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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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Daily consumption of Reliv Glucaffect for 8 weeks significantly lowered blood glucose and body weight in 50 subjects.
Belcaro, G, Cesarone, M, Silvia, E, Ledda, A, Stuard, S, G, V, Dougall, M, Cornelli, U, Hastings, C, Schönlau, F
Phytotherapy research : PTR. 2009;(12):1673-7
Abstract
A public change to healthier lifestyles with more physical activity and better nutrition, including caloric restriction, is required to address the obesity epidemic. Weight loss can be achieved by caloric restrictions; current research suggests that this may be achieved by consumption of slowly absorbed carbohydrates owing to the resulting prolonged satiety. Our rationale was to prolong the satiety of overweight volunteers by supplementation with a proprietary formulation Glucaffect which delays absorption of carbohydrates. Glucaffect provides potent alpha-glucosidase inhibitors of herbal source such Pycnogenol, Madeglucyl and various others which obstruct absorption of carbohydrates, such as starch. Fifty overweight subjects received either Glucaffect or an inactive control product for eight weeks. Consumption of Glucaffect was found to statistically significantly lower blood-fasting glucose from baseline 145.3 mg/dL to 101.1 mg/dL (-30.4%) and Hba1c from 7.59% to 6.33% as compared to the control group where values decreased only marginally. The weight and the body mass index (BMI) decreased significantly from an average of 88.5 kg (BMI 26.8 kg/m2) to 81.3 kg (BMI 24.5 kg/m2) as compared to the control group. In conclusion, Glucaffect enabled subjects with metabolic syndrome to achieve healthy BMI and blood glucose levels. Glucaffect was well tolerated and no subject dropped out.
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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.
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Short-term administration of orlistat reduced daytime triglyceridemia in obese women with the metabolic syndrome.
Tzotzas, T, Samara, M, Constantinidis, T, Tziomalos, K, Krassas, G
Angiology. 2007;(1):26-33
Abstract
The objective of this prospective, controlled, randomized study was to evaluate the effect of orlistat administration for 10 days on daytime capillary triglyceridemia in obese women with metabolic syndrome (MetSyn). Thirty-two obese, nondiabetic women with MetSyn were evaluated. The presence of MetSyn was defined according to the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATP III) criteria. Patients were randomized into 2 similar groups: group A (orlistat), mean age 50.1 -/+ 8.2 years, received a low-calorie diet combined with orlistat 120 mg tid for 10 days and group B (control), mean age 51.2 -/+ 9.1 years, received only the low-calorie diet for the same period of time. Anthropometric, lipids, and parameters of insulin resistance were measured before and after 10 days of intervention. Capillary triglycerides (TGc) were measured at 6 different time points during the day and daytime triglyceridemia was expressed as area under the curve of TGc (AUC-TGc). Most anthropometric measurements (body weight, body mass index, waist circumference, and percentage of fat mass) and most metabolic parameters (total cholesterol [TC], fasting venous triglycerides [TGfv], high-density lipoprotein cholesterol [HDL-C] levels, fasting glucose [FG], fasting insulin [FI], and homeostasis model for assessment [HOMA] for insulin resistance index) decreased significantly in both groups, while waist-to-hip ratio (WHR) and systolic (SBP) and diastolic blood pressure (DBP) did not change significantly in both groups and low-density lipoprotein cholesterol (LDL-C) levels decreased only in the orlistat group. Following minimal weight loss, TGc at most time points and AUC-TGc were significantly reduced only in group A. In group A, AUG-TGc decreased by 17% from 36.4 -/+11.8 to 30.2 -/+9.9 mmol/Lxh(-1) (p < 0.001), and this reduction was significantly greater compared with the control group (p < 0.05) and remained significant after percentage of weight loss was taken into account. This decrease of AUC-TGc significantly correlated with the decrease of HOMA index (p < 0.05, r = 0.39) and the decrease of TGfv (p < 0.001, r = 0.62). The tolerability of orlistat was very good and side effects were transient and of minimal intensity. In conclusion, short-term administration of orlistat significantly reduced daytime triglyceridemia in obese, nondiabetic women with MetSyn. This reduction could offer cardiovascular benefits in these high-risk patients. Long-term studies with more patients are needed to reach definite conclusions.
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The ORLIstat and CArdiovascular risk profile in patients with metabolic syndrome and type 2 DIAbetes (ORLICARDIA) Study.
