NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study
ABSTRACT The frequency of obesity has risen dramatically in recent years but only few safe and effective drugs are currently available. We assessed the effect of liraglutide on bodyweight and tolerability in obese individuals without type 2 diabetes.
We did a double-blind, placebo-controlled 20-week trial, with open-label orlistat comparator in 19 sites in Europe. 564 individuals (18-65 years of age, body-mass index 30-40 kg/m2) were randomly assigned, with a telephone or web-based system, to one of four liraglutide doses (1.2 mg, 1.8 mg, 2.4 mg, or 3.0 mg, n=90-95) or to placebo (n=98) administered once a day subcutaneously, or orlistat (120 mg, n=95) three times a day orally. All individuals had a 500 kcal per day energy-deficit diet and increased their physical activity throughout the trial, including the 2-week run-in. Weight change analysed by intention to treat was the primary endpoint. An 84-week open-label extension followed. This study is registered with ClinicalTrials.gov, number NCT00422058.
Participants on liraglutide lost significantly more weight than did those on placebo (p=0.003 for liraglutide 1.2 mg and p<0.0001 for liraglutide 1.8-3.0 mg) and orlistat (p=0.003 for liraglutide 2.4 mg and p<0.0001 for liraglutide 3.0 mg). Mean weight loss with liraglutide 1.2-3.0 mg was 4.8 kg, 5.5 kg, 6.3 kg, and 7.2 kg compared with 2.8 kg with placebo and 4.1 kg with orlistat, and was 2.1 kg (95% CI 0.6-3.6) to 4.4 kg (2.9-6.0) greater than that with placebo. More individuals (76%, n=70) lost more than 5% weight with liraglutide 3.0 mg that with placebo (30%, n=29) or orlistat (44%, n=42). Liraglutide reduced blood pressure at all doses, and reduced the prevalence of prediabetes (84-96% reduction) with 1.8-3.0 mg per day. Nausea and vomiting occurred more often in individuals on liraglutide than in those on placebo, but adverse events were mainly transient and rarely led to discontinuation of treatment.
Liraglutide treatment over 20 weeks is well tolerated, induces weight loss, improves certain obesity-related risk factors, and reduces prediabetes.
Novo Nordisk A/S, Bagsvaerd, Denmark.
- SourceAvailable from: Kristy Heppner
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- "s the time that the drug remains in circulation ( Knudsen et al . , 2000 ) . The half - life for liraglutide is about 10 – 14 h in humans ( Agerso et al . , 2002 ) and is recommended for once - daily administration . Both exenatide ( DeFronzo et al . , 2005 ; Heine et al . , 2005 ; Moretto et al . , 2008 ; Norris et al . , 2009 ) and liraglutide ( Astrup et al . , 2009 ; Garber et al . , 2009 ; Niswender et al . , 2013 ; Lean et al . , 2014 ) significantly improve glycemic control and cause a significant body weight loss in T2DM patients . Gastrointestinal side effects including nau - sea and vomiting have been reported with both exenatide and liraglutide treatment although these side effects are ofte"
ABSTRACT: Glucagon-like peptide-1 (GLP-1) enhances meal-related insulin secretion, which lowers blood glucose excursions. In addition to its incretin action, GLP-1 acts on the GLP-1 receptor (GLP-1R) in the brain to suppress feeding. These combined actions of GLP-1R signaling cause improvements in glycemic control as well as weight loss in type II diabetes (T2DM) patients treated with GLP-1R agonists. This is a superior advantage of GLP-1R pharmaceuticals as many other drugs used to treat T2DM are weight neutral or actual cause weight gain. This review summarizes GLP-1R action on energy and glucose metabolism, the effectiveness of current GLP-1R agonists on weight loss in T2DM patients, as well as GLP-1R combination therapies.Frontiers in Neuroscience 03/2015; 9:92. DOI:10.3389/fnins.2015.00092 · 3.66 Impact Factor
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- "Glucagon-like peptide-1 receptor (GLP-1R) agonists represent the best-in-class pharmacotherapies for treating type 2 diabetes (Drucker & Nauck, 2006). Emerging evidence supports that GLP-1R agonism can lower body weight in obese subjects (Astrup et al, 2009; Madsbad, 2014), corroborating rodent studies. In humans, however, the anorectic efficacy of GLP-1 mimetics is modest (Vilsboll et al, 2012). "
ABSTRACT: We assessed the efficacy of simultaneous agonism at the glucagon-like peptide-1 receptor (GLP-1R) and the melanocortin-4 receptor (MC4R) for the treatment of obesity and diabetes in rodents. Diet-induced obese (DIO) mice were chronically treated with either the long-acting GLP-1R agonist liraglutide, the MC4R agonist RM-493 or a combination of RM-493 and liraglutide. Co-treatment of DIO mice with RM-493 and liraglutide improves body weight loss and enhances glycemic control and cholesterol metabolism beyond what can be achieved with either mono-therapy. The superior metabolic efficacy of this combination therapy is attributed to the anorectic and glycemic actions of both drugs, along with the ability of RM-493 to increase energy expenditure. Interestingly, compared to mice treated with liraglutide alone, hypothalamic Glp-1r expression was higher in mice treated with the combination therapy after both acute and chronic treatment. Further, RM-493 enhanced hypothalamic Mc4r expression. Hence, co-dosing with MC4R and GLP-1R agonists increases expression of each receptor, indicative of minimized receptor desensitization. Together, these findings suggest potential opportunities for employing combination treatments that comprise parallel MC4R and GLP-1R agonism for the treatment of obesity and diabetes.EMBO Molecular Medicine 02/2015; 7(3). DOI:10.15252/emmm.201404508 · 8.67 Impact Factor
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- "GLP-1 receptor agonists are currently used for the treatment of type 2 diabetes. It has been observed that these drugs also produce a relevant weight loss (Monami et al., 2009); for this reason, some of the molecules of this class are currently under development as a treatment for obesity in non-diabetic individuals, with interesting results from clinical trials (Astrup et al., 2009, 2012). Mechanisms of weight loss with GLP-1 and its analogs are probably complex and not completely elucidated. "
ABSTRACT: Glucagon-Like Peptide-1 (GLP-1) receptor agonists, used as glucose-lowering drugs, also induce weight loss by inhibiting food intake. The present study was aimed at the assessment of the in vitro effects of the GLP-1 receptor agonist liraglutide on proliferation and differentiation of human adipose stem cells (ASC) obtained from subcutaneous adipose tissue of morbidly obese subjects undergoing bariatric surgery. Liraglutide (10-100 nM) significantly inhibited ASC proliferation and viability, with a maximum effect at 6 days of culture (45% and 50%, for liraglutide 10 and 100 nM, respectively); the effect was reverted by exendin 9-39. Glucose uptake was significantly reduced by liraglutide in a dose dependent manner. Treatment with liraglutide reduced intracellular lipid accumulation in differentiating ASC, together with FABP-4 mRNA expression (-18%, -23%, -46%, for 1 nM, 10 nM and 100 nM, respectively), whereas it stimulated adiponectin (APN) expression (1.86, 2.64, 2.28 fold increase, for 1 nM, 10 nM and 100 nM, respectively). Liraglutide exerts effects on human adipose cell precursors, inhibiting proliferation and differentiation, while stimulating the expression of the insulin-sensitizing adipokine APN. These effects could contribute to the actions of GLP-1 receptor agonists on body weight and insulin sensitivity. Copyright © 2014. Published by Elsevier Ireland Ltd.Molecular and Cellular Endocrinology 01/2015; 402. DOI:10.1016/j.mce.2014.12.021 · 4.41 Impact Factor