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Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.
Astrup, A, Carraro, R, Finer, N, Harper, A, Kunesova, M, Lean, ME, Niskanen, L, Rasmussen, MF, Rissanen, A, Rössner, S, et al
International journal of obesity (2005). 2012;(6):843-54
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Abstract
OBJECTIVE Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years. DESIGN A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers. SUBJECTS A total of 564 adults (n=90-98 per group; body mass index 30-40 kg m(-2)) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90-95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007-April 2009 and is registered with Clinicaltrials.gov, number NCT00480909. RESULTS From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7-8.0) more weight than those on placebo and 3.8 kg (1.6-6.0) more than those on orlistat (P0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3-4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids. CONCLUSION Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.
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Effects of the new dual PPAR α/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism.
Cariou, B, Zaïr, Y, Staels, B, Bruckert, E
Diabetes care. 2011;(9):2008-14
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Abstract
OBJECTIVE We evaluated the metabolic effects and tolerability of GFT505, a novel dual peroxisome proliferator-activated receptor α/δ agonist, in abdominally obese patients with either combined dyslipidemia or prediabetes. RESEARCH DESIGN AND METHODS The S1 study was conducted in 94 patients with combined dyslipidemia while the S2 study was conducted in 47 patients with prediabetes. Participants were randomly assigned in a double-blind manner to GFT505 at 80 mg/day or placebo for 28 (S1) or 35 (S2) days. Primary efficacy end points were changes from baseline at week 4 in both fasting plasma triglycerides and HDL cholesterol in the S1 group and 2-h glucose upon oral glucose tolerance test in the S2 group. RESULTS In comparison with placebo, GFT505 significantly reduced fasting plasma triglycerides (S1: least squares means -16.7% [95% one-sided CI -∞ to -5.3], P = 0.005; S2: -24.8% [-∞ to -10.5], P = 0.0003) and increased HDL cholesterol (S1: 7.8% [3.0 to ∞], P = 0.004; S2: 9.3% [1.7 to ∞], P = 0.009) in both studies, whereas LDL cholesterol only decreased in S2 (-11.0% [ -∞ to -3.5], P = 0.002). In S2, GFT505 did not reduce 2-h glucose (-0.52 mmol/L [-∞ to 0.61], P = 0.18) but led to a significant decrease of homeostasis model assessment of insulin resistance (-31.4% [-∞ to 12.5], P = 0.001), fasting plasma glucose (-0.37 mmol/L [-∞ to -0.10], P = 0.01) and fructosamine (-3.6% [-∞ to -0.20], P = 0.02). GFT505 also reduced γ glutamyl transferase levels in both studies (S1: -19.9% [-∞ to -12.8], P < 0.0001; S2: -15.1% [-∞ to -1.1], P = 0.004). No specific adverse safety signals were reported during the studies. CONCLUSIONS GFT505 may be considered a new drug candidate for the treatment of lipid and glucose disorders associated with the metabolic syndrome.
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[Cardiometabolic effects of rimonabant in obese/overweight subjects with dyslipidaemia or type 2 diabetes].
Scheen, AJ, Van Gaal, LF
Revue medicale de Liege. 2007;(2):81-5
Abstract
Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. It has been evaluated in the RIO ("Rimonabant In Obesity and related disorders") programme including above 6.600 overweight/obese patients with or without comorbidities followed for 1 to 2 years. Compared to placebo, rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. In patients with type 2 diabetes, rimonabant also diminishes HbA1c levels, an effect confirmed in the recent SERENADE trial. Almost half of the metabolic effects occurs beyond weight loss, suggesting direct peripheral effects of rimonabant. Rimonabant is indicated in Europe as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.