Orlistat-induced weight loss

Orlistat-induced weight loss:
improves fasting glycemia, left ventricular diastolic function, and sympathovagal balance in severely obese patients with type 2 diabetes.

orlistat may further improve LDL phenotype in overweight/obese patients.

the orlistat group were 2.44 times more likely to experience a weight loss ≥5%

Addition of orlistat should be considered as part of a weight loss intervention

Faster improvement of glycemic profile and FPI was obtained with orlistat There was a significant reduction of lipid profile with orlistat, not with placebo.
Orlistat was more effective than placebo in ameliorating inflammatory parameters such as ADN and TNF-alpha,

Orlistat improves ventricular diastolic functions and decreases LV mass. It also contributes to partial improvement in right ventricular systolic function.

Orlistat plus l-carnitine gave a better improvement in body weight, glycemic and lipid profile compared to orlistat alone; furthermore, a faster and better improvement in inflammatory parameters was observed with orlistat plus l-carnitine compared to orlistat alone.

Amplify’d from www.ncbi.nlm.nih.gov

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Rapid Commun Mass Spectrom. 2011 Feb 15;25(3):449-52. doi: 10.1002/rcm.4875.

Visualizing inhibition of fatty acid synthase through mass spectrometric analysis of mitochondria from melanoma cells.

Zecchin KG, Alberici LC, Riccio MF, Eberlin MN, Vercesi AE, Graner E, Catharino RR.

Departamento de Diagnóstico Oral, Faculdade de Odontologia de Piracicaba, Universidade Estadual de Campinas (UNICAMP), Piracicaba, SP, 13414-018, Brazil. kgzecchin@yahoo.com


Fatty acid synthase (FASN) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long-chain fatty acid palmitate. In contrast to most normal cells, FASN is overexpressed in a variety of human cancers including cutaneous melanoma, in which its levels of expression are associated with a poor prognosis and depth of invasion. Recently, we have demonstrated the mitochondrial involvement in FASN inhibition-induced apoptosis in melanoma cells. Herein we compare, via electrospray ionization mass spectrometry (ESI-MS), free fatty acids (FFA) composition of mitochondria isolated from control (EtOH-treated cells) and Orlistat-treated B16-F10 mouse melanoma cells. Principal component analysis (PCA) was applied to the ESI-MS data and found to separate the two groups of samples. Mitochondria from control cells showed predominance of six ions, that is, those of m/z 157 (Pelargonic, 9:0), 255 (Palmitic, 16:0), 281 (Oleic, 18:1), 311 (Arachidic, 20:0), 327 (Docosahexaenoic, 22:6) and 339 (Behenic, 22:0). In contrast, FASN inhibition with Orlistat changes significantly mitochondrial FFA composition by reducing synthesis of palmitic acid, and its elongation and unsaturation products, such as arachidic and behenic acids, and oleic acid, respectively. ESI-MS of mitochondria isolated from Orlistat-treated cells presented therefore three major ions of m/z 157 (Pelargonic, 9:0), 193 (unknown) and 199 (Lauric, 12:0). These findings demonstrate therefore that FASN inhibition by Orlistat induces significant changes in the FFA composition of mitochondria.

Copyright © 2011 John Wiley & Sons, Ltd.

PMID: 21213365 [PubMed – in process]

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Lab Invest. 2011 Feb;91(2):232-40. Epub 2010 Aug 30.

Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis.

Zecchin KG, Rossato FA, Raposo HF, Melo DR, Alberici LC, Oliveira HC, Castilho RF, Coletta RD, Vercesi AE, Graner E.

1] Departamento de Diagnóstico Oral, Faculdade de Odontologia de Piracicaba, Universidade Estadual de Campinas (UNICAMP), Piracicaba, São Paulo, Brazil [2] Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil.


Fatty acid synthase (FASN) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long-chain fatty acid, palmitate. In contrast to most normal cells, FASN is overexpressed in a variety of human cancers, including cutaneous melanoma, in which its levels of expression are associated with tumor invasion and poor prognosis. We have previously shown that FASN inhibition with orlistat significantly reduces the number of spontaneous mediastinal lymph node metastases following the implantation of B16-F10 mouse melanoma cells in the peritoneal cavity of C57BL/6 mice. In this study, we investigate the biological mechanisms responsible for the FASN inhibition-induced apoptosis in B16-F10 cells. Both FASN inhibitors, cerulenin and orlistat, significantly reduced melanoma cell proliferation and activated the intrinsic pathway of apoptosis, as demonstrated by the cytochrome c release and caspase-9 and -3 activation. Further, apoptosis was preceded by an increase in both reactive oxygen species production and cytosolic calcium concentrations and independent of p53 activation and mitochondrial permeability transition. Taken together, these findings demonstrate the mitochondrial involvement in FASN inhibition-induced apoptosis in melanoma cells.

PMID: 20805790 [PubMed – in process]

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Pediatr Clin North Am. 2011 Feb;58(1):139-53.

Pharmacotherapy for obese adolescents.

Greydanus DE, Bricker LA, Feucht C.

Department of Pediatrics and Human Development, Michigan State University College of Human Medicine, MSU/Kalamazoo Center for Medical Studies, 1000 Oakland Drive, Kalamazoo, MI 49009-1284, USA.


The pharmaceutical search to induce weight loss was precipitated by the United States Food and Drug Administration’s (FDA) 1959 formal approval of phentermine for short-term weight loss despite limited research supporting its assertions of weight loss. In addition to sympathomimetic amine products like phentermine, other medications considered in this article include herbal products, sibutramine, orlistat, metformin, and rimonabant. The use of pharmacotherapy for morbidly obese adolescents should be part of a comprehensive weight-loss program that recommends diet, exercise, and behavioral modification. Side effects and the possibility of major adverse effects should be remembered when considering use of these products.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID: 21281853 [PubMed – in process]

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Cardiovasc Diabetol. 2011 Jan 27;10(1):11. [Epub ahead of print]

“The metabolic syndrome… is dead”: These reports are an exaggeration.

Tenenbaum A, Fisman EZ.


ABSTRACT: The debates continue over the validity of the metabolic syndrome concept. The continuous increment of the obesity pandemic is almost worldwide paralleled by rising rates of metabolic syndrome prevalence. Then, it seems obvious that these debates drove the need for further investigations as well as a deeper cooperation between relevant national and international organizations regarding the issue. Instead, part of the scientific community elected to totally “dismiss” the concept of the metabolic syndrome. Meanwhile, the best available evidence from three consecutive large meta-analyses has systematically shown that people with metabolic syndrome are at increased risk of cardiovascular events. The most recent and largest of them included near one million patients (total n = 951,083). The investigators concluded that the metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality rates. One of the ways to hit the metabolic syndrome is an utterly simplistic view on this concept as a predictive tool only. Of course, the presence of the metabolic syndrome possesses a definite predictive value, but first of all it is a widely accepted concept regarding a biological condition based on the complex and interrelated pathophysiological mechanisms starting from excess central adiposity and insulin resistance. Therefore, it is completely unfair to compare it with statistically constructed predictive tools, including stronger prognostic variables even unrelated to each other from the biological point of view. For example, in the criteria for metabolic syndrome (in contrast to Framingham score) age and cholesterol – presumably low density lipoprotein – cholesterol (LDL-C) – levels are not included, as well as a variety of strong predictors used in other risk-stratification scores: previous myocardial infarction, heart failure, smoking, family history, etc. However, the metabolic syndrome identifies additional important residual vascular risk mainly associated with insulin resistance and atherogenic dyslipidemia (low high density lipoprotein-cholesterol (HDL-C), high triglycerides, small, dense LDL-C). Therefore, the metabolic syndrome could be a useful additional contributor in estimation of global cardiovascular risk beyond age, high LDL-C or other standard risk factors. The components of the metabolic syndrome have partially overlapping mechanisms of pathogenic actions mediated through common metabolic pathways. Therefore their total combined effect could be less than the summed of the individual effects. The concept that the metabolic syndrome is a consequence of obesity and insulin resistance, provides a useful “life-style changes” approach for prevention and treatment: caloric restriction, weight-loss and increased physical activity. The next step could theoretically be pharmacological interventions such as metformin, acarbose, fibrates, weight-loss drugs (currently only orlistat is practically available) and perhaps glucagon-like peptide-1 agonists. A third step should probably be kept for bariatric surgery.

PMID: 21269524 [PubMed – as supplied by publisher]Free Article

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Br J Pharmacol. 2011 Jan 26. doi: 10.1111/j.1476-5381.2011.01245.x. [Epub ahead of print]

The utility of animal models to evaluate novel anti-obesity agents.

Vickers SP, Jackson HC, Cheetham SC.

RenaSci Consultancy Ltd., BioCity, Pennyfoot Street, Nottingham. UK. NG1 1GF.


The global incidence of obesity continues to rise and is a major driver of morbidity and mortality through cardiovascular and cerebrovascular diseases. Animal models employed in the discovery of novel treatments for obesity range from straightforward measures of food intake in lean rodents to long term studies in animals exhibiting obesity due to the continuous access to diets high in fat. The utility of these animal models can be extended to determine, for example, that weight loss is due to fat loss and/or assess whether beneficial changes in key plasma parameters (e.g. insulin) are evident. In addition, behavioural models such as the behavioural satiety sequence can be used to confirm that a drug treatment has a selective effect on food intake. Typically, animal models have excellent predictive validity whereby drug-induced weight loss in rodents subsequently translates to weight loss in man. However, despite this, at the time of writing orlistat (Europe; USA) remains the only drug currently marketed for the treatment of obesity, with sibutramine having recently been withdrawn from sale globally due to the increased incidence of serious, non-fatal cardiovascular events. Whilst the utility of rodent models in predicting clinical weight loss is detailed, the review also discusses whether animals can be used to predict adverse events such as those seen with recent anti-obesity drugs in the clinic.

© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

PMID: 21265828 [PubMed – as supplied by publisher]

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J Obes. 2011;2011:394658. Epub 2010 Dec 23.

Impact of orlistat-induced weight loss on diastolic function and heart rate variability in severely obese subjects with diabetes.

Martin J, Paquette C, Marceau S, Hould FS, Lebel S, Simard S, Dumesnil JG, Poirier P.

Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), 2725 Chemin Ste-Foy, QC, Canada G1V 4G5.


