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Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials.
Clément, K, van den Akker, E, Argente, J, Bahm, A, Chung, WK, Connors, H, De Waele, K, Farooqi, IS, Gonneau-Lejeune, J, Gordon, G, et al
The lancet. Diabetes & endocrinology. 2020;(12):960-970
Abstract
BACKGROUND The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity. METHODS These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the proportion of participants with at least 10% weight loss compared with baseline at approximately 1 year. A key secondary endpoint was mean percentage change in the most hunger score of the 11-point Likert-type scale at approximately 1 year on the therapeutic dose, which was assessed in a subset of participants aged 12 years or older in the full analysis set who demonstrated at least 5 kg weight loss (or ≥5% in paediatric participants if baseline bodyweight was <100 kg) over the 12-week open-label treatment phase and subsequently proceeded into the placebo-controlled withdrawal sequence, regardless of later disposition. These studies are registered with ClinicalTrials.gov, NCT02896192 and NCT03287960. FINDINGS Between Feb 14, 2017, and Sept 7, 2018, ten participants were enrolled in the POMC trial and 11 participants were enrolled in the LEPR trial, and included in the full analysis and safety sets. Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year. The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants. In the LEPR trial, the most commonly reported treatment-related adverse events were injection site reaction in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials. INTERPRETATION Our results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency. FUNDING Rhythm Pharmaceuticals.
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Efficacy of a novel herbal formulation for weight loss demonstrated in a 16-week randomized, double-blind, placebo-controlled clinical trial with healthy overweight adults.
Dixit, K, Kamath, DV, Alluri, KV, Davis, BA
Diabetes, obesity & metabolism. 2018;(11):2633-2641
Abstract
AIM: To re-evaluate the weight loss efficacy of LI85008F in healthy overweight adults via a 16-week randomized, double-blind, placebo-controlled clinical study. MATERIALS AND METHODS One hundred and forty overweight participants (body mass index [BMI] 27-29.9 kg/m2 , 29.3% male; ages 21-50 years) were randomized into placebo (n =70) and LI85008F (n =70) groups. The participants received either 900 mg/d of LI85008F in two divided doses or two identical placebo capsules. In addition, participants were counselled to follow an ~1800 kcal/d diet and to engage in walking for 30 min, 5 d/wk throughout the study. RESULTS At the end of the trial period, the LI85008F supplemented group showed significant reductions in body weight (5.36 ± 1.769 vs. 0.87 ± 1.381 kg; P < 0.0001) and BMI (2.05 ± 0.693 vs. 0.34 ± 0.559 kg/m2 ; P < 0.0001), compared with placebo. Significant reductions in waist and hip circumferences, and a 2.08-fold reduction of waist/hip ratio, were noted in the LI85008F supplemented group. LI85008F supplementation also resulted in significant improvements in lipid profiles, compared with the placebo; low-density lipoprotein (LDL) cholesterol decreased, while high-density lipoprotein (HDL) cholesterol increased, resulting in a significantly improved LDL/HDL ratio. No major adverse events were reported by the participants during the study. CONCLUSIONS The unique herbal extract blend LI85008F, combined with modest calorie restriction and physical activity, is well tolerated, safe, and effective for weight management in overweight men and women.
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Metformin-associated prevention of weight gain in insulin-treated type 2 diabetic patients cannot be explained by decreased energy intake: A post hoc analysis of a randomized placebo-controlled 4.3-year trial.
Out, M, Miedema, I, Jager-Wittenaar, H, van der Schans, C, Krijnen, W, Lehert, P, Stehouwer, C, Kooy, A
Diabetes, obesity & metabolism. 2018;(1):219-223
Abstract
Metformin prevents weight gain in patients with type 2 diabetes (T2D). However, the mechanisms involved are still unknown. In this post hoc analysis of the HOME trial, we aimed to determine whether metformin affects energy intake. Patients with T2D were treated with 850 mg metformin or received placebo added to insulin (1-3 times daily) for 4.3 years. Dietary intake was assessed at baseline, after 1 year and after 4.3 years, according to the dietary history method. Among the 310 included participants, 179 (93 placebo, 86 metformin) completed all 3 dietary assessments. We found no significant difference in energy intake after 4.3 years between the groups (metformin vs placebo: -31.0 kcal/d; 95% CI, -107.4 to 45.4; F-value, 1.3; df = 415; P = .27). Body weight in placebo users increased significantly more than in metformin-users during 4.3 years (4.9 ± 4.9 vs 1.1 ± 5.2 kg; t test: P ≤ .001). Linear mixed models did not show a significant effect of energy intake as explanation for the difference in weight gain between the groups (F-value, 0.1; df = 1; P = .82). In conclusion, the prevention of weight gain by metformin cannot be explained by reduced energy intake.