Didangelos, TP, Thanopoulou, AK, Bousboulas, SH, Sambanis, CL, Athyros, VG, Spanou, EA, Dimitriou, KC, Pappas, SI, Karamanos, BG, Karamitsos, DT
Current medical research and opinion. 2004;(9):1393-401
Abstract
BACKGROUND Metabolic syndrome (MetSyn) is associated with a marked increase in the risk of cardiovascular disease, especially in patients with type 2 diabetes mellitus (DM). AIM: To investigate the effect of orlistat plus hypocaloric diet (HCD) vs HCD alone on the cardiovascular risk profile in patients with both MetSyn (National Cholesterol Educational Program--NCEP--Adult Treatment Panel III definition) and type 2 DM. METHODS This was a prospective, multicentre, open-label, randomized, controlled study. One hundred and twenty-six patients, free of cardiovascular disease at baseline, were included in the final analysis. Ninety-four (73%) patients were treated with orlistat (360 mg/day) and HCD for a 6-month period, while 34 (27%) were on HCD alone. Analysis of covariance was used to assess differences between the treatment groups over time. MAIN OUTCOME MEASURES Components of the MetSyn criteria assessed were: waist circumference; systolic and diastolic blood pressure; fasting glucose, triglycerides; high-density lipoprotein cholesterol (HDL-C) plus body mass index; glycosylated haemoglobin (HbA1C); homeostasis model for assessment of insulin resistance (HOMA) index; and total and low-density lipoprotein cholesterol (LDL-C). RESULTS By protocol, all patients had MetSyn at baseline. After a 6 month treatment period there were significant differences between the orlistat plus HCD vs the HCD-alone groups in body weight (p = 0.0001), waist circumference (p < 0.0001), fasting glucose (p < 0.0001), HbA(1C) (p < 0.0001), systolic blood pressure (p = 0.024), total cholesterol (p < 0.0001), LDL-C (p = 0.034), and HOMA index (p = 0.022), while there were no significant differences in triglycerides and HDL-C. Orlistat was well tolerated. By the end of the study, 65% of the patients on orlistat plus HCD were still meeting the MetSyn criteria and 41% had four to five MetSyn components vs 91% (p < 0.0001) and 53% (p = 0.017), respectively, of those on HCD alone. CONCLUSIONS Orlistat plus HCD favourably modified several cardiovascular risk factors in patients with both MetSyn and type 2 DM. These effects might partly offset the excess cardiovascular risk and improve outcome in this patient population.
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The prevalence of the metabolic syndrome in patients with schizoaffective disorder--bipolar subtype.
Basu, R, Brar, JS, Chengappa, KN, John, V, Parepally, H, Gershon, S, Schlicht, P, Kupfer, DJ
Bipolar disorders. 2004;(4):314-8
Abstract
OBJECTIVES To evaluate the point prevalence of the metabolic syndrome in patients with schizoaffective disorder--bipolar type. METHODS Consenting patients who were participants in an ongoing clinical trial of adjunctive topiramate treatment for schizoaffective disorder, bipolar type were evaluated at baseline for the point prevalence of the metabolic syndrome. The criteria for the metabolic syndrome included: (a) waist circumference > 102 cm (40 inches) in males, or > 88 cm (35 inches) in females; (b) fasting serum triglyceride levels > or = 150 mg/dL; (c) fasting high density lipoproteins (HDL) cholesterol <40 mg/dL in men or <50 mg/dL in women; (d) blood pressure > or = 130/85 mmHg; and (e) fasting glucose > or = 110 mg/dL. Subjects who had at least three of these five criteria were defined as meeting criteria for the metabolic syndrome. RESULTS Thirty-six subjects (males = 15, females = 21) were evaluated, and three were excluded for missing data. Among those 33 subjects with complete data, 14 subjects (42.4%, males = 7, females = 7, African Americans = 6, Caucasians = 8) met criteria for the metabolic syndrome. Not unexpectedly, those with the metabolic syndrome were significantly more likely to be obese, and have significantly higher mean systolic and diastolic blood pressure, mean fasting triglyceride levels and larger mean waist circumferences, and significantly lower HDL cholesterol levels; and a trend toward higher fasting blood glucose levels. Furthermore, the fasting mean total cholesterol in those with the metabolic syndrome was 217 mg/dL (+/-46). CONCLUSIONS This preliminary report suggests that the point prevalence of the metabolic syndrome in patients with schizoaffective disorder appears to be higher than that reported in the general population of the USA. Targeted weight reduction and life style change strategies (increased exercise, smoking cessation, stress reduction) may provide useful interventions to decrease the morbidity and mortality that accompanies the presence of the metabolic syndrome in patients with psychiatric illnesses.