Objective. Determine the impact of Orlistat-induced weight loss on metabolic profile and cardiovascular function in severely obese patients with type 2 diabetes. Methods. Twenty-nine patients were randomized either to a nonplacebo control group or to a treatment group with Orlistat thrice a day. Metabolic profile, anthropometric parameters, heart rate variability indices, and echocardiographic variables were measured before and after a 12-week treatment period. Results. Treatment with Orlistat induced a modest but significant weight loss compared to controls (3.7 ± 3.0 versus 0.5 ± 2.2 kg, resp.; P = .003). There was significant decrease in fasting glycemia (7.9 ± 3.0 versus 6.7 ± 2.2 mmol/L; P = .03) and significant improvements in left ventricular diastolic function (P = .03) and in the sympathovagal balance (LF/HF ratio) (P = .04) in the Orlistat group. Conclusion. These results suggest that a modest weight loss improves fasting glycemia, left ventricular diastolic function, and sympathovagal balance in severely obese patients with type 2 diabetes.

PMID: 21253512 [PubMed – in process]PMCID: PMC3021886Free PMC Article

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J Obes. 2011;2011:179674. Epub 2010 Dec 12.

Pharmacotherapies for obesity: past, current, and future therapies.

Ioannides-Demos LL, Piccenna L, McNeil JJ.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Alfred Centre, Commercial Road, Melbourne, VIC 3004, Australia.


Past therapies for the treatment of obesity have typically involved pharmacological agents usually in combination with a calorie-controlled diet. This paper reviews the efficacy and safety of pharmacotherapies for obesity focusing on drugs approved for long-term therapy (orlistat), drugs approved for short-term use (amfepramone [diethylpropion], phentermine), recently withdrawn therapies (rimonabant, sibutamine) and drugs evaluated in Phase III studies (taranabant, pramlintide, lorcaserin and tesofensine and combination therapies of topiramate plus phentermine, bupropion plus naltrexone, and bupropion plus zonisamide). No current pharmacotherapy possesses the efficacy needed to produce substantial weight loss in morbidly obese patients. Meta-analyses support a significant though modest loss in bodyweight with a mean weight difference of 4.7 kg (95% CI 4.1 to 5.3 kg) for rimonabant, 4.2 kg (95% CI 3.6 to 4.8 kg) for sibutramine and 2.9 kg (95% CI 2.5 to 3.2 kg) for orlistat compared to placebo at ≥12 months. Of the Phase III pharmacotherapies, lorcaserin, taranabant, topiramate and bupropion with naltrexone have demonstrated significant weight loss compared to placebo at ≥12 months. Some pharmacotherapies have also demonstrated clinical benefits. Further studies are required in some populations such as younger and older people whilst the long term safety continues to be a major consideration and has led to the withdrawal of several drugs.

PMID: 21197148 [PubMed – in process]PMCID: PMC3006492Free PMC Article

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J Obes. 2011;2011:806896. Epub 2010 Nov 11.

Taking Orlistat: Predicting Weight Loss over 6 Months.

Hollywood A, Ogden J.

Department of Psychology, University of Surrey, Guildford, Surrey GU2 7XH, UK.


This study explored the predictors of weight loss following orlistat with a focus on both baseline variables and changes in beliefs and behaviours occurring over the course of taking the drug. Patients (n = 566) prescribed orlistat completed a questionnaire at baseline and after 6 months concerning their weight, beliefs and behaviours. By 6 months the majority had lost some weight and showed improvements in diet. Many had also stopped taking the drug and a large minority reported using it flexibly as a lifestyle drug. Those who lost most weight showed a decrease in beliefs in a medical solution, a decrease in unhealthy eating, an increased belief in treatment control and an increased belief that the unpleasant consequences are both due to their eating behaviour and just part of the drug. When taken with fatty food orlistat causes symptoms such as anal leakage and oily stools. These may encourage some patients to focus on the behavioural aspects of their weight problem thus promoting the dietary changes needed for both short and longer term weight loss. When prescribing orlistat, clinicians should encourage patients to see the consequences as an education as a means to promote the effectiveness of this form of medical management.

PMID: 21113309 [PubMed – in process]PMCID: PMC2989378Free PMC Article

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J Obes. 2011;2011. pii: 984245. Epub 2010 Sep 19.

Weight considerations in pharmacotherapy for type 2 diabetes.

Cheng V, Kashyap SR.

Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.


Obesity has been increasing in prevalence worldwide and the majority of patients with type 2 diabetes are either overweight or obese. Diabetes management in this population has been difficult since a number of antidiabetes agents are associated with weight gain. The effects of various antidiabetes agents and antiobesity agents on glycemic control and body weight will be reviewed. Briefly, sulfonylureas, thiazolidinediones, and insulin are associated with weight gain, whereas metformin and amylin analogs are weight neutral or associated with modest weight loss. Dipeptidyl-peptidase-4 inhibitors are weight neutral, whereas glucagon-like peptide-1 analogs are associated with weight loss. The effect of orlistat and sibutramine in type 2 diabetes is also evaluated. The treatment of diabetes should not only focus on glycemic control as its sole intention, but it should factor in the effect of these various agents on weight, as well, since obesity aggravates insulin resistance, beta cell failure, and cardiovascular risk.

PMID: 20885921 [PubMed – in process]PMCID: PMC2946585Free PMC Article

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J Obes. 2011;2011. pii: 482021. Epub 2010 Sep 1.

Refsum’s Disease-Use of the Intestinal Lipase Inhibitor, Orlistat, as a Novel Therapeutic Approach to a Complex Disorder.

Perera NJ, Lewis B, Tran H, Fietz M, Sullivan DR.

Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney, Camperdown, NSW 2050, Australia.


Refsum’s Disease is an inherited metabolic disorder in which a metabolite of branched chain fatty acids accumulates due to lack of appropriate oxidative enzymes. Patients have elevated plasma phytanic acid levels and high concentrations of phytanic acid in a variety of tissues leading to progressive tissue damage. Besides retinal degeneration or retinal dystrophy associated with adult onset retinitis pigmentosa, additional symptoms include chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, anosmia, ichthyosis, as well as skeletal, cardiac, hepatic, and renal abnormalities. Current management includes avoidance of dietary sources of branched chain fatty acids and regular plasmapheresis to prevent accumulation of these compounds to ameliorate progressive neurological deficits. Two brothers with Refsum’s disease who experienced progressive symptoms despite optimal diet and plasmapheresis were commenced on a novel therapy. We report the effect of the intestinal lipase inhibitor, Orlistat, which led to significant reduction (P-value <0.001 on 2-sample unpaired t-test) of mean preplasmapheresis phytanic acid levels with retardation of the progression of most of their dermatological and neurological symptoms.

PMID: 20871815 [PubMed – in process]PMCID: PMC2943115Free PMC Article

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J Pharmacol Exp Ther. 2010 Dec 7. [Epub ahead of print]

JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, suppresses food intake and gastric emptying with the elevation of plasma peptide YY and glucagon-like peptide-1 in a dietary fat-dependent manner.

Hata T, Mera Y, Ishii Y, Tadaki H, Tomimoto D, Kuroki Y, Ota T, Kawai T, Kakutani M.



The microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. In this study, we investigated the effects of JTT-130 [diethyl-2-({3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl) amino] phenyl}acetyloxymethyl)-2-phenylmalonate], a novel intestine-specific MTP inhibitor, on food intake, gastric emptying and gut peptides using Sprague-Dawley rats fed 3.1% fat, 13% fat or 35% fat diets. JTT-130 treatment suppressed cumulative food intake and gastric emptying in rats fed a 35% fat diet, but not a 3.1% fat diet. In rats fed a 13% fat diet, JTT-130 treatment decreased cumulative food intake, but not gastric emptying. Also, the treatment with orlistat, a lipase inhibitor, completely abolished the reduction of food intake and gastric emptying by JTT-130 in rats fed a 35% fat diet. On the other hand, JTT-130 treatment increased the plasma concentrations of gut peptides, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) but not cholecystokinin, in the portal vein in rats fed a 35% fat diet. These elevations in PYY and GLP-1 were also abolished by the treatment with orlistat. Furthermore, JTT-130 treatment in rats fed a 35% fat diet increased the contents of triglycerides and free fatty acids in the intestinal lumen, which might contribute to the elevation of PYY and GLP-1 levels. The present findings indicate that JTT-130 causes satiety responses, decreased food intake and gastric emptying, in a dietary fat-dependent manner, with enhanced production of gut peptides such as PYY and GLP-1 from the intestine.

PMID: 21139060 [PubMed – as supplied by publisher]Free Article

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Diabetes Obes Metab. 2010 Dec 3. doi: 10.1111/j.1463-1326.2010.01346.x. [Epub ahead of print]

Pharmacotherapy for overweight/obesity in ethnic minorities and white Caucasians: a systematic review and meta-analysis.

Osei-Assibey G, Adi Y, Kyrou I, Kumar S, Matyka K.

Unit of Diabetes and Metabolism, Clinical Sciences Research Institute, University of Warwick Medical School, University Hospital Coventry, Coventry CV2 2DX, UK Sheikh Abdullah Bahamdan’s Research Chair for Evidence-Based Health Care and Knowledge Translation, College of Medicine, King Saud University. P.O.Box 2925, Riyadh 11461, Saudi Arabia Section of Population Health, University of Aberdeen, Health Sciences Building, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.


Background: Ethnic minorities in the West exhibit a higher prevalence of obesity and also under-achieve in weight management compared to white Caucasians. A systematic review of randomized controlled trials in adults (mean age ≥18 years, duration of ≥6 months, and published in the English language) was undertaken to evaluate the effectiveness of anti-obesity drugs in ethnic minorities and white Caucasians. Methods: Data sources between 1990 to 2010 were searched including MEDLINE, EMBASE, Cochrane Controlled Trials Register, CINAHL, and references cited in the included studies of other reviews. Eighteen randomised controlled trials (RCTs) that met the inclusion criteria were included in this review (6 sibutramine and 12 orlistat). A random effects model was used for meta-analysis. Results: An indirect comparison of weight loss in sibutramine treated patients in ethnic minorities was significantly lower than in white Caucasians: -2.7 kg (95% CI: -3.1 to -2.3) vs. -4.4 kg (95% CI: -5.0 to -3.8), respectively. For orlistat weight loss was similar in the two groups: -2.3 kg (95% CI: -2.6 to -2.0) in ethnic minorities and -2.8 kg (95% CI: -5.1 to -0.5) in white Caucasian participants. Discussion: Overall there were few studies of weight loss pharmacotherapy for comparison for this review and it was not possible to analyse data based on ethnic groupings. More ethnically tailored studies are needed to assess the most effective weight loss strategies in these most metabolically vulnerable of groups.