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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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Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
Greenway, FL, Fujioka, K, Plodkowski, RA, Mudaliar, S, Guttadauria, M, Erickson, J, Kim, DD, Dunayevich, E, ,
Lancet (London, England). 2010;(9741):595-605
Abstract
BACKGROUND Despite increasing public health concerns regarding obesity, few safe and effective drug treatments are available. Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight. The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants. METHODS Men and women aged 18-65 years who had a body-mass index (BMI) of 30-45 kg/m(2) and uncomplicated obesity or BMI 27-45 kg/m(2) with dyslipidaemia or hypertension were eligible for enrolment in this randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 34 sites in the USA. Participants were prescribed mild hypocaloric diet and exercise and were randomly assigned in a 1:1:1 ratio to receive sustained-release naltrexone 32 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB32), sustained-release naltrexone 16 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB16), or matching placebo twice a day, given orally for 56 weeks. The trial included a 3-week dose escalation. Randomisation was done by use of a centralised, computer-generated, web-based system and was stratified by study centre. Co-primary efficacy endpoints at 56 weeks were percentage change in bodyweight and proportion of participants who achieved a decrease in bodyweight of 5% or more. The primary analysis included all randomised participants with a baseline weight measurement and a post-baseline weight measurement while on study drug (last observation carried forward). This study is registered with ClinicalTrials.gov, number NCT00532779. FINDINGS 1742 participants were enrolled and randomised to double-blind treatment (naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus bupropion, n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of treatment (n=296; n=284; n=290, respectively) and 1453 (83%) were included in the primary analysis (n=471; n=471; n=511). Mean change in bodyweight was -1.3% (SE 0.3) in the placebo group, -6.1% (0.3) in the naltrexone 32 mg plus bupropion group (p<0.0001 vs placebo) and -5.0% (0.3) in the naltrexone 16 mg plus bupropion group (p<0.0001 vs placebo). 84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion (p<0.0001 vs placebo) and 186 (39%) assigned to naltrexone 16 mg plus bupropion (p<0.0001 vs placebo). The most frequent adverse event in participants assigned to combination treatment was nausea (naltrexone 32 mg plus bupropion, 171 participants [29.8%]; naltrexone 16 mg plus bupropion, 155 [27.2%]; placebo, 30 [5.3%]). Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups than in the placebo group. A transient increase of around 1.5 mm Hg in mean systolic and diastolic blood pressure was followed by a reduction of around 1 mm Hg below baseline in the naltrexone plus bupropion groups. Combination treatment was not associated with increased depression or suicidality events compared with placebo. INTERPRETATION A sustained-release combination of naltrexone plus bupropion could be a useful therapeutic option for treatment of obesity. FUNDING Orexigen Therapeutics.
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A randomized double-blind study comparing the efficacy and safety of orlistat versus placebo in obese patients with mild to moderate hypercholesterolemia.
de Castro, JJ, Dias, T, Chambel, P, Carvalheiro, M, Correia, LG, Guerreiro, L, Marques, O, Medina, JL, Nobre, E, Nunes, JS, et al
Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology. 2009;(12):1361-74
Abstract
INTRODUCTION Obesity is a chronic disease and a serious health problem that leads to increased prevalence of diabetes, hypertension, dyslipidemia and gallbladder disease. OBJECTIVE To evaluate the efficacy of orlistat for weight loss and improved lipid profile compared to placebo in obese patients with hypercholesterolemia, treated over a period of 6 months. METHODOLOGY In a 6-month, multicenter (10 centers in Portugal), double-blind, parallel, placebo-controlled study, 166 patients, aged 18-65 years, body mass index (BMI) > or = 27 kg/m2, LDL cholesterol > 155 mg/dl, were randomized to a reduced calorie diet (600 kcal/day deficit) plus orlistat three times a day or placebo. Exclusion criteria included triglycerides > 400 mg/dl, severe cardiovascular disease, uncontrolled hypertension, type 1 or 2 diabetes under pharmacological treatment, and gastrointestinal or pancreatic disease. RESULTS The mean difference in weight from baseline was 5.9% (5.6 kg) in the orlistat group vs. 2.3% (2.2 kg) in the placebo group. In the orlistat group 49% of patients achieved 5-10% weight loss and 8.8% achieved > 10%. The orlistat group showed a significant reduction in total and LDL cholesterol, with similar changes for HDL in both treatment groups. The frequency of gastrointestinal adverse events was slightly higher in the orlistat group than in the placebo group, leading to discontinuation in 7 patients. CONCLUSION Treatment with orlistat plus a reduced calorie diet for 6 months achieved significant reductions in weight, BMI and lipid parameters.
