Pharmacokinetics and Pharmacodynamics of Liraglutide, a Long‐Acting, Potent Glucagon‐Like Peptide‐1 Analog

Meece, Jerry

doi:10.1592/phco.29.pt2.33s

Cited by 24 publications

(18 citation statements)

References 69 publications

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“…Indeed, the PK profile of liraglutide and exendin-4 are quite different. In humans, levels of liraglutide are steadily maintained for ~24hr after injection, whereas exenatide levels rapidly peak and decline 10–12hr after injection, thus yielding more variation throughout the day (Meece, 2009). Regardless of these differences between the two drugs, it is the case that in most instances food intake suppression by the GLP-1R agonists does not occur without concomitant pica.…”

Section: Discussionmentioning

confidence: 99%

The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide

et al. 2012

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The FDA-approved glucagon-like-peptide-1 receptor (GLP-1R) agonists exendin-4 and liraglutide reduce food intake and body weight. Nausea is the most common adverse side effect reported with these GLP-1R agonists. Whether food intake suppression by exendin-4 and liraglutide occurs independently of nausea is unknown. Further, the neurophysiological mechanisms mediating the nausea associated with peripheral GLP-1R agonist use are poorly understood. Using two established rodent models of nausea [conditioned taste avoidance (CTA) and pica (ingestion of non-nutritive substances)], results show that all peripheral doses of exendin-4 that suppress food intake also produce CTA, whereas one dose of liraglutide suppresses intake without producing CTA. Chronic (12 days) daily peripheral administration of exendin-4 produces a progressive increase in pica coupled with stable, sustained food intake and body weight suppression, whereas the pica response and food intake reduction by daily liraglutide are more transient. Results demonstrate that the nausea response accompanying peripheral exendin-4 occurs via a vagal-independent pathway involving GLP-1R activation in the brain as the exendin-4-induced pica response is attenuated with CNS co-administration of the GLP-1R antagonist exendin-(9-39), but not by vagotomy. Direct administration of exendin-4 to the medial subnucleus of the nucleus tractus solitarius (mNTS), but not to the central nucleus of the amygdala, reduced food intake and produced a pica response, establishing the mNTS as a potential GLP-1R-expressing site mediating nausea responses associated with GLP-1R agonists.

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Section: Discussionmentioning

confidence: 99%

The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide

et al. 2012

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“…Greater weight reduction with liraglutide compared with sitagliptin can also be attributed to the mechanistic differences of GLP‐1 analogues and DPP‐4 inhibitors. Previous studies have shown that GLP‐1 receptor agonists increase satiety, reduce food intake and promote weight loss (13,14), whereas DPP‐4 inhibitors are generally weight‐neutral (3).…”

Section: Discussionmentioning

confidence: 99%

One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial

Pratley

Nauck

Bailey

et al. 2011

International Journal of Clinical Practice

232

242

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AimThe aim of this study was to compare the efficacy and safety of once-daily human glucagon-like peptide-1 analogue liraglutide with dipeptidyl peptidase-4 inhibitor sitagliptin, each added to metformin, over 52 weeks in individuals with type 2 diabetes.MethodsIn an open-label, parallel-group trial, metformin-treated participants were randomised to liraglutide 1.2 mg/day (n= 225), liraglutide 1.8 mg/day (n= 221) or sitagliptin 100 mg/day (n= 219) for 26 weeks (main phase). Participants continued the same treatment in a 26-week extension.ResultsLiraglutide (1.2 or 1.8 mg) was superior to sitagliptin for reducing HbA1c from baseline (8.4–8.5%) to 52 weeks: −1.29% and −1.51% vs. −0.88% respectively. Estimated mean treatment differences between liraglutide and sitagliptin were as follows: −0.40% (95% confidence interval −0.59 to −0.22) for 1.2 mg and −0.63% (−0.81 to −0.44) for 1.8 mg (both p < 0.0001). Weight loss was greater with liraglutide 1.2 mg (−2.78 kg) and 1.8 mg (−3.68 kg) than sitagliptin (−1.16 kg) (both p < 0.0001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly more with liraglutide 1.8 mg than with sitagliptin (p = 0.03). Proportions of participants reporting adverse events were generally comparable; minor hypoglycaemia was 8.1%, 8.3% and 6.4% for liraglutide 1.2 mg, 1.8 mg and sitagliptin respectively. Gastrointestinal side effects, mainly nausea, initially occurred more frequently with liraglutide, but declined after several weeks.ConclusionLiraglutide provides greater sustained glycaemic control and body weight reduction over 52 weeks. Treatment satisfaction was significantly greater with 1.8 mg liraglutide, similar to 26-week results. The safety profiles of liraglutide and sitagliptin are consistent with previous reports.

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“…As stated, liraglutide is 97% homologous to the endogenous GLP‐1 hormone, with substitutions made at position 34 (replacing lysine with arginine) and a lipophilic moiety added to lysine at position 26 (a palmitic acid added through a glutamoyl spacer) . The prolonged activity of the molecule is achieved through self‐association because liraglutide forms heptamers in solution, as well as high plasma protein binding (more than 98%) and stability from degradation by the DPP‐4 enzyme . Bioavailability for subcutaneously administered liraglutide is ~55%, with similar absorption when administered in the abdomen, thigh, and upper arm .…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

Liraglutide: A New Option for the Treatment of Obesity

2015

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Obesity continues to pose a major public health risk to the United States and across the world, with an estimated one-third of adult Americans being defined as obese. Obesity treatment guidelines recommend the use of pharmacologic therapy in adults who have a body mass index (BMI) of 30 kg/m(2) or higher or in patients with a BMI of 27 kg/m(2) or higher who have at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, insulin resistance, type 2 diabetes mellitus). Liraglutide is a glucagon-like peptide-1 receptor agonist that has been successfully used in the treatment of type 2 diabetes for several years. Weight loss has been well described as an additional benefit with liraglutide therapy, which prompted the manufacturer to evaluate and develop a higher dose formulation specifically for the treatment of obesity. Liraglutide 3 mg/day was approved by the U.S. Food and Drug Administration for this indication in December 2014. We performed a search of the Medline database to identify relevant literature focused on liraglutide's role specifically in treating obesity. Five clinical trials with this primary end point were identified. Data demonstrated that liraglutide can successfully achieve weight-loss benchmarks of 5% or more and 10% or more loss from baseline. The most common adverse effects were gastrointestinal and mild to moderate in intensity. The cost of therapy is high, averaging over $1000/month for out-of-pocket expenses if insurance coverage is not available. Liraglutide is also available for delivery only by subcutaneous injection, which may represent a barrier for patients. Liraglutide 3 mg/day represents another pharmacologic option for the treatment of obesity.

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Pharmacokinetics and Pharmacodynamics of Liraglutide, a Long‐Acting, Potent Glucagon‐Like Peptide‐1 Analog

Cited by 24 publications

References 69 publications

The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide

The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide

One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial

Liraglutide: A New Option for the Treatment of Obesity

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