© 2010 Blackwell Publishing Ltd.

PMID: 21205118 [PubMed – as supplied by publisher]

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Appetite. 2010 Dec;55(3):407-12. Epub 2010 Jul 27.

Carbohydrate and fat digestion is necessary for maximal suppression of total plasma ghrelin in healthy adults.

Tai K, Hammond AJ, Wishart JM, Horowitz M, Chapman IM.

University of Adelaide Discipline of Medicine, Royal Adelaide Hospital, South Australia, Australia. kamilia.tai@alumni.adelaide.edu.au


It is uncertain whether the postprandial suppression of ghrelin is dependent on digestion and absorption of nutrients or whether the presence of nutrients in the small intestine is sufficient. Twenty-four healthy young adults with a mean age of 23 ± 0.6 years were examined on 3 separate days after an overnight fast. Twelve subjects participated in Part A, and the other 12 subjects in Part B. In Part A, subjects consumed, in random order, one of three study drinks: 300 mL water; 300 mL high-fat drink, with and without, 120 mg orlistat. In Part B, subjects received, in random order, one of three drinks: 300 mL water; 300 mL sucrose, with and without, 100mg acarbose. In both parts gastric emptying as measured by 2-D ultrasound. In Part A, plasma ghrelin concentrations decreased following ingestion of the high-fat drink, but did not change with the high-fat-orlistat drink or water. In Part B, the suppression of plasma ghrelin following the sucrose drink, was attenuated by acarbose. Orlistat accelerated gastric emptying of the high-fat drink, while acarbose delayed gastric emptying of the sucrose drink. In conclusion, fat and carbohydrate digestion is required for maximal suppression of ghrelin secretion.

Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20670666 [PubMed – in process]

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Expert Opin Pharmacother. 2010 Dec;11(18):2973-83. Epub 2010 Oct 19.

Pharmacological treatment of obesity in children and adolescents: current status and perspectives.

Catoira N, Nagel M, Di Girolamo G, Gonzalez CD.

Hospital Enrique Tornú, Department of Pharmacology, Universidad de Buenos Aires, Argentina.


IMPORTANCE OF THE FIELD: The prevalence of overweight and obesity in children and adolescents is increasing rapidly, while the short- and long-term morbid outcomes make these entities a major public health concern. Initial steps in therapy are based on dietary and lifestyle intervention. In the presence of an insufficient progress, medication or – eventually – surgery may be recommended. Three drugs are currently used: orlistat, metformin, and sibutramine; other candidates are in development. However, trials assessing the efficacy and safety of the current medications are frequently affected by methodological limitations, in particular insufficient power and period of follow-up.

AREAS COVERED IN THIS REVIEW: The efficacy and safety of antiobesity drugs currently used for children and adolescents are reviewed. Additional information on upcoming agents is presented.

WHAT THE READER WILL GAIN: This is an exhaustive review of current state on controversial issues regarding drugs used in children and adolescent obesity, specifically related with their efficacy and safety.

TAKE HOME MESSAGE: The efficacy of these drugs is modest. Our knowledge of their efficacy and safety comes from clinical trials affected by insufficient follow-up (1 year or less); very often, these trials are of limited power. Further data from larger and longer well-designed clinical trials would be advisable.

PMID: 20958104 [PubMed – in process]

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Pharm World Sci. 2010 Dec;32(6):752-8. Epub 2010 Aug 29.

Cardiovascular co-medication among users of antiobesity drugs: a population-based study.

Amundsen MO, Engdahl B, Berg C, Nordeng H.

Department of Pharmacy, School of Pharmacy, University of Oslo, P.O. Box 1065, 0316, Blindern, Norway.


Aim The purpose of this study was to investigate to what extent patients using prescription antiobesity drugs (orlistat, sibutramine and rimonabant) used cardiovascular and antidiabetic drugs. An additional aim was to investigate whether such co-medication differed according to gender, age and amount of antiobesity drugs used. Method Data were retrieved from the Norwegian Prescription Database (NorPD). All patients who had an antiobesity drug (ATC code A08A) dispensed from a Norwegian pharmacy between January 2004 and December 2007 were included in the study. Results During the 4-year study period 83,717 patients had antiobesity drugs dispensed. One in three patients using antiobesity drugs had at least on one occasion used a cardiovascular and/or an antidiabetic drug concomitantly. A significantly higher percentage of men used antihypertensives (40.4 vs. 27.2%, P < 0.0005), lipid modifying agents (24.4 vs. 11.9%, P < 0.0005) and drugs used in diabetes (12.7 vs. 6.4%, P < 0.0005) concomitantly with antiobesity drugs when compared to women. The percentage of patients who had concomitant drug use increased markedly with age. One in four patients had antiobesity drugs dispensed only once during the period 2004-2007. Conclusion Use of cardiovascular and antidiabetic drugs among patients using antiobesity drugs was extensive, especially among men and elderly patients. Overall, there was a high degree of polypharmacy among users of antiobesity drugs. Also, many patients dispensed antiobesity drugs in amounts that indicated use less than the recommended daily dose, and many dispensed antiobesity drugs only once. When prescribing antiobesity drugs to patients the potential benefits of antiobesity drugs should be considered in relation to the patients other chronic diseases and to the total complexity of the patients drug regimen.

PMID: 20803315 [PubMed – in process]PMCID: PMC2993886Free PMC Article

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Chem Commun (Camb). 2010 Nov 28;46(44):8335-7. Epub 2010 Jun 24.

Click-based synthesis and proteomic profiling of lipstatin analogues.

Ngai MH, Yang PY, Liu K, Shen Y, Wenk MR, Yao SQ, Lear MJ.

Department of Chemistry, and Medicinal Chemistry Program of the Life Sciences Institute, National University of Singapore, 3 Science Drive 3, Singapore 117543.


Using click chemistry to enable both structural diversity and proteome profiling within a natural product derived library, two out of nineteen lipstatin analogues showed similar activity to Orlistat against fatty acid synthase (FAS), but with an improved ability to induce tumour cell death.

PMID: 20577697 [PubMed – in process]

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Innate Immun. 2010 Nov 18. [Epub ahead of print]

Both inflammatory and classical lipolytic pathways are involved in lipopolysaccharides-induced lipolysis in human adipocytes.

Grisouard J, Bouillet E, Timper K, Radimerski T, Dembinski K, Frey DM, Peterli R, Zulewski H, Keller U, Müeller B, Christ-Crain M.

Department of Biomedicine, Metabolism Group, University Hospital Basel, Basel, Switzerland.


High fat diet-induced endotoxaemia triggers low-grade inflammation and lipid release from adipose tissue. This study aims to unravel the cellular mechanisms leading to the lipopolysaccharide (LPS) effects in human adipocytes. Subcutaneous pre-adipocytes surgically isolated from patients were differentiated into mature adipocytes in vitro. Lipolysis was assessed by measurement of glycerol release and mRNA expression of pro-inflammatory cytokines were evaluated by real-time PCR. Treatment with LPS for 24 h induced a dose-dependent increase in interleukin (IL)-6 and IL-8 mRNA expression. At 1 µg/ml LPS, IL-6 and IL-8 were induced to 19.5 ± 1.8-fold and 662.7 ± 91.5-fold (P < 0.01 vs basal), respectively. From 100 ng/ml to 1 µg/ml, LPS-induced lipolysis increased to a plateau of 3.1-fold above basal level (P < 0.001 vs basal). Co-treatment with inhibitors of inhibitory kappa B kinase kinase beta (IKKβ) or NF-κB inhibited LPS-induced glycerol release. Co-treatment with the protein kinase A (PKA) inhibitor H-89, the lipase inhibitor orlistat or the hormone-sensitive lipase (HSL) inhibitor CAY10499 abolished the lipolytic effects of LPS. Co-treatment with the MAPK inhibitor, U0126 also reduced LPS-induced glycerol release. Inhibition of lipolysis by orlistat or CAY10499 reduced LPS-induced IL-6 and IL-8 mRNA expression. Induction of lipolysis by the synthetic catecholamine isoproterenol or the phosphodiesterase type III inhibitor milrinone did not alter basal IL-6 and IL-8 mRNA expression after 24 treatments whereas these compounds enhanced LPS-induced IL-6 and IL-8 mRNA expression. Both the inflammatory IKKβ/NF-κB pathway and the lipolytic PKA/HSL pathways mediate LPS-induced lipolysis. In turn, LPS-induced lipolysis reinforces the expression of pro-inflammatory cytokines and, thereby, triggers its own lipolytic activity.

PMID: 21088047 [PubMed – as supplied by publisher]

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Fundam Clin Pharmacol. 2010 Nov 16. doi: 10.1111/j.1472-8206.2010.00888.x. [Epub ahead of print]

Comparison between orlistat plus l-carnitine and orlistat alone on inflammation parameters in obese diabetic patients.

Derosa G, Maffioli P, Ferrari I, D’Angelo A, Fogari E, Palumbo I, Randazzo S, Cicero AF.

Fondazione IRCCS Policlinico S. Matteo, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, P.le C. Golgi, 2 – 27100 PAVIA, Italy “G. Descovich” Atherosclerosis Study Center, Department of Internal Medicine, Aging and Kidney diseases, University of Bologna, Bologna, Italy.


To evaluate the effects of 1-year treatment with orlistat plus l-carnitine compared to orlistat alone on body weight, glycemic and lipid control, and inflammatory parameters in obese type 2 diabetic patients. Two hundred and fifty-eight patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c) ) > 8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take orlistat 120 mg three times a day plus l-carnitine 2 g one time a day or orlistat 120 mg three times a day. We evaluated the following parameters at baseline and after 3, 6, 9, and 12 months : body weight, body mass index (BMI), glycated hemoglobin (HbA(1c) ), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (Tg), adiponectin (ADN), leptin, tumor necrosis factor-α (TNF-α), vaspin, and high-sensitivity C-reactive protein (Hs-CRP). We observed a better decrease in body weight, glycemic profile, HOMA-IR, LDL-C, and ADN and a faster improvement in FPI, TC, Tg, leptin, TNF-α, Hs-CRP with orlistat plus l-carnitine compared to orlistat alone. We also recorded an improvement in vaspin with orlistat plus l-carnitine not reached with orlistat alone. Orlistat plus l-carnitine gave a better improvement in body weight, glycemic and lipid profile compared to orlistat alone; furthermore, a faster and better improvement in inflammatory parameters was observed with orlistat plus l-carnitine compared to orlistat alone.