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Weight loss larger than 10% is needed for general improvement of levels of circulating adiponectin and markers of inflammation in obese subjects: a 3-year weight loss study.
Madsen, EL, Rissanen, A, Bruun, JM, Skogstrand, K, Tonstad, S, Hougaard, DM, Richelsen, B
European journal of endocrinology. 2008;(2):179-87
Abstract
OBJECTIVE To investigate the effects of: I) short- (8 weeks), II) long-term (3 years) weight loss, and III) the degree of weight loss on circulating levels of adiponectin, high sensitive-C reactive protein (hs-CRP), and fibrinogen in obese subjects. Moreover, to evaluate the effect of the lipase inhibitor, orlistat, on these parameters. DESIGN Weight loss induced in 93 obese subjects (mean weight: 108.9+/-15.8 kg) through 8-week very-low-energy diet (VLED, 800 kcal/day) followed by randomization to orlistat or placebo together with lifestyle intervention for further 3 years. Adiponectin and hs-CRP were measured at baseline, after 8 weeks of VLED and 6, 12, and 36 months after the VLED by flowmetric xMAP technology (Luminex Multi-Analyte Profiling System, Luminex Corp., Austin, TX, USA). Fibrinogen was measured in a coagulation assay. RESULTS Weight loss after VLED treatment was 14.3+/-4.5 kg and after 3 years 7.7+/-8.7 kg. Orlistat-treated subjects regained 3.9 kg less than placebo-treated from the end of the VLED to 3 years (P=0.01). No differences were detected between the two groups regarding changes in adiponectin, hs-CRP, or fibrinogen. Accordingly, the groups were combined for further analyses. Serum adiponectin increased by 22% (P<0.05) after the VLED but returned to baseline after 3 years. Both short- and long-term weight losses needed to be in excess of 10% (approximately 12 kg) in order to increase adiponectin levels significantly. Weight loss was associated with a significant decrease in hs-CRP. Fibrinogen decreased by 12% (P<0.05) after 3 years. CONCLUSIONS In obese subjects, weight loss was associated with an increase in serum adiponectin and a decrease in hs-CRP and plasma fibrinogen. Long-term weight loss (3 years) must exceed 10% to induce a combined significant improvement in these inflammatory markers.
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Orlistat increases serum paraoxonase activity in obese patients.
Audikovszky, M, Pados, G, Seres, I, Harangi, M, Fülöp, P, Katona, E, Illyés, L, Winkler, G, Katona, EM, Paragh, G
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2007;(4):268-73
Abstract
BACKGROUND AND AIM Previous studies have demonstrated that oxidative stress is increased in obese patients. The high-density lipoprotein (HDL) associated human paraoxonase 1 (PON1) can inhibit low-density lipoprotein oxidation and has an antiatherogenic effect. Our objective was to assess the effects of orlistat therapy combined with diet on body mass index (BMI), waist circumference, lipid parameters, blood pressure, serum glucose level and PON1 activity. METHODS AND RESULTS A longitudinal, multicenter, randomized study with and without orlistat treatment was performed. One hundred thirty nine otherwise healthy, obese subjects were divided in to two groups: 78 persons received orlistat (120 mg three times a day) combined with diet while 61 persons were kept on diet only. Anthropometrical parameters, serum lipid levels and PON1 activity were measured at baseline and after 6 months of treatment. BMI and waist circumference were reduced more pronouncedly in the orlistat group than in the control group. Patients receiving orlistat also had significantly greater improvements in fasting blood glucose levels and blood pressure. The orlistat-treated group showed a greater reduction in total cholesterol and triglyceride levels. In addition, the serum PON1 activity in these patients was significantly increased compared to the diet-only group. CONCLUSIONS The 6-month treatment with orlistat had a beneficial effect on the lipid profile and improved the antioxidant status by increasing serum PON1 activity. However, because of the limited therapeutic effectiveness, obese patients with hypercholesterolemia should receive additional lipid lowering medications.
