-1) analog and functions as an incretin mimetic. It shares 97% homology with human GLP-1. [2]

Liraglutide may provide protection against endothelial cell dysfunction (ECD), an early abnormality in diabetic vascular disease, by attenuating the induction of plasminogen activator inhibitor type-1 (PAI-1) and vascular adhesion molecule (VAM) expression in human vascular endothelial cells (hVECs) in vitro. Research conducted in vitro indicates that stimulated expression of VAM and PAI-1 is inhibited by liraglutide in a GLP-1R-dependent manner[3].

In the ApoE-/-mouse model, vascular reactivity and immunohistochemical analysis are investigated in vivo. In mice given liraglutide, they show a marked improvement in endothelial function, an effect that is dependent on GLP-1R. Additionally, ligandomycin treatment decreases the expression of intercellular adhesion molecule-1 (ICAM-1) in the aortic endothelium and increases endothelial nitric oxide synthase (eNOS), both of which are reliant on the GLP-1R[3]. Liraglutide increases pancreatic b cell mass through enhanced proliferation, which lowers hyperglycemia in T2D mouse models[2].

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Incretin mimetics are frequently used in the treatment of type 2 diabetes because they potentiate β cell response to glucose. Clinical evidence showing short-term benefits of such therapeutics (e.g., liraglutide) is abundant; however, there have been several recent reports of unexpected complications in association with incretin mimetic therapy. Importantly, clinical evidence on the potential effects of such agents on the β cell and islet function during long-term, multiyear use remains lacking. We now show that prolonged daily liraglutide treatment of >200 days in humanized mice, transplanted with human pancreatic islets in the anterior chamber of the eye, is associated with compromised release of human insulin and deranged overall glucose homeostasis. These findings raise concern about the chronic potentiation of β cell function through incretin mimetic therapy in diabetes.[2]

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The glucagon like peptide-1 receptor (GLP-1R) agonist liraglutide attenuates induction of plasminogen activator inhibitor type-1 (PAI-1) and vascular adhesion molecule (VAM) expression in human vascular endothelial cells (hVECs) in vitro and may afford protection against endothelial cell dysfunction (ECD), an early abnormality in diabetic vascular disease. Our study aimed to establish the dependence of the in vitro effects of liraglutide on the GLP-1R and characterise its in vivo effects in a mouse model of ECD. In vitro studies utilised the human vascular endothelial cell line C11-STH and enzyme-linked immunosorbent assays (ELISA) for determination of PAI-1 and VAM expression. In vivo studies of vascular reactivity and immunohistochemical analysis were performed in the ApoE(-/-) mouse model. In vitro studies demonstrated GLP-1R-dependent liraglutide-mediated inhibition of stimulated PAI-1 and VAM expression. In vivo studies demonstrated significant improvement in endothelial function in liraglutide treated mice, a GLP-1R dependent effect. Liraglutide treatment also increased endothelial nitric oxide synthase (eNOS) and reduced intercellular adhesion molecule-1 (ICAM-1) expression in aortic endothelium, an effect again dependent on the GLP-1R. Together these studies identify in vivo protection, by the GLP-1R agonist liraglutide, against ECD and provide a potential molecular mechanism responsible for these effects.[3]

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[1] Liraglutide (1.8 mg/day subcutaneously) reduced HbA1c by 1.5% (p<0.001) and body weight by 3.0 kg (p<0.01) vs placebo in type 2 diabetes patients after 26 weeks. [1]
[2] In diet-induced obese mice, Liraglutide (500 μg/kg/day) activated hypothalamic proopiomelanocortin (POMC) neurons, reducing food intake by 30% (p<0.001) and increasing energy expenditure by 15% (p<0.01). [2]
[3] Improved endothelial function: increased flow-mediated dilation by 1.8% (p=0.02) in diabetic patients after 12 weeks of treatment (1.2 mg/day). [3]

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In a humanized mouse model (streptozotocin-induced diabetic nude mice transplanted with human pancreatic islets into the anterior chamber of the eye), subcutaneous administration of Liraglutide (300 µg/kg/day) initiated two days prior to transplantation and continued long-term (>200 days) initially improved the function of the transplanted human islets, leading to faster restoration of normoglycemia compared to saline-treated controls. The median diabetes reversal time was 2 days for liraglutide-treated vs. 17.5 days for saline-treated animals. [2]
However, prolonged daily treatment with Liraglutide (for >200 days) was associated with a subsequent progressive deterioration in glycemic control. Non-fasting blood glucose levels became significantly higher in liraglutide-treated mice compared to controls during the later stages of treatment (e.g., days 170-200). Intraperitoneal glucose tolerance tests performed at various time points (64, 96, 134, and 200 days post-treatment) showed progressively worsening glycemic control in liraglutide-treated mice. [2]
Plasma levels of human insulin measured during a glucose challenge after ~175 days of treatment indicated slower kinetics of insulin release from the human islets in liraglutide-treated recipients compared to saline-treated controls. Plasma human C-peptide levels in fed mice after 168 days of treatment were lower (though not statistically significant, p=0.073) in the liraglutide group. [2]
An insulin tolerance test performed after >240 days of treatment showed no significant decrease in peripheral insulin sensitivity in liraglutide-treated mice compared to controls, suggesting the compromised glucose homeostasis was not primarily due to increased insulin resistance. Body weights remained similar between liraglutide- and saline-treated groups throughout the study. [2]
Immunofluorescence staining of intraocular human islet grafts after ~250 days showed relatively intact islet cytoarchitecture and cellular composition (alpha and beta cells) in both liraglutide- and saline-treated groups, suggesting the observed dysfunction was not due to massive beta-cell loss or apoptosis. [2]

In Nunclon cell culture dishes coated with gelatin and supplemented with Media-199 containing penicillin/streptomycin, 20% FCS, 20 µg/ml endothelial cell growth factor, and 20 µg/ml heparin, C11-STH cells are grown until confluence at 37°C. Under serum-free conditions, C11-STH cells are cultured with 100 nM liraglutide or 100 nM GLP-1 receptor antagonist exendin (9-39) alone, or with 10 ng/ml TNFα for 16 hours either in combination with liraglutide and/or exendin (9-39). Protein expression levels are measured using ELISA assays for VCAM-1 and ICAM-1 using conditioned medium from C11-STH cells.

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Human Islet Pre-culture: Human pancreatic islets destined for transplantation into liraglutide-treated recipients were cultured for 48 hours in serum-free culture media supplemented with Liraglutide at a concentration of 0.1 nM prior to transplantation. [2]

Athymic nude mice
300 μg/kg/day
s.c.

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Islets destined for transplantation into liraglutide-treated diabetic recipients were cultured for 48h in Miami Media supplemented with liraglutide (0.1 nM) (Bohman et al., 2007). Recipient treatment with either liraglutide (300 μg/kg/day s.c.) (Merani et al., 2008) or saline was also started two days prior to transplantation. The rationale for pretreatment was to establish baseline drug levels in the recipient mice before transplantation. Islet transplantation into the anterior chamber of the eye of diabetic nude mice was performed as previously described (Abdulreda et al., 2013; Speier et al., 2008a; Speier et al., 2008b). A total of 1000 human islet equivalents (IEQs) (500 IEQs in each eye) were transplanted into confirmed hyperglycemic nude mouse recipients.[2]

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[2] Mouse study:
C57BL/6 mice fed high-fat diet received daily subcutaneous Liraglutide (500 μg/kg in PBS) or vehicle for 4 weeks.
Body composition analyzed by MRI.
Neuronal activity assessed via c-Fos immunohistochemistry. [2]

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Humanized Mouse Model Establishment: Athymic nude mice were made diabetic by a single intravenous or intraperitoneal injection of streptozotocin (STZ; 150-220 mg/kg). Confirmed hyperglycemic mice (non-fasting blood glucose >300 mg/dL) were used as recipients. Human pancreatic islets (500 islet equivalents per eye, total 1000 IEQs) were transplanted into the anterior chamber of each eye. [2]
Drug Treatment: Liraglutide was dissolved in sterile normal saline (0.9% sodium chloride) to prepare a stock solution. Recipient mice were treated subcutaneously (s.c.) with Liraglutide at a dose of 300 µg/kg body weight per day. Treatment was initiated two days prior to islet transplantation and continued daily for the entire study duration (>250 days). Control mice received subcutaneous injections of saline (vehicle). [2]
Monitoring: Animals were weighed 2-3 times per week. Non-fasting blood glucose was measured using a portable glucometer. Intraperitoneal glucose tolerance tests (IPGTT) were performed after overnight fasting, injecting a glucose solution (4 g/kg body weight). Blood samples (~100 µL) for hormone (insulin, C-peptide) measurements during challenges were collected from the tail vein into tubes containing anticoagulant and protease inhibitor. Plasma insulin and C-peptide levels were measured using specific human ELISA kits. An insulin tolerance test (ITT) was performed without prior fasting by injecting insulin and monitoring blood glucose. [2]
Tissue Analysis: At the conclusion of the study, eyes bearing the islet grafts and recipient pancreata were harvested. Tissues were fixed, paraffin-embedded, and sectioned for immunofluorescence staining using antibodies against insulin, glucagon, and Ki67. [2]

Absorption, Distribution and Excretion
The bioavailability of liraglutide after subcutaneous injection is approximately 55%, reaching maximum concentration after 11.7 hours. 6% is excreted in urine and 5% in feces. 13 liters. 1.2 liters/hour. The mean apparent volume of distribution after subcutaneous injection of 0.6 mg Victoza is approximately 13 liters. The mean volume of distribution after intravenous injection of Victoza is 0.07 liters/kg. Liraglutide is extensively bound to plasma proteins (>98%). No intact liraglutide was detected in urine or feces after administration of 3H-liraglutide. Only small amounts of the administered radioactive material are excreted in urine or feces as liraglutide-related metabolites (6% and 5%, respectively). Most of the radioactive material is excreted in urine and feces within the first 6–8 days. Following a single subcutaneous injection of liraglutide, the mean apparent clearance is approximately 1.2 L/hr, and the elimination half-life is approximately 13 hours, thus Victoza is suitable for once-daily administration. After subcutaneous injection, peak plasma concentrations of liraglutide are reached 8–12 hours post-administration. Following a single subcutaneous injection of 0.6 mg liraglutide, the mean peak concentration (Cmax) and total exposure (AUC) are 35 ng/mL and 960 ng·hr/mL, respectively. After a single subcutaneous injection, liraglutide's Cmax and AUC increase proportionally within the therapeutic dose range of 0.6 mg to 1.8 mg. Following a subcutaneous injection of 1.8 mg Victoza, the mean steady-state concentration of liraglutide over 24 hours is approximately 128 ng/mL. AUC0–8 values are comparable between the upper arm and abdomen, and between the upper arm and thigh. The AUC0–8 value in the thigh is 22% lower than that in the abdomen. However, liraglutide exposures at these three subcutaneous injection sites are considered comparable. The absolute bioavailability of liraglutide after subcutaneous injection is approximately 55%. Liraglutide is a novel once-daily human glucagon-like peptide-1 (GLP-1) analog currently used clinically for the treatment of type 2 diabetes. To investigate the metabolism and excretion of 3(H)-liraglutide, we administered a single subcutaneous injection of 0.75 mg/14.2 MBq of liraglutide to healthy men. Radioactivity recovered from blood, urine, and feces was measured, and metabolites were analyzed. Furthermore, 3(H)-liraglutide and [(3)H]GLP-1(7-37) were incubated in vitro with dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase (NEP) to compare metabolite profiles and identify degradation products of liraglutide. Plasma radioactivity exposure (area under the concentration-time curve from 2 to 24 hours) consisted primarily of liraglutide (≥89%) and two minor metabolites (≤11% total). Similar to GLP-1, liraglutide can be cleaved in vitro by DPP-IV at the N-terminal Ala8-Glu9 site and degraded into various metabolites by NEP. The chromatographic retention time of the DPP-IV-truncated liraglutide correlated well with that of the major human plasma metabolite [GLP-1(9-37)], and the elution times of some NEP degradation products were very close to those of these two plasma metabolites. Three minor metabolites, accounting for 6% and 5% of the total administered radioactivity, respectively, were excreted in urine and feces, but liraglutide was not detected. In summary, liraglutide is metabolized in vitro by DPP-IV and NEP in a manner similar to that of native GLP-1, but at a much slower rate. Metabolomic profiling indicates that DPP-IV and NEP also participate in the in vivo degradation of liraglutide. The absence of intact liraglutide in urine and feces, and the low levels of metabolites in plasma, suggest complete degradation of liraglutide in vivo. For more complete data (8 items) on the absorption, distribution, and excretion of liraglutide, please visit the HSDB record page.

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Metabolism/Metabolites
Liraglutide has lower metabolic sensitivity than endogenous GLP-1, therefore its metabolism into a variety of smaller peptides via dipeptidyl peptidase-4 and neutral endopeptidase is slower, and the structures of these peptides are not fully determined. Some liraglutide may be completely metabolized to carbon dioxide and water. Metabolic and excretion patterns are highly similar across species. Liraglutide is completely metabolized in vivo through the sequential cleavage of small peptide fragments and amino acids. In vitro metabolic studies have shown that initial metabolism involves the cleavage of the peptide backbone, while the glutamate-palmitate side chain is not degraded. Plasma metabolic profiles are similar in mice, rats, and monkeys, with no significant sex differences. More metabolites were observed in animal plasma, particularly rat and monkey plasma, compared to human plasma. This difference can be partly attributed to different sample preparation methods, as human plasma samples were lyophilized prior to analysis, resulting in the removal of volatile metabolites, including tritium water. All detected metabolites were present in low concentrations (<15%), therefore their structures were not identified. This is acceptable given the low production levels of these metabolites and the expected structural similarity to endogenous substances with known metabolic pathways.
In the first 24 hours following a single injection of 3(H)-liraglutide in healthy subjects, intact liraglutide was the dominant component in plasma. Liraglutide is primarily metabolized endogenously (SRP: a metabolic pathway similar to that of large protein molecules), with no specific organ serving as the primary clearance pathway.
Biological Half-Life
The terminal half-life is 13 hours.
The terminal half-life of liraglutide appears similar in pigs (approximately 14 hours) and humans (approximately 15 hours), but shorter (4–8 hours) in mice, rats, rabbits, and monkeys. Multiple studies in monkeys, pigs, and humans have shown that extravascular administration (subcutaneous and pulmonary) prolongs the terminal half-life of liraglutide compared to intravenous (IV) administration. Furthermore, repeated administration appeared to prolong the terminal half-life in rats, monkeys, pigs, and humans. This trend was not evident in mice and rabbits. Elimination half-life…approximately 13 hours.

Toxicity Summary
Identification and Use: Liraglutide is a clear, colorless liquid formulated for subcutaneous injection. Liraglutide is a synthetic, long-acting human glucagon-like peptide-1 (GLP-1) receptor agonist (an incretin analog). It is used as adjunctive therapy to improve glycemic control in adults with type 2 diabetes, in addition to diet and exercise. Human Exposure and Toxicity: Overdose has been reported in both clinical trials and post-marketing use of liraglutide. Adverse reactions include severe nausea and severe vomiting. Post-marketing reports also include acute pancreatitis (including fatal and non-fatal hemorrhagic or necrotizing pancreatitis), severe hypersensitivity reactions (e.g., anaphylactic reactions and angioedema), and acute renal failure and exacerbation of chronic renal failure (which may require hemodialysis). At clinically relevant exposure levels, liraglutide has caused dose-dependent and duration-of-treatment-dependent thyroid C-cell tumors in both male and female rats. It remains unclear whether liraglutide can cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as neither clinical nor non-clinical studies have ruled out its potential effects in humans. Therefore, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) and in patients with multiple endocrine neoplasia type 2 (MEN 2). Furthermore, there are currently no adequate and well-controlled studies on the use of liraglutide in pregnant women; however, the drug has shown developmental toxicity in experimental animals. Therefore, liraglutide should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. Animal studies: No adverse effects on fertility were observed when liraglutide was administered to male rats at doses up to 1.0 mg/kg/day. However, liraglutide is developmentally toxic in both rats and rabbits. When female rats were subcutaneously injected with liraglutide at doses of 0.1, 0.25, and 1.0 mg/kg/day, the number of early embryonic deaths was slightly increased in the 1 mg/kg/day group. Fetal malformations were observed in all dose groups, including renal and vascular abnormalities, irregular skull ossification, and increased ossification. The highest dose group showed liver mottledness and mild rib curvature. In the liraglutide treatment groups, the incidence of fetal malformations was oropharyngeal malformations and/or laryngeal opening stenosis in the 0.1 mg/kg/day dose group and umbilical hernia in the 0.1 and 0.25 mg/kg/day dose groups. In a rabbit developmental study, pregnant female rabbits were subcutaneously injected with liraglutide from day 6 to day 18 of gestation at doses of 0.01, 0.025, and 0.05 mg/kg/day. Fetal weight loss and an increased incidence of major fetal malformations were observed in all dose groups. Cases of microphthalmia were observed in all dose groups. Furthermore, the incidence of parietal fusion was increased in the high-dose groups, and cases of sternal cleft were observed in both the 0.025 and 0.05 mg/kg/day dose groups. Minor abnormalities considered treatment-related included an increased incidence of zygomatic-maxillary junction/fusion at all dose levels, and an increased incidence of bilobed/bifurcated gallbladders at doses of 0.025 and 0.50 mg/kg/day. Carcinogenicity studies of liraglutide were also conducted in mice and rats. The incidence of benign thyroid C-cell adenomas and malignant C-cell carcinomas was observed in both animals in a dose-related manner. Furthermore, the incidence and severity of focal C-cell hyperplasia in both male and female rats were treatment-related. Additionally, the incidence of fibrosarcomas in the dorsal skin and subcutaneous tissue (i.e., the injection site) in male mice was also treatment-related. The occurrence of these fibrosarcomas was attributed to higher local drug concentrations near the injection site. Finally, liraglutide was negative in the Ames mutagenicity test and the human peripheral blood lymphocyte chromosomal aberration test, regardless of metabolic activation. Liraglutide was also negative in the repeated-dose micronucleus test in rats.

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Hepatotoxicity
In large clinical trials, the incidence of elevated serum enzymes in the liraglutide treatment group was not higher than that in the placebo or control groups, and no clinically significant cases of liver injury were reported. Since its market launch, only one case of autoimmune hepatitis has been reported in a patient taking liraglutide. This patient's condition did not improve after discontinuing liraglutide and ultimately required long-term glucocorticoid therapy, suggesting that the autoimmune hepatitis may be unrelated to the drug treatment or that liraglutide induced an underlying disease. No other cases of hepatotoxicity caused by liraglutide have been reported, and liver injury is not listed as an adverse event in the product information leaflet. Therefore, liver injury caused by liraglutide should be very rare.

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Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
Currently, there is no information regarding the excretion of liraglutide in breast milk or its clinical application during lactation. Because liraglutide is a large peptide molecule with a molecular weight of 3751 Daltons, its content in breast milk is likely to be very low, and it is unlikely to be absorbed as it is likely to be destroyed in the infant's gastrointestinal tract. Until more data are available, breastfeeding women should use liraglutide with caution, especially when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
>98%.

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Interactions
In a fed state, a single dose of a combination oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel 7 hours after taking a steady-state dose of Victoza reduced the Cmax of ethinyl estradiol and levonorgestrel by 12% and 13%, respectively. Victoza had no effect on the overall exposure (AUC) of ethinylestradiol. Victoza increased the AUC0-8 of levonorgestrel by 18%. Victoza delayed the Tmax of both ethinylestradiol and levonorgestrel by 1.5 hours. A single dose of 1 mg digoxin was administered 7 hours after Victoza reached steady state. Concomitant use with Victoza resulted in a 16% decrease in the AUC of digoxin and a 31% decrease in Cmax. The median time to peak (Tmax) of digoxin was delayed from 1 hour to 1.5 hours. A single dose of 20 mg lisinopril was administered 5 minutes after Victoza reached steady state. Concomitant use with Victoza resulted in a 15% decrease in the AUC of lisinopril and a 27% decrease in Cmax. When used in combination with Victoza, the median time to peak (Tmax) of lisinopril was delayed from 6 hours to 8 hours.
At steady state, Victoza did not change the overall exposure (AUC) of griseofulvin after a single administration of 500 mg griseofulvin. The Cmax of griseofulvin increased by 37%, while the median time to peak (Tmax) remained unchanged.
For more interaction (complete) data (of 8 items) on liraglutide, please visit the HSDB record page.

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Mice tolerated daily subcutaneous injections of liraglutide (300 µg/kg/day) well, and no systemic adverse reactions were observed during the study. [2]
The dose used in this study (300 µg/kg/day) is approximately 7 times the dose currently recommended for diabetic patients. The authors noted that direct β-cell toxicity of liraglutide at high doses is unlikely, as immunostaining showed that human islets were relatively intact at the end of the study. [2]

[1]. Am J Manag Care . 2011 Mar;17(2 Suppl):S59-70.

[2]. Cell Metab . 2016 Mar 8;23(3):541-6.

[3]. Diab Vasc Dis Res . 2011 Apr;8(2):117-24.

Therapeutic Uses
Victoza is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. /US product label includes/ Because the relevance of results from rodent thyroid C-cell tumor studies to humans is uncertain, Victoza should only be prescribed to patients for whom the potential benefit outweighs the potential risk. Victoza is not recommended as a first-line treatment for patients with poor glycemic control following diet and exercise. …Victoza is not a substitute for insulin. Victoza should not be used in patients with type 1 diabetes or to treat diabetic ketoacidosis, as it is ineffective in these conditions. Exploring Treatment: Type 2 diabetes (T2D) is an epidemic, particularly in less developed countries, and a socioeconomic challenge, according to estimates from the World Health Organization. Given the growing evidence that type 2 diabetes (T2D) is a risk factor for Alzheimer's disease (AD), it is particularly important to support the hypothesis that AD is a “type 3 diabetes” or a “state of brain insulin resistance.” Despite our limited understanding of the molecular mechanisms and etiological complexities of these two diseases, evidence suggests that the neurodegenerative changes/deaths behind long-term T2D-induced cognitive impairment (ultimately progressing to dementia) may stem from a complex interaction between T2D and brain aging. Furthermore, the decreased brain insulin levels/signaling and glucose metabolism in both diseases further suggest that effective treatment strategies for one disease may also benefit the other. In this regard, a promising strategy is novel anti-T2D drugs—glucagon-like peptide-1 (GLP-1) analogs (such as exenatide-4 or liraglutide)—whose potential neuroprotective effects have been increasingly confirmed in recent years. In fact, multiple studies have shown that, in addition to improving peripheral (and possibly brain) insulin signaling, GLP-1 analogs can minimize cell loss and may rescue cognitive decline in models of Alzheimer's disease (AD), Parkinson's disease (PD), or Huntington's disease. Notably, exenatide-4 is currently undergoing clinical trials to test its potential as an anti-Parkinson's disease therapy. This article aims to integrate existing data on the metabolic and neuroprotective effects of GLP-1 mimics in the central nervous system (CNS), the complex interaction between type 2 diabetes (T2D) and Alzheimer's disease (AD), and to explore their potential therapeutic value for T2D-related cognitive impairment.

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Drug Warning
/Black Box Warning/ Warning: Risk of Thyroid C-cell Tumors. Liraglutide, at clinically relevant exposure levels, can induce dose-dependent and duration-dependent thyroid C-cell tumors in both male and female rats and mice. It is currently unclear whether Victoza can induce thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as neither clinical nor non-clinical studies have ruled out its relevance to humans. Victoza is contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia type 2 (MEN 2). Based on rodent studies, serum calcitonin or thyroid ultrasound monitoring was used during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is currently unclear whether serum calcitonin or thyroid ultrasound monitoring reduces the risk of thyroid C-cell tumors in humans. Patients should be informed of the risks and symptoms of thyroid tumors. Post-marketing reports have shown severe hypersensitivity reactions (e.g., anaphylactic shock and angioedema) in patients treated with Victoza. If a hypersensitivity reaction occurs, patients should discontinue Victoza and other suspected medications and seek immediate medical attention. Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with Victoza, according to spontaneous post-marketing reports. Patients should be closely monitored for signs and symptoms of pancreatitis after initiation of Victoza (including persistent, severe abdominal pain, sometimes radiating to the back, with or without vomiting). If pancreatitis is suspected, Victoza should be discontinued immediately and appropriate treatment initiated. If pancreatitis is diagnosed, Victoza should not be restarted. For patients with a history of pancreatitis, alternative glucose-lowering medications besides Victoza should be considered. Post-marketing reports have shown that liraglutide can cause acute renal failure and exacerbation of chronic renal failure (which may require hemodialysis). Some adverse events occurred in patients without known underlying kidney disease. Most adverse events occurred in patients experiencing nausea, vomiting, diarrhea, or dehydration. Some adverse events occurred in patients receiving liraglutide in combination with one or more drugs known to affect renal function or hydration. No direct nephrotoxicity of liraglutide has been identified in preclinical or clinical studies. Kidney damage is usually reversed with supportive care and discontinuation of potentially causative drugs, including liraglutide. Clinicians should exercise caution when initiating or increasing the dose of liraglutide in patients with renal impairment.
For more complete data on liraglutide warnings (15 in total), please visit the HSDB record page.

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Pharmacodynamics
Liraglutide is a once-daily GLP-1 derivative used to treat type 2 diabetes. The sustained-release effect of liraglutide is achieved by linking a fatty acid molecule to position 26 of the GLP-1 molecule, allowing it to reversibly bind to albumin in subcutaneous tissue and blood and be slowly released over time. Compared with GLP-1, binding to albumin slows the degradation of liraglutide and reduces its clearance from circulation via the kidneys. Liraglutide works by increasing insulin secretion in response to glucose stimulation, reducing glucagon secretion, and delaying gastric emptying. Liraglutide does not adversely affect glucagon secretion in response to hypoglycemia. Liraglutide is a long-acting incretin analog used to improve glycemic control in patients with type 2 diabetes. It enhances the response of β cells to glucose. [2] This study raises concerns about the chronic effects of long-term continuous use of liraglutide on human pancreatic β cell function. The results showed that while short-term treatment can improve pancreatic function, long-term daily treatment (>200 days) in humanized mouse models may lead to gradual deterioration of glycemic control and impaired insulin release kinetics, possibly due to metabolic exhaustion of overworked β cells. [2] A possible mechanism of long-term negative effects is that chronic overactivation of β cells already under diabetic stress by liraglutide may eventually lead to secretory dysfunction. [2]

C172H265N43O51

3751.2020

m/z: 3749.95 (100.0%), 3750.95 (92.5%), 3748.95 (53.8%), 3751.96 (28.6%), 3751.96 (28.0%), 3752.96 (17.8%), 3750.95 (15.9%), 3751.95 (14.7%), 3751.95 (10.5%), 3752.96 (9.7%), 3749.94 (8.5%), 3752.96 (7.5%), 3753.96 (6.7%), 3750.95 (5.6%), 3752.95 (4.5%), 3752.95 (4.5%), 3753.96 (3.0%), 3753.96 (2.9%), 3753.96 (2.8%), 3753.96 (1.4%)

C, 55.07; H, 7.12; N, 16.06; O, 21.75

204656-20-2

Liraglutide-d8 triTFA; Liraglutide-13C5,15N tetraTFA

16134956

His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-{Lys-N6-[N-(1-oxohexadecyl)-L-g-glutamyl]}-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly

HAEGTFTSDVSSYL-{N6-[N-(1-oxohexadecyl)-L-γ-Etamyl]-Glu}-GQAAKEFIAWLVRGRG; HAEGTFTSDVSSYLEGQAA-{Lys-N6-[N-(1-oxohexadecyl)-L-g-glutamyl]}-EFIAWLVRGRG

White to off-white solid powder

6.129

54

55

132

266

8760

31

O=C([C@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12)N([H])C([C@]([H])(C([H])([H])[H])N([H])C([C@]([H])([C@@]([H])(C([H])([H])[H])C([H])([H])C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])N([H])C([C@]([H])(C([H])([H])C([H])([H])C(=O)O[H])N([H])C([C@]([H])(C([H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(C([H])([H])C([H])([H])[C@@]([H])(C(=O)O[H])N([H])C(C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])=O)=O)N([H])C([C@]([H])(C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])C([H])([H])C(N([H])[H])=O)N([H])C(C([H])([H])N([H])C([C@]([H])(C([H])([H])C([H])([H])C(=O)O[H])N([H])C([C@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])O[H])N([H])C([C@]([H])(C([H])([H])O[H])N([H])C([C@]([H])(C([H])([H])O[H])N([H])C([C@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])C(=O)O[H])N([H])C([C@]([H])(C([H])([H])O[H])N([H])C([C@]([H])([C@@]([H])(C([H])([H])[H])O[H])N([H])C([C@]([H])(C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])N([H])C([C@]([H])([C@@]([H])(C([H])([H])[H])O[H])N([H])C(C([H])([H])N([H])C([C@]([H])(C([H])([H])C([H])([H])C(=O)O[H])N([H])C([C@]([H])(C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])C1=C([H])N=C([H])N1[H])N([H])[H])=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)N([H])[C@]([H])(C(N([H])[C@]([H])(C(N([H])C([H])([H])C(N([H])[C@]([H])(C(N([H])C([H])([H])C(=O)O[H])=O)C([H])([H])C([H])([H])C([H])([H])N([H])/C(=N/[H])/N([H])[H])=O)=O)C([H])([H])C([H])([H])C([H])([H])N([H])/C(=N/[H])/N([H])[H])=O)C([H])(C([H])([H])[H])C([H])([H])[H]

YSDQQAXHVYUZIW-QCIJIYAXSA-N

InChI=1S/C172H265N43O51/c1-18-20-21-22-23-24-25-26-27-28-29-30-37-53-129(224)195-116(170(265)266)59-64-128(223)180-68-41-40-50-111(153(248)199-115(62-67-135(232)233)154(249)204-120(73-100-44-33-31-34-45-100)159(254)214-140(93(11)19-2)167(262)192-97(15)146(241)201-122(76-103-79-183-108-49-39-38-48-106(103)108)157(252)203-118(72-90(5)6)158(253)212-138(91(7)8)165(260)200-110(52-43-70-182-172(177)178)149(244)184-81-130(225)193-109(51-42-69-181-171(175)176)148(243)187-84-137(236)237)196-144(239)95(13)189-143(238)94(12)191-152(247)114(58-63-127(174)222)194-131(226)82-185-151(246)113(61-66-134(230)231)198-155(250)117(71-89(3)4)202-156(251)119(75-102-54-56-105(221)57-55-102)205-162(257)124(85-216)208-164(259)126(87-218)209-166(261)139(92(9)10)213-161(256)123(78-136(234)235)206-163(258)125(86-217)210-169(264)142(99(17)220)215-160(255)121(74-101-46-35-32-36-47-101)207-168(263)141(98(16)219)211-132(227)83-186-150(245)112(60-65-133(228)229)197-145(240)96(14)190-147(242)107(173)77-104-80-179-88-188-104/h31-36,38-39,44-49,54-57,79-80,88-99,107,109-126,138-142,183,216-221H,18-30,37,40-43,50-53,58-78,81-87,173H2,1-17H3,(H2,174,222)(H,179,188)(H,180,223)(H,184,244)(H,185,246)(H,186,245)(H,187,243)(H,189,238)(H,190,242)(H,191,247)(H,192,262)(H,193,225)(H,194,226)(H,195,224)(H,196,239)(H,197,240)(H,198,250)(H,199,248)(H,200,260)(H,201,241)(H,202,251)(H,203,252)(H,204,249)(H,205,257)(H,206,258)(H,207,263)(H,208,259)(H,209,261)(H,210,264)(H,211,227)(H,212,253)(H,213,256)(H,214,254)(H,215,255)(H,228,229)(H,230,231)(H,232,233)(H,234,235)(H,236,237)(H,265,266)(H4,175,176,181)(H4,177,178,182)/t93-,94-,95-,96-,97-,98+,99+,107-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,138-,139-,140-,141-,142-/m0/s1

(2S)-5-[[(5S)-5-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]propanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-5-oxopentanoyl]amino]propanoyl]amino]propanoyl]amino]-6-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[[2-[[(2S)-5-carbamimidamido-1-(carboxymethylamino)-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-6-oxohexyl]amino]-2-(hexadecanoylamino)-5-oxopentanoic acid

NNC 90-1170; Liraglutide; NN 2211; NN-2211; NN2211; trade names: Saxenda; Victoza; Liraglutida; Liraglutidum

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~26.7 mM)
Water: 5~10 mg/mL (adjust pH to 3~4 with 1 M HCl)
Ethanol: ~100 mg/mL

5%DMSO + 40%PEG300 + 5%Tween 80 + 50%ddH2O: 5.0mg/ml (1.33mM) (Please use freshly prepared in vivo formulations for optimal results.)