© 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

PMID: 21077943 [PubMed – as supplied by publisher]

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J Pharm Biomed Anal. 2010 Nov 2;53(3):767-72. Epub 2010 May 16.

Comparison of impurity profiles of Orlistat pharmaceutical products using HPLC tandem mass spectrometry.

Schneider A, Wessjohann LA.

IDrug GmbH, Berlin, Germany; Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Halle, Saale, Germany. schneider@idrug.de


HPLC-UV and MS/MS studies of impurity profiles of original (Xenical, F. Hoffmann-La Roche Ltd., Switzerland) and generic (Cobese, Ranbaxy Laboratories Limited, India, and Orsoten, KRKA, Russia) products were carried out. The drug and related impurities were extracted by dissolving commercial samples in ethanol. The generic formulations contained higher levels of impurities than the original product. Impurity profiles (HPLC-MS/MS) of the generic samples are similar among themselves, whilst different in comparison to the impurity profile of the original product. The number of detected impurities for generics (14 impurities in Cobese and 13 impurities in Orsoten) is higher than for the original product (3 impurities in Xenical). Based on these analyses the overall analytical quality follows the order Xenical (best)>Orsoten>Cobese.

Copyright (c) 2010 Elsevier B.V. All rights reserved.

PMID: 20570457 [PubMed – indexed for MEDLINE]

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Appl Biochem Biotechnol. 2010 Nov;162(5):1483-96. Epub 2010 Apr 10.

Purification and biochemical characterization of an acid-stable lipase from the pyloric caeca of sardine (Sardinella aurita).

Smichi N, Fendri A, Chaâbouni R, Ben Rebah F, Gargouri Y, Miled N.

Laboratoire de Biochimie et de Génie Enzymatique des Lipases, ENIS route de Soukra, 3038 Sfax, Tunisia.


A lipolytic activity was located in the sardine digestive glands (pyloric caeca), from which a sardine digestive lipase (SaDL) was purified. Pure SaDL has a molecular mass of 43 kDa as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis. The enzyme was found to be more active on short-chain triacylglycerols than on long-chain ones. SaDL does not present the interfacial activation phenomenon. Control experiments were performed under the same experimental conditions, with dromedary and turkey pancreatic lipases and showed a positive interfacial activation phenomenon. Sodium deoxycholate (NaDC) has an inhibitory effect on the lipase activity. The pure enzyme lost 40% of its activity in presence of 8 mM NaDC. SaDL was found to be mostly stable at low pH values. Interestingly, no colipase was detected in the sardine pyloric caeca. Analogous results were reported for the scorpion and the crab digestive systems. This is in line with the idea that colipase might has evolved in mammal animals simultaneously with the appearance of an exocrine pancreas. No similarity was found between the NH(2)-terminal amino acid residues of SaDL and those of lipases from the digestive tract of other species. Altogether, these results suggest that SaDL is a member of a new group of lipases belonging to aquatic species.

PMID: 20383604 [PubMed – indexed for MEDLINE]

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Curr Vasc Pharmacol. 2010 Nov;8(6):820-30.

Effect of non-statin lipid lowering and anti-obesity drugs on LDL subfractions in patients with mixed dyslipidaemia.

Florentin M, Tselepis AD, Elisaf MS, Rizos CV, Mikhailidis DP, Liberopoulos EN.

Department of Clinical Biochemistry (Vascular Disease Prevention clinics), Royal Free campus, University College London Medical School, University College London (UCL), London, UK.


Small, dense low density lipoprotein (sdLDL) particles are considered an emerging cardiovascular risk factor. Obese patients with mixed dyslipidaemia frequently have elevated sdLDL cholesterol (sdLDL-C) levels. Therefore, agents that favourably modulate the LDL phenotype may be of clinical value in these patients. We review the efficacy of anti-obesity and lipid lowering drugs other than statins on LDL subfractions in patients with mixed dyslipidaemia primarily focusing on those who are overweight/obese. The literature search was based on PubMed listings up to 26 November 2009. In most studies ezetimibe decreases the large and medium LDL subclasses and, to a lesser extent, the sdLDL particles, while it does not substantially influence LDL size. Fibrates and niacin reduce sdLDL particles and shift LDL size towards large, buoyant LDL particles. More studies are needed to elucidate the effects of fish oils and resins on LDL phenotype. Orlistat and rimonabant have been associated with reductions in sdLDL-C levels along with an increase in LDL particle size. We did not find any literature describing the effect of sibutramine on sdLDL profile. Treatment with fibrates and niacin seems to be beneficial in patients with mixed dyslipidaemia. The addition of orlistat may further improve LDL phenotype in overweight/obese patients.

PMID: 20180768 [PubMed – in process]

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Diabetes Obes Metab. 2010 Nov;12(11):947-57. doi: 10.1111/j.1463-1326.2010.01286.x.

Managing childhood obesity: when lifestyle change is not enough.

Hearnshaw C, Matyka K.

Birmingham Children’s Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham, UK.


The management of childhood obesity is a clinical dilemma. Paediatricians will see those children whose weight is at the severe end of the spectrum with obesity-related co-morbidities and for whom more intensive weight loss therapies may be appropriate. A literature review was performed (January 1995-January 2010) of the roles of pharmacotherapy or bariatric surgery in the management of childhood obesity. Three hundred and eighty-three abstracts were reviewed and 76 full-text articles were requested. Of these, 34 were excluded and a total of 21 pharmacotherapy papers and 22 papers on surgery were reviewed in detail. All studies involved adolescents. Pharmacotherapy: Most studies were small and of short duration, the notable exceptions being two large RCTs of sibutramine and orlistat. Sibutramine led to a mean estimated change in BMI from baseline of -3.1 kg/m(2) vs. -0.3 kg/m(2) for placebo over 12 months. Orlistat was also beneficial with a mean reduction in BMI of 0.55 vs. an increase of 0.31 kg/m(2) in the placebo group at 12 months. Bariatric surgery: Most papers presented clinical observations and there were no randomised controlled trials (RCTs). Robust selection criteria were not used and ideal candidate selection remains unclear. Most papers showed a significant benefit of surgery in severely obese adolescents in the short term but long-term data were sparse. There were a surprisingly large number of papers examining the benefits of intensive weight management in obese adolescents. The study design of many was inadequate and the role of pharmacotherapy or surgery in childhood obesity remains unclear.

© 2010 Blackwell Publishing Ltd.

PMID: 20880341 [PubMed – in process]

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Obes Rev. 2010 Nov;11(11):777-91. doi: 10.1111/j.1467-789X.2009.00693.x.

Long-term changes in blood pressure following orlistat and sibutramine treatment: a meta-analysis.

Johansson K, Sundström J, Neovius K, Rössner S, Neovius M.

Obesity Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. kari.johansson@ki.se


Previous meta-analyses investigating blood pressure effects of anti-obesity drugs have included studies using non-licensed doses, but not data from head-to-head studies. Furthermore, although diabetes is an important comorbidity in obesity, variation in blood pressure effects across diabetes status has not been investigated. The objective of this study was to estimate the effects on systolic (SBP) and diastolic blood pressure (DBP) of orlistat and sibutramine. Medline, EMBASE, the Cochrane controlled trials register and reference lists of identified articles from 1990 to February 2009 were searched. All placebo-controlled randomized controlled trials of 12-month duration or randomized head-to-head studies of any duration on adults using standard doses were included. Studies/study arms were excluded if they only evaluated weight maintenance after weight loss. Randomized controlled trials were identified, subjected to inclusion and exclusion criteria, and reviewed. Random effects models were used for assessment of weighted mean differences. Eighteen placebo-controlled (12 orlistat, 5540 patients; 6 sibutramine, 1495 patients) and four head-to-head trials (348 patients) met the inclusion criteria. Three orlistat and three sibutramine studies examined overweight subjects with type 2 diabetes (T2DM), as did two head-to-head trials. Mean baseline SBP ranged from 119 to 153 mmHg, and mean DBP from 69 to 98 mmHg. Overall, the placebo-controlled SBP change was -1.9 (95% CI; -2.7, -1.1) mmHg for orlistat, and 0.5 (-1.1, 2.1) mmHg for sibutramine. The corresponding values for DBP were -1.5 (-2.2, -0.8) and 1.7 (0.7, 2.6). Compared with patients without diabetes, diabetic patients treated with orlistat experienced smaller and non-significant reductions of SBP (-0.9; -2.6, 0.7 vs. -2.2; -3.0, -1.3) and DBP (-1.0; -2.4, 0.3 vs. -1.6; -2.4, -0.8). For sibutramine, higher on-treatment elevations in SBP (1.6; -1.3, 4.5 vs. 0.1; -1.8, 2.0) and DBP (2.4; 0.6, 4.1 vs. 1.4; 0.3, 2.5) were seen in patients with vs. without diabetes. In head-to-head trials, the overall differences between sibutramine and orlistat were small and non-significant for both SBP (1.0; -2.3, 4.3) and DBP (-0.2; -2.9, 2.5). In conclusion, in the studies using approved sibutramine doses, the drug caused significant elevations in DBP, while the overall SBP effect was near null. Moreover, absence of a blood pressure-lowering effect of orlistat ad a higher DBP elevation by sibutramine were observed for persons with diabetes. Head-to-head studies indicated that an indirect comparison of placebo-adjusted blood pressure effects may overestimate the adverse effects associated with sibutramine, but these studies were small, of shorter duration and of lower quality.

© 2009 The Authors. obesity reviews © 2009 International Association for the Study of Obesity.

PMID: 20025693 [PubMed – indexed for MEDLINE]

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Obesity (Silver Spring). 2010 Nov;18(11):2105-10. Epub 2010 Mar 25.

Effects of weight reduction on serum vaspin concentrations in obese subjects: modification by insulin resistance.

Chang HM, Lee HJ, Park HS, Kang JH, Kim KS, Song YS, Jang YJ.

Department of Family Medicine, University of Ulsan College of Medicine, Seoul, Korea.


Visceral adipose tissue-derived serpin (vaspin) has been regarded as a novel adipokine with potential insulin sensitizing properties. We investigated the changes of serum vaspin concentration in response to weight reduction, and the associations between changes in serum vaspin concentrations and changes of anthropometric and metabolic variables in obese subjects after weight reduction. We performed a longitudinal clinical intervention study on 63 obese persons enrolled in a 12-week weight reduction program that included lifestyle modification and adjuvant treatment with the antiobesity agent orlistat. Anthropometric variables, lipid profiles, fasting glucose, fasting insulin, and serum vaspin concentrations were measured. Statistical analyses were performed according to the homeostasis model assessment of insulin resistance (HOMA(IR)). Serum vaspin concentrations decreased significantly in responders (≥2% reduction in baseline weight), but not in nonresponders (<2% reduction in baseline weight). Changes in serum vaspin concentrations were significantly correlated with body weight, BMI, waist circumference, and hip circumference in the higher, but not in the lower, HOMA(IR) group. In multivariate linear regression analysis, change in serum vaspin concentrations in the higher, but not in the lower, HOMA(IR) group was positively correlated with change in BMI and negatively correlated with initial HOMA(IR) level. The associations between changes in serum vaspin concentrations and changes in anthropometric and metabolic parameters differed according to insulin resistance status in obese subjects. These relationships were more prominent in the higher HOMA(IR) group. Insulin resistance may influence the correlations between changes in serum vaspin concentration and related metabolic variables.

PMID: 20339362 [PubMed – in process]

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Prescrire Int. 2010 Nov;19(110):250.

Orlistat without a prescription. The SPC now contains more situations where patients are advised to consult a doctor.

[No authors listed]


Despite the broad media attention given to this self-medication product, patients are still not getting their money’s worth.

PMID: 21287716 [PubMed – in process]

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Int J Eat Disord. 2010 Oct 18. [Epub ahead of print]

Predictive significance of changes in dietary restraint in obese patients with binge eating disorder during treatment.

Blomquist KK, Grilo CM.

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.


OBJECTIVE: To examine whether changes in different aspects of dietary restraint in obese patients with binge eating disorder (BED) participating in a treatment study predict outcomes.

METHOD: Fifty obese patients with BED in a randomized controlled study of orlistat administered with cognitive-behavioral therapy, guided-self-help (CBTgsh) completed dietary restraint measures at baseline, during- and post-treatment, and three-month follow-up.

RESULTS: Change in the restraint scale of the Eating Disorder Examination-Questionnaire did not predict binge abstinence or 5% weight loss. Increased flexible restraint subscale of the Three Factor Eating Questionnaire (TFEQ) during treatment significantly predicted binge abstinence at post-treatment and three-month follow-up and 5% weight loss at post-treatment. Change in the rigid restraint subscale of the TFEQ predicted binge abstinence at post-treatment.

DISCUSSION: Our findings clarify further pathologic and adaptive aspects of restraint and suggest the importance of enhancing flexible restraint in order to improve both binge eating and weight loss outcomes. © 2010 by Wiley Periodicals, Inc. (Int J Eat Disord 2010).

PMID: 20957705 [PubMed – as supplied by publisher]PMCID: PMC3025064 [Available on 2012/4/1]

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Eur J Pharm Sci. 2010 Oct 9;41(2):276-80. Epub 2010 Jul 3.

Investigation of Orlistat effects on PXR activation and CYP3A4 expression in primary human hepatocytes and human intestinal LS174T cells.

Novotna A, Doricakova A, Vrzal R, Maurel P, Pavek P, Dvorak Z.

Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 11, Olomouc, Czech Republic.


Drugs for weight loss have been in use for nearly hundred years. Orlistat (Xenical) is a non-centrally acting anti-obesity drug that inactivates gastric and intestinal lipases, thus, preventing absorption of dietary triglycerides. There are reports indicating that Orlistat reduces bioavailability of Cyclosporin to a clinically relevant degree. Since Cyclosporin is metabolized by cytochrome P450 CYP3A4, we examined whether interaction between Orlistat and Cyclosporin involves induction of CYP3A4. Human Caucasian colon adenocarcinoma cells LS174T and primary cultures of human hepatocytes were used, as in vitro models of intestinal and hepatic cells, respectively. Treatment of LS174T cells for 24h with Orlistat (1-100mg/L) did not cause induction of CYP3A4 mRNA levels as compared to control cells while Orlistat (100mg/L) slightly induced CYP3A4 mRNA in human hepatocytes. Rifampicin, a model CYP3A4 inducer, significantly induced CYP3A4 mRNA in both types of cells. The level of CYP3A4 protein in human hepatocytes was increased by Orlistat after 48h, while rifampicin strongly induced CYP3A4 protein level. In addition, Orlistat moderately dose-independently activated pregnane X receptor (PXR) in LS174T cells transiently transfected with p3A4-luc reporter construct containing the basal promoter (-362/+53) with proximal PXR response element and the distal xenobiotic responsive enhancer module (-7836/-7208) of the CYP3A4 gene 5′-flanking region. In conclusion, we report here that Orlistat is weak PXR activator and CYP3A4 inducer in human hepatocytes, but it has no effect on CYP3A4 in intestinal cells, implying no role of CYP3A4 induction in the interaction between Orlistat and Cyclosporin in absorption process.

PMID: 20599501 [PubMed – indexed for MEDLINE]

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Am J Physiol Endocrinol Metab. 2010 Oct;299(4):E576-83. Epub 2010 Jul 13.

Fatty acids increase glucose uptake and metabolism in C2C12 myoblasts stably transfected with human lipoprotein lipase.

Capell WH, Schlaepfer IR, Wolfe P, Watson PA, Bessesen DH, Pagliassotti MJ, Eckel RH.

Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA.


Cellular effects of FFA might differ from those of lipoprotein triglyceride (TG)-derived fatty acids (TGFA). The aim of the current study was to examine the relationship between lipoprotein lipase (LPL) expression, TGFA, or FFA availability and glucose metabolism in the absence of insulin in C2C12 myoblasts. Control myoblasts or myoblasts stably transfected with human lipoprotein lipase (C2/LPL; 15-fold greater LPL activity) were incubated for 12 h in fetal bovine serum-free medium in the absence or presence of Intralipid-20. Intracellular retention of labeled medium glucose was assessed in a subset of experiments. In the presence of Intralipid, medium glucose disappearance was increased in C2/LPL cells but not in control cells. In both cell types, glucose label retention in cellular TG was increased in the presence of Intralipid; incubation with albumin-bound oleate produced similar results. In the presence of Intralipid, the LPL hydrolytic inhibitor tetrahydrolipstatin blocked excess glucose retention in cellular TG but did not significantly decrease glucose disappearance in C2/LPL cells. Changes in glucose transport or hexokinase II did not explain the altered glucose disappearance in C2/LPL cells. Our results suggest that LPL overexpression in these cells leads to chronic metabolic adaptations that alter glucose uptake and retention.

PMID: 20628023 [PubMed – indexed for MEDLINE]PMCID: PMC2957863 [Available on 2011/10/1]

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Curr Pharm Des. 2010 Oct;16(30):3401-16.

Combination of fenofibrate with non-statin drug regimens.

Agouridis AP, Filippatos TD, Derdemezis CS, Mikhailidis DP, Elisaf MS.

Department of Internal Medicine, Medical School, University of Ioannina, 451 10 Ioannina, Greece.


OBJECTIVE: We present the available data on the effects of combined therapy of fenofibrate with drugs affecting lipid metabolism other than statins.

METHODS: We consider studies evaluating the effects of combined therapy of fenofibrate with bile acid sequestrants (BAS), ezetimibe, niacin, n-3 fatty acids, plant sterols, orlistat, rimonabant, metformin and glitazones.

RESULTS: Combination of BAS (especially colesevelam) with fenofibrate had additional effects on metabolic parameters in patients with mixed hyperlipidemia. Combination of ezetimibe with fenofibrate may be a useful approach to improve the overall lipid profile of patients with mixed hyperlipidemia. There is a further reduction in triglyceride levels when n-3 fatty acids are administered with fenofibrate in patients with severe hypertriglyceridemia. Combined fenofibrate and orlistat treatment further improves metabolic parameters in overweight/obese patients with metabolic syndrome. The fenofibrate/thiazolidinedione combination is an alternative for diabetic patients intolerant to statins, though differences exist between pioglitazone and rosiglitazone.

CONCLUSIONS: For patients who cannot tolerate statins there are useful combinations of fenofibrate with other drugs affecting lipid metabolism. These combinations improve several metabolic parameters, but more trials should be carried out to reach more robust conclusions about their effects on cardiovascular events.

PMID: 20819059 [PubMed – in process]

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Eur J Endocrinol. 2010 Oct;163(4):515-22. Epub 2010 Aug 4.

Pituitary adenomas in childhood, adolescence and young adulthood: presentation, management, endocrine and metabolic outcomes.

Steele CA, MacFarlane IA, Blair J, Cuthbertson DJ, Didi M, Mallucci C, Javadpour M, Daousi C.

Diabetes and Endocrinology Clinical Research Group, Department of Endocrinology and Diabetes, Clinical Sciences Centre, Aintree University Hospitals NHS Foundation Trust, Lower Lane, Liverpool, UK. c.a.steele@liverpool.ac.uk


OBJECTIVE: To elucidate the long-term outcomes of pituitary adenomas diagnosed in childhood and adolescence, knowledge of which remains sparse.

DESIGN AND METHODS: A retrospective review of patients aged ≤21 years at diagnosis of pituitary adenoma, attending a neuroendocrine service in Liverpool, UK, between 1984-2009.

RESULTS: There were 41 patients (33 female), mean age at diagnosis 17.3 years (range 11-21) and mean follow-up 9.6 years; 29 patients had prolactinomas (15 macroprolactinomas), 6 non-functioning pituitary adenomas (NFPAs), 5 Cushing’s disease (CD) and 1 acromegaly. All prolactinoma patients received dopamine agonists (DAs) and three also underwent pituitary surgery. Furthermore, ten patients underwent surgery: five with CD, one with acromegaly and four with NFPA. Four received radiotherapy after surgery. Another ten patients received hormone replacement: nine hydrocortisone, five thyroxine, seven sex steroids and five GH; another seven had severe asymptomatic GH deficiency. Three female patients were treated for infertility (two successfully). Thirteen patients gained significant weight (body mass index (BMI) increase >2 kg/m(2)) since diagnosis and 16 in total are now obese (BMI>30 kg/m(2)). Five were treated with orlistat and one attended a weight management service. Two received antihypertensive medications, two had type 2 diabetes and four were treated for dyslipidaemia.

CONCLUSIONS: This is one of the largest reviews of patients aged 21 or younger at diagnosis of pituitary adenoma followed up by a single service. Two-thirds had prolactinomas, all were treated with DAs and three underwent surgery. Increased cardiovascular risk factors (obesity and dyslipidaemia) and infertility are important sequelae and active identification and treatment are necessary.