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Effect of orlistat on weight regain and cardiovascular risk factors following a very-low-energy diet in abdominally obese patients: a 3-year randomized, placebo-controlled study.
Richelsen, B, Tonstad, S, Rössner, S, Toubro, S, Niskanen, L, Madsbad, S, Mustajoki, P, Rissanen, A
Diabetes care. 2007;(1):27-32
Abstract
OBJECTIVE To investigate the efficacy of orlistat on the maintenance of weight loss over 3 years following a major weight loss induced by very-low-energy diet (VLED) in obese patients with metabolic risk factors such as dyslipidemia, impaired fasting glucose, and diet-treated type 2 diabetes. RESEARCH DESIGN AND METHODS Initially, weight loss was induced by an 8-week VLED (600-800 kcal/day) in 383 patients with a mean BMI of 37.5 kg/m(2) (range 30.0-45.2). Those who lost > or = 5% of their body weight (309 of 383 patients) were then randomized to receive lifestyle counseling for 3 years together with either orlistat 120 mg t.i.d. or matching placebo capsules. Primary end points were the maintenance of > or = 5% weight loss after 3 years. Additionally, differences in the development of type 2 diabetes between orlistat and placebo were analyzed. RESULTS The VLED induced a mean weight loss of 14.4 +/- 2.0 kg among the subsequently randomized patients. The mean weight gain after 3 years was lower with orlistat than with placebo (4.6 +/- 8.6 vs. 7.0 +/- 7.1 kg; P < 0.02). The number of participants who achieved > or =5% weight loss also favored orlistat (67 vs. 56%; P = 0.037). Waist circumference was significantly more reduced in the orlistat group (P < 0.05), but no other differences in the risk factors were observed between the two groups. The incidences of new cases of type 2 diabetes were significantly reduced in the orlistat group (8 cases out of 153 subjects) versus placebo (17 cases out of 156 subjects) (P = 0.041). CONCLUSIONS The addition of orlistat to lifestyle intervention was associated with maintenance of an extra 2.4 kg weight loss after VLED for up to 3 years in obese subjects. The combination of orlistat and lifestyle intervention was associated with a reduced occurrence of type 2 diabetes.
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Orlistat in the treatment of overweight or obese Chinese patients with newly diagnosed Type 2 diabetes.
Shi, YF, Pan, CY, Hill, J, Gao, Y
Diabetic medicine : a journal of the British Diabetic Association. 2005;(12):1737-43
Abstract
AIMS: Orlistat promotes weight loss in overweight and obese patients with Type 2 diabetes receiving hypoglycaemic treatment, but has not been investigated in patients with newly diagnosed and previously untreated Type 2 diabetes. We evaluated the efficacy of 24 weeks' treatment with orlistat, combined with a mildly reduced-calorie diet, on weight loss and glycaemic control in overweight and obese patients with newly diagnosed and previously untreated Type 2 diabetes. METHODS A total of 249 Chinese patients (body mass index 25-40 kg/m2) with recently diagnosed Type 2 diabetes were randomized to placebo (n=124) or orlistat 120 mg (n=125) three times daily; all patients followed a mildly reduced-calorie diet. Patients had HbA1c 6.5-8.5% (mean 7.3%) and had never received any glucose-lowering medication. RESULTS Orlistat-treated patients achieved significantly greater weight loss at the study end than placebo-treated patients (-5.4 vs. -2.4 kg; P<0.0001). More orlistat than placebo patients lost>or=5% (60.5 vs. 26.8%; P<0.0001) and >or=10% of their body weight (20.2 vs. 4.9%; P=0.0002). A significantly greater decrease in HbA(1c) from baseline was obtained with orlistat than placebo (-1.0 vs. -0.6%; P=0.0008). Orlistat-treated patients achieved a significantly greater decrease in fasting plasma glucose (-1.3 vs. -0.5 mmol/l; P=0.0003) and in the 2-h oral glucose tolerance test (-4.1 vs. -1.4 mmol/l; P<0.0001) than placebo recipients. Also, more orlistat- than placebo-treated patients improved from diabetic status to normal or impaired glucose tolerance (44.3 vs. 32.5%; P=0.0763) after 24 weeks. Orlistat also produced improvements in lipid profiles and waist circumference. CONCLUSIONS In combination with a mildly reduced-calorie diet, orlistat significantly reduces body weight, and improves glycaemic control and several cardiovascular risk factors in overweight and obese Chinese patients with newly diagnosed Type 2 diabetes.