PMID: 20685833 [PubMed – indexed for MEDLINE]

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Nat Rev Endocrinol. 2010 Oct;6(10):578-88. Epub 2010 Aug 3.

Behavioral and pharmacologic therapies for obesity.

Vetter ML, Faulconbridge LF, Webb VL, Wadden TA.

Department of Psychiatry, Center for Weight and Eating Disorders, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.


This article reviews novel developments in the behavioral and pharmacologic treatment of obesity and explores the potential contribution of genomics research to weight control. A comprehensive program of lifestyle modification, comprised of diet, physical activity and behavior therapy, induces a mean loss of 7-10% of initial weight in individuals with obesity. Two trials demonstrated that weight loss of this magnitude, combined with increased physical activity, substantially reduced the risk of developing type 2 diabetes mellitus in individuals with impaired glucose tolerance. A third trial is now investigating whether lifestyle intervention will reduce cardiovascular morbidity and mortality in overweight individuals who already have diabetes mellitus. Pharmacotherapy is recommended, in some patients, as an adjunct to lifestyle modification. Two medications-orlistat and sibutramine-are currently approved in the US for long-term weight loss. Both are efficacious when combined with lifestyle modification, although health concerns have been raised about the use of sibutramine. Several novel combination therapies, which target multiple hypothalamic pathways that regulate appetite and body weight, are currently under investigation. Genomic studies provide further evidence for the role of these pathways in the regulation of body weight. Identification of new genes controlling satiety and energy expenditure may yield valuable clues for the development of novel pharmacologic treatments.

PMID: 20680034 [PubMed – in process]PMCID: PMC3031864 [Available on 2011/4/1]

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Phytochemistry. 2010 Oct;71(14-15):1625-41. Epub 2010 Aug 21.

Possible anti-obesity therapeutics from nature–a review.

Yun JW.

Department of Biotechnology, Daegu University, Kyungsan, Kyungbuk, Republic of Korea. jwyun@daegu.ac.kr


Obesity is associated with many diseases, particularly diabetes, hypertension, osteoarthritis, and heart disease. The obesity incidence has increased at an alarming rate in recent years, becoming a worldwide health problem, with incalculable social costs. Two different obesity-treatment drugs are currently on the market: orlistat, which reduces intestinal fat absorption via inhibiting pancreatic lipase; and sibutramine, an anorectic or appetite suppressant. Both drugs have hazardous side-effects, including increased blood pressure, dry mouth, constipation, headache, and insomnia. For this reason, a wide variety of natural materials have been explored for their obesity treatment potential. These are mainly complex products having several components with different chemical and pharmacological features. This review aimed to survey the literature covering natural products with anti-obesity activity and to review the scientific data, including experimental methodologies, active components, and mechanisms of action against obesity.

Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20732701 [PubMed – indexed for MEDLINE]

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Vnitr Lek. 2010 Oct;56(10):1078-81.

[Treatment of an obese diabetic].

[Article in Czech]

Svacina S.

III. Interní klinika 1. lékarské fakulty UKa VFN Praha. stepan.svacina@lf1.cuni.cz


Weight reduction is an important component of comprehensive management of diabetes. Weight reduction can be achieved using 6 methods: 1. diet 2. physical activity, 3. psychotherapy, 4. bariatric surgery, 5. pharmacotherapy of obesity, 6. selection of an appropriate antidiabetic medication. Orlistat is the only antiobesity agent presently available in the Czech Republic. Weight neutral (metformin and gliptins) and weight reducing antidiabetics (incretine analogues exenatide and liraglutide) and insulin analogue detemir are suitable antidiabetic drugs. We thus have a sufficient range of options available for weight reduction in diabetic patients.

PMID: 21105456 [PubMed – indexed for MEDLINE]

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Endocr J. 2010 Sep 29;57(9):777-86. Epub 2010 Jul 30.

Orlistat and L-carnitine compared to orlistat alone on insulin resistance in obese diabetic patients.

Derosa G, Maffioli P, Ferrari I, D’Angelo A, Fogari E, Palumbo I, Randazzo S, Cicero AF.

Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. giuseppe.derosa@unipv.it


Our study wants to evaluate the effects of one year treatment with orlistat plus L-carnitine compared to orlistat alone on body weight, glycemic and lipid control, and insulin resistance state in type 2 diabetic patients. Two hundred and fifty-eight patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c)) > 8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomised to take orlistat 120 mg three times a day plus L-carnitine 2 g one time a day or orlistat 120 mg three times a day. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), HbA(1c), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), retinol binding protein-4 (RBP-4), resistin, visfatin, high sensitivity-C reactive protein (Hs-CRP). We observed a faster, and better decrease of body weight, HbA(1c), FPG, PPG, LDL-C, HOMA-IR with orlistat plus L-carnitine compared to orlistat. A faster improvement of TC, Tg, FPI, resistin, RBP-4, visfatin, and Hs-CRP was reached with orlistat plus L-carnitine compared to orlistat. We can safely conclude that the association of orlistat plus L-carnitine was better than orlistat in improving body weight, glycemic and lipid profile, insulin resistance, and inflammatory parameters and no significant adverse events were recorded.

PMID: 20683173 [PubMed – in process]Free Article

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J Biol Chem. 2010 Sep 24;285(39):30050-60. Epub 2010 Jul 23.

Tetrahydrolipstatin inhibition, functional analyses, and three-dimensional structure of a lipase essential for mycobacterial viability.

Crellin PK, Vivian JP, Scoble J, Chow FM, West NP, Brammananth R, Proellocks NI, Shahine A, Le Nours J, Wilce MC, Britton WJ, Coppel RL, Rossjohn J, Beddoe T.

Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, Victoria 3800, Australia. paul.crellin@monash.edu


The highly complex and unique mycobacterial cell wall is critical to the survival of Mycobacteria in host cells. However, the biosynthetic pathways responsible for its synthesis are, in general, incompletely characterized. Rv3802c from Mycobacterium tuberculosis is a partially characterized phospholipase/thioesterase encoded within a genetic cluster dedicated to the synthesis of core structures of the mycobacterial cell wall, including mycolic acids and arabinogalactan. Enzymatic assays performed with purified recombinant proteins Rv3802c and its close homologs from Mycobacterium smegmatis (MSMEG_6394) and Corynebacterium glutamicum (NCgl2775) show that they all have significant lipase activities that are inhibited by tetrahydrolipstatin, an anti-obesity drug that coincidently inhibits mycobacterial cell wall biosynthesis. The crystal structure of MSMEG_6394, solved to 2.9 Å resolution, revealed an α/β hydrolase fold and a catalytic triad typically present in esterases and lipases. Furthermore, we demonstrate direct evidence of gene essentiality in M. smegmatis and show the structural consequences of loss of MSMEG_6394 function on the cellular integrity of the organism. These findings, combined with the predicted essentiality of Rv3802c in M. tuberculosis, indicate that the Rv3802c family performs a fundamental and indispensable lipase-associated function in mycobacteria.

PMID: 20656688 [PubMed – indexed for MEDLINE]PMCID: PMC2943268 [Available on 2011/9/24]

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Int J Pediatr Obes. 2010 Sep 22. [Epub ahead of print]

Early weight loss and outcome at one year in obese adolescents treated with orlistat or placebo.

Chanoine JP, Richard M.

Endocrinology and Diabetes Unit.


Abstract Background. Pharmacotherapy, associated with a comprehensive weight loss intervention, has emerged as a promising therapeutic approach in adolescents. Identification of subjects who best respond to a pharmacological intervention remains difficult. Objective. To compare the value of early weight loss after 12 weeks of treatment with placebo or orlistat (120 mg three times a day) in predicting treatment outcome after 52 weeks. Methods. Secondary analysis of a randomized control trial in 182 placebo-treated and 357 orlistat-treated obese adolescents (Body mass index [BMI] ≥2 kg/m(2) above the 95(th) percentile). Results. Percent weight change at 12 weeks was positively correlated with percent change in weight (r(2) ≥ 0.41), BMI (r(2) ≥ 0.33) and waist circumference (r(2) ≥ 0.20) at 52 weeks in both the placebo and orlistat groups (P < 0.001). A weight loss ≥5% of baseline weight at 12 weeks was associated with a mean weight loss of 8.1% (95% CI: 6.4 to 9.7) at the study end that was independent of treatment. Subjects in the orlistat group were 2.44 times (95% CI: 1.34 to 4.46) more likely to experience a weight loss ≥5% after 12 weeks than subjects in the placebo group (P = 0.0028). Conclusions. Early weight loss predicts a favourable outcome in both placebo-treated and orlistat-treated subjects but is more than 2 times more likely to occur in the orlistat group. Addition of orlistat should be considered as part of a weight loss intervention but reevaluated after 3 months of treatment.

PMID: 20858149 [PubMed – as supplied by publisher]

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Am Fam Physician. 2010 Sep 15;82(6):630-4.

Weight loss maintenance.

Grief SN, Miranda RL.

University of Illinois at Chicago (UIC), Department of Family Medicine, Chicago, Illinois 60612, USA. sgrief@uic.edu

Original report in:


Successful long-term weight loss maintenance can be achieved by various means. A combination of dietary and physical activity interventions, along with one or more behavioral approaches, has proven successful in some persons, as documented by the National Weight Control Registry, but is limited by adherence to a consistent weight loss regimen. Successful approaches to weight loss maintenance include consulting with a physician, nutritionist, or another support source; adhering to a stable diet with a limited variety of food; monitoring weight; eating breakfast; and exercising regularly. Long-term pharmacologic treatments for weight loss maintenance have been studied and were found to have modest success, with some weight regain typically reported. Sibutramine and orlistat are the two medications approved by the U.S. Food and Drug Administration with the potential to help patients achieve long-term weight loss maintenance. Bariatric surgery is another modality for accomplishing successful long-term weight loss maintenance in patients with morbid or complicated obesity. Its success is due in large part to better weight loss outcomes, more successful long-term weight loss maintenance, and remission of comorbid medical conditions.

PMID: 20842990 [PubMed – indexed for MEDLINE]

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Mt Sinai J Med. 2010 Sep-Oct;77(5):407-17.

Medical therapy for obesity.

Bray GA.

Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA. George.Bray@pbrc.edu


Obesity results from a prolonged small positive energy imbalance, and treatment needs to reverse this imbalance. Many different diets have been tried to treat obesity, and weight loss occurs with all of them. There is currently no evidence that supports the superiority of one macronutrient composition for diets over any other. The principal effect seems to be the degree of adherence to the prescribed calorie reduction. Obesity drugs have been developed that tap brain mechanisms for controlling feeding and the gastrointestinal tract and its peptides. Orlistat blocks intestinal lipase and produces modest weight loss. Sibutramine is a serotonin-norepinephrine reuptake inhibitor that has a warning on its label from the US Food and Drug Administration because of cardiovascular risk. Its marketing has been suspended in Europe. Several drug combinations are on the horizon for treatment of obesity.

PMID: 20960545 [PubMed – in process]

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Neuroscience. 2010 Sep 1;169(3):1268-78. Epub 2010 May 27.

Endocannabinoid-mediated synaptically evoked suppression of GABAergic transmission in the cerebellar cortex.

Urbanski MJ, Kovacs FE, Szabo B.

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Albertstrasse 25, D-79104 Freiburg im Breisgau, Germany.


Presynaptic CB(1) cannabinoid receptors are frequently targets of endogenous cannabinoids (endocannabinoids) released from postsynaptic neurons. It is known that the glutamatergic afferent input to a neuron can trigger endocannabinoid production and that the released endocannabinoid can suppress the glutamatergic input. We tested the hypothesis that activation of the glutamatergic input to a neuron leads to an endocannabinoid-mediated suppression of the GABAergic afferent input to the same neuron. Spontaneous postsynaptic currents (sPSCs) were recorded with patch-clamp techniques in Purkinje cells in mouse cerebellar brain slices. Activation of the climbing fiber-mediated glutamatergic input to Purkinje cells led to a suppression of the sPSCs by 34+/-3%. This suppression was mostly due to suppression of GABAergic spontaneous inhibitory postsynaptic current (sIPSCs), because 93% of the sPSCs recorded in Purkinje cells were GABAergic sIPSCs. Blockade of ionotropic, but not metabotropic glutamate receptors, prevented the suppression. The climbing fiber activation led to an increase in calcium concentration in the Purkinje cells, and this increase was necessary for the suppression of sPSCs, because the suppression did not occur when the calcium increase was prevented by BAPTA. No sPSC suppression was observed in the presence of the CB(1) antagonist rimonabant or the diacylglycerol lipase inhibitor orlistat. In a further series of experiments GABAergic sIPSCs were recorded: these sIPSCs were also suppressed after climbing fiber activation, and the suppression was sensitive to the CB(1) antagonist SLV319. Finally, the GABAergic synaptic transmission between molecular layer interneurons and Purkinje cells was directly studied on simultaneously patch-clamped neuron pairs. Climbing fiber activation led to suppression of the interneuron –> Purkinje cell synaptic transmission. The results point to a novel form of endocannabinoid-mediated heterosynaptic plasticity. The endocannabinoid production in a neuron is triggered by its glutamatergic synaptic input and is dependent on an increase in intracellular calcium concentration. The produced endocannabinoid, in turn, suppresses the GABAergic synaptic input to the neuron by activating CB(1) cannabinoid receptors.

Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

PMID: 20553815 [PubMed – indexed for MEDLINE]

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Int J Pharm. 2010 Aug 30;396(1-2):149-55. Epub 2010 Jun 9.

Nanosized particles of orlistat with enhanced in vitro dissolution rate and lipase inhibition.

Dolenc A, Govedarica B, Dreu R, Kocbek P, Srcic S, Kristl J.

University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia.


Orlistat is locally acting inhibitor of gastrointestinal lipases which has been developed for the treatment of obesity. The present study was designed with the intent to formulate orlistat in a different way compared to the current practice and investigate its inhibition of gastrointestinal lipases. Orlistat is considered as a technologically problematic and unmanageable substance because of waxy nature, low melting point and low chemical stability. The manuscript presents the critical issues regarding engineering of its nanosuspension with controlled particle size by melt emulsification and high pressure homogenization. In order to formulate dry product, lactose was dissolved in nanosuspension as filler and spray drying has been performed for obtaining the final powder product. Laser diffraction, scanning electron microscopy and atomic force microscopy have been used for orlistat nanosuspension characterization, dissolution studies and lipase inhibition studies were performed to characterize the in vitro efficacy of formulated orlistat. The advantage of selected technological procedures is nanosized orlistat with elevated in vitro dissolution rate in comparison to raw drug, physical mixture and marketed product. Furthermore, nanosuspension demonstrated significantly higher in vitro lipase inhibition in comparison to references. To conclude, the results show new technological solution and remarkable increase of pharmacological effect which could potentially lead to decreasing the dose and consequently dose dependent side effects.

Copyright 2010 Elsevier B.V. All rights reserved.

PMID: 20540997 [PubMed – indexed for MEDLINE]

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J Clin Psychiatry. 2010 Aug 24. [Epub ahead of print]

Orlistat in clozapine- or olanzapine-treated patients with overweight or obesity: a 16-week open-label extension phase and both phases of a randomized controlled trial.

Tchoukhine E, Takala P, Hakko H, Raidma M, Putkonen H, Räsänen P, Terevnikov V, Stenberg JH, Eronen M, Joffe G.

Helsinki University Central Hospital, Peijas Hospital, 01400 Vantaa, Helsinki, Finland evgueni.tchoukhine@hus.fi.


OBJECTIVE: To explore long-term effects of orlistat in adult clozapine- or olanzapine-treated patients with DSM-IV-diagnosed schizophrenia and overweight or obesity who tolerate orlistat.

METHOD: Orlistat or placebo was added to clozapine or olanzapine in stable doses in a 16-week randomized controlled trial. Open-label orlistat was added to the antipsychotics during a 16-week extension phase for those completing the double-blind phase. No low-calorie diet or participation in behavioral programs was required. Body weight (primary outcome) and some metabolic parameters were measured prospectively. Analyses were performed for those completing both phases (ie, population differing from that reported earlier). The study was conducted from 2004 through 2005.

RESULTS: During the open-label phase, the 44 patients experienced mean ± SD body weight loss of -1.29 ± 3.04 kg, P = .007. During both phases, men (but not women) showed a weight loss of -2.39 ± 5.45 kg, P = .023. Some subgroups showed desirable changes in several metabolic parameters. Prolonged (32 weeks) orlistat treatment yielded no additional benefits as compared to short (16 weeks) treatment.

CONCLUSIONS: In clozapine- or olanzapine-treated overweight or obese patients able to take orlistat on a long-term basis, the drug, with no concomitant hypocaloric diet or behavioral interventions, caused moderate weight loss only in men. However, some metabolic benefits may be achieved independently of weight changes. In patients who do not respond to orlistat within the first 16 weeks, continuation treatment may provide no additional benefits.

TRIAL REGISTRATION: controlled-trials.com Identifier: ISRCTN65731856.

© Copyright 2010 Physicians Postgraduate Press, Inc.

PMID: 20816037 [PubMed – as supplied by publisher]

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Curr Treat Options Cardiovasc Med. 2010 Aug;12(4):381-95.

Therapeutic approaches to obesity.

Powell TM, Khera A.

University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, HA9.133, Dallas, TX, 75390, USA.


OPINION STATEMENT: Obesity in the United States has become a public health crisis, with one third of the US population having a body mass index ≥30 kg/m(2). Given the profound impact of obesity on cardiovascular disease (CVD), studies of lifestyle modification, pharmacotherapy, and surgical interventions must be reappraised to better define the roles of these approaches in preventing cardiovascular events. Recent clinical trials have attempted to quell the debate over macronutrient composition versus caloric restriction in the dietary approach to weight loss. Our interpretation of these results is that caloric reduction and adherence to diets are of greater consequence than the particular dietary content for weight reduction. For cardiovascular risk factor modification, however, specific macronutrient composition of the diet may have additional impact outside weight loss, although the ultimate relationship between various dietary macronutrients and clinical cardiovascular outcomes is unclear. Although pharmacotherapy has been used for decades to treat obesity, there currently are limited options and recurrent cautionary tales; therefore, we use these agents sparingly. Sibutramine, one of only two medications approved by the US Food and Drug Administration for the long-term treatment of obesity, recently came under intense scrutiny because of a possible increase in cardiovascular events, and it now is contraindicated in patients with established CVD. Orlistat and its over-the-counter form, Alli (GlaxoSmithKline, Research Triangle Park, NC), can induce modest weight loss but frequently are not tolerated because of unpleasant gastrointestinal side effects. Fortunately, there are new medications in phase 3 clinical trials that hold promise as potential alternatives for obesity treatment. Finally, bariatric surgery for morbid obesity refractory to lifestyle interventions has become considerably more common. Surgery can effectively reduce body weight and treat cardiovascular risk factors, particularly diabetes, with acceptable complication rates and should be considered a viable option for appropriate patients. Ongoing clinical trials will clarify the impact of bariatric surgery on cardiovascular events and mortality, as well as the role of surgery as a treatment option that may be considered earlier than currently recommended.

PMID: 20842561 [PubMed – in process]

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Expert Opin Pharmacother. 2010 Aug;11(12):1971-82.

Comparison of orlistat treatment and placebo in obese type 2 diabetic patients.

Derosa G, Maffioli P, Salvadeo SA, Ferrari I, Gravina A, Mereu R, D’Angelo A, Fogari E, Palumbo I, Randazzo S, Cicero AF.

University of Pavia, Department of Internal Medicine and Therapeutics, 27100 Pavia, Italy. giuseppe.derosa@unipv.it


AIM: To evaluate the effects of 1-year treatment with orlistat compared with placebo on different inflammatory parameters in type 2 obese diabetic patients.

MATERIALS AND METHODS: Two hundred and fifty-four type 2 diabetic patients were randomized to take orlistat 120 mg three times a day or placebo for 12 months. We evaluated at baseline and after 3, 6, 9 and 12 months: leptin, tumor necrosis factor (TNF)-alpha, adiponectin (ADN), vaspin and high-sensitivity C-reactive protein (HS-CRP), body weight, waist circumference, body mass index (BMI), lipid profile, glycemic profile, fasting plasma insulin (FPI) and homeostasis model assessment insulin resistance index (HOMA-IR).

RESULTS: Regarding inflammatory parameters, there was a significant improvement of ADN and TNF-alpha, and a faster decrease of leptin and HS-CRP in the orlistat group compared with the control group. We also recorded a significant reduction of body weight and BMI with orlistat, but not with placebo. A faster improvement of glycemic profile and FPI was obtained with orlistat compared with the controls. Also, there was a significant reduction of lipid profile with orlistat, not reached with placebo.

CONCLUSIONS: Orlistat was more effective than placebo in ameliorating inflammatory parameters such as ADN and TNF-alpha, and anthropometric parameters.

PMID: 20569086 [PubMed – indexed for MEDLINE]

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Internist (Berl). 2010 Aug;51(8):1064-6.

[Therapy of obesity with liraglutide. NN8022-1807 study].

[Article in German]

Scherbaum WA, Nitschmann S.

Klinik für Endokrinologie, Diabetologie und Rheumatologie, Universitätsklinikum Düsseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany. Scherbaum@uni-duesseldorf.de

PMID: 20628715 [PubMed – indexed for MEDLINE]

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Obes Facts. 2010 Aug;3(4):231-7. Epub 2010 Aug 9.

Pharmaceutical quality of nine generic orlistat products compared with Xenical(r).

Taylor PW, Arnet I, Fischer A, Simpson IN.

Department of Pharmaceutics, London School of Pharmacy, London, UK. peter.taylor@pharmacy.ac.uk


OBJECTIVE: To compare the pharmaceutical quality of Xenical (chemically produced orlistat) with nine generic products, each produced by fermentation processes.

METHODS: Xenical 120 mg capsules (Roche, Basel, Switzerland) were used as reference material. Generic products were from India, Malaysia, Argentina, Philippines, Uruguay, and Taiwan. Colour, melting temperature, crystalline form, particle size, capsule fill mass, active pharmaceutical ingredient content, amount of impurities, and dissolution were compared. Standard physical and chemical laboratory tests were those developed by Roche for Xenical.

RESULTS: All nine generic products failed the Xenical specifications in four or more tests, and two generic products failed in seven tests. A failure common to all generic products was the amount of impurities present, mostly due to different by-products, including side-chain homologues not present in Xenical. Some impurities were unidentified. Two generic products tested failed the dissolution test, one product formed a capsule-shaped agglomerate on storage and resulted in poor (</=15%) dissolution. Six generic products were powder formulations.

CONCLUSIONS: All tested generic orlistat products were pharmaceutically inferior to Xenical. The high levels of impurities in generic orlistat products are a major safety and tolerability concern.

Copyright © 2010 S. Karger AG, Basel.

PMID: 20823686 [PubMed – indexed for MEDLINE]

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Obes Rev. 2010 Aug;11(8):593-602. Epub 2009 Nov 17.

Efficacy and safety of anti-obesity drugs in children and adolescents: systematic review and meta-analysis.

Viner RM, Hsia Y, Tomsic T, Wong IC.

UCL Institute of Child Health, University College London, UK. r.viner@ich.ucl.ac.uk


We undertook a meta-analysis of randomized controlled trials to summarize the efficacy of anti-obesity drugs in reducing BMI and improving health in children and adolescents. Data sources included Medline, Embase, the Cochrane controlled trials register and other registers of controlled trials, together with reference lists of identified articles. All data sources were searched from January 1996 to July 2008. We searched for double blind randomized placebo controlled trials of approved anti-obesity drugs used in children and adolescents (age < 20) with primary obesity for > or = 6 months. Six trials, 4 of sibutramine (total patients = 686) and 2 of orlistat (n = 573) met inclusion criteria. No trials of rimonabant were identified. Compared with placebo, sibutramine together with behavioural support reduced BMI by 2.20 kg/m(2) (95% CI: 1.57 to 2.83) and orlistat together with behavioural support reduced BMI by 0.83 kg/m(2) (95% CI 0.47 to 1.19). Sibutramine improved waist circumference, triglycerides and high density lipoprotein (HDL)-cholesterol, but raised systolic and diastolic blood pressure and pulse. Orlistat increased rates of gastrointestinal side-effects. We conclude that sibutramine in adolescents produces clinically meaningful reductions in BMI and waist circumference of approximately 0.63 SD, with improvements in cardiometabolic risk. Orlistat modestly reduces BMI (effect size approximately 0.24 SD) with a high prevalence of gastrointestinal adverse effects.

PMID: 19922432 [PubMed – indexed for MEDLINE]

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J Med Chem. 2010 Jul 22;53(14):5281-9.

Thiadiazole carbamates: potent inhibitors of lysosomal acid lipase and potential Niemann-Pick type C disease therapeutics.

Rosenbaum AI, Cosner CC, Mariani CJ, Maxfield FR, Wiest O, Helquist P.

Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.


Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized at the cellular level by abnormal accumulation of cholesterol and other lipids in lysosomal storage organelles. Lysosomal acid lipase (LAL) has been recently identified as a potential therapeutic target for NPC. LAL can be specifically inhibited by a variety of 3,4-disubstituted thiadiazole carbamates. An efficient synthesis of the C(3) oxygenated/C(4) aminated analogues has been developed that furnishes the products in high yields and high degrees of purity. Common intermediates can also be used for the synthesis of the C(3) carbon substituted derivatives. Herein we tested various thiadiazole carbamates, amides, esters, and ketones for inhibition of LAL. In addition, we tested a diverse selection of commercially available non-thiadiazole carbamates. Our studies show that, among the compounds examined herein, only thiadiazole carbamates are effective inhibitors of LAL. We present a mechanism for LAL inhibition by these compounds whereby LAL transiently carbamoylates the enzyme similarly to previously described inhibition of acetylcholinesterase by rivastigmine and other carbamates as well as acylation of various lipases by orlistat.

PMID: 20557099 [PubMed – indexed for MEDLINE]PMCID: PMC2912405 [Available on 2011/7/1]

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Evid Based Nurs. 2010 Jul;13(3):98-100.

Over-the-counter weight loss with orlistat?

[No authors listed]

Republished from:


Orlistat first became available (as 120 mg capsules [Xenical]) around 10 years ago as a prescription-only treatment for obesity.1 Earlier this year, orlistat 60 mg capsules (alli – GlaxoSmithKline Consumer Healthcare) became available for sale without a prescription to the public in the European Union. Orlistat 60 mg is available in the UK as a Pharmacy (P) medicine and so can be purchased over-the-counter (OTC) from pharmacies. OTC orlistat is promoted as a new weight loss aid, “boosting weight loss by 50%” when added to a reduced calorie, lower-fat diet. Here we review the place of OTC orlistat in tackling obesity.

PMID: 20584843 [PubMed]

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Int J Eat Disord. 2010 Jul;43(5):472-9.

A prevalence study and description of alli use by patients with eating disorders.

Steffen KJ, Mitchell JE, le Grange D, Crow SJ, Attia E, Bulik CM, Dellava JE, Bermudez O, Erickson AL, Crosby RD, Bansal-Dev VP.

Neuropsychiatric Research Institute, Fargo, North Dakota 58103, USA. ksteffen@nrifargo.com


OBJECTIVE: This study examined the frequency and characteristics of alli use among patients in eating disorder treatment facilities.

METHOD: Patients from five treatment centers completed the Survey of Eating and Related Behaviors. Diagnoses were determined from survey responses.

RESULTS: Of 417 survey respondents, 26 (6.2%) reported a history of alli use. Of those, 15 (57.7%) met criteria for an eating disorder, including one of 29 patients (3.4%) with anorexia nervosa binge-purge subtype, six of 66 patients (9.1%) with full or subthreshold bulimia nervosa, four of 49 (8.2%) with binge eating disorder, one of six (16.7%) with purging disorder, and three of 80 (3.8%) with an eating disorder not otherwise specified.

DISCUSSION: The results of this survey suggest that patients with eating disorders use alli, albeit relatively uncommonly. Therefore, it is worthwhile for clinicians to inquire about alli use when evaluating or treating these patients in any clinical setting.

2010 by Wiley Periodicals, Inc.

PMID: 20527049 [PubMed – indexed for MEDLINE]

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Am Fam Physician. 2010 Jun 15;81(12):1449-56 ; quiz 1429.

Office-based strategies for the management of obesity.

Rao G.

University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. raog@upmc.edu

Comment in:


Roughly two thirds of U.S. adults are overweight or obese. Obesity increases the risk of hypertension, type 2 diabetes mellitus, hyperlipidemia, heart disease, pulmonary disease, hepatobiliary disease, cancer, and a number of psychosocial complications. Physicians often feel unprepared to handle this important problem. Practical office-based strategies include: (1) making recommendations for assisted self-management, including guidance on popular diets, (2) advising patients about commercial weight-loss programs, (3) advising patients about and prescribing medications, (4) recommending bariatric surgery, and (5) supplementing these strategies with counseling about lifestyle changes using a systematic approach. Family physicians should provide basic information about the effectiveness and safety of popular diets and commercial weight-loss programs, and refer patients to appropriate information sources. Sibutramine and orlistat, the only medications currently approved for the long-term treatment of obesity, should only be prescribed in combination with lifestyle changes. Bariatric surgery is an option for adults with a body mass index of 40 kg per m2 or higher, or for those with a body mass index of 35 kg per m2 or higher who have obesity-related comorbidities such as type 2 diabetes. The five A’s behavioral counseling paradigm (ask, advise, assess, assist, and arrange) can be used as the basis for a systematic, practical approach to the management of obesity that incorporates evidence for managing common obesity-related behaviors.

PMID: 20540483 [PubMed – indexed for MEDLINE]

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Aging Clin Exp Res. 2010 Jun;22(3):206-11.

Effects of weight loss on ventricular systolic and diastolic functions and left ventricular mass assessed by tissue doppler imaging in obese geriatric women: preliminary report.

Varli M, Turhan S, Aras S, Atli T, Erdogan G.

Department of Geriatric Medicine, Ankara University School of Medicine, Cebeci, Ankara, Turkey. mvarli2003@yahoo.com


BACKGROUND AND AIMS: Obesity is one of the most common diseases in the world. Particularly in elderly subjects, the effects of weight loss on cardiac functions have not been previously investigated by means of pulsed wave tissue doppler imaging (PWTDI). Using PWTDI, we examined the effects of weight loss on cardiac functions and left ventricular (LV) mass in obese geriatric women.

METHODS: Thirteen obese women aged 66-83 years (mean age 71.2+/-4.9 yrs) with a body mass index 35.6-49 kg/m2 (mean body mass index 39.9+/-4.3 kg/m2) were evaluated by echocardiography and PWTDI. Only subjects with uncomplicated obesity were included. All measurements, including anthropometric variables, systolic and diastolic indices, and LV mass, were made before and after a 6-month Orlistat plus hypocaloric diet. Myocardial systolic wave (Sm) velocity, isovolumic acceleration (IVA), myocardial precontraction time (PCTm) and the PCTm to contraction time (CTm) ratio were calculated as systolic indices. Early diastolic wave (Em), late diastolic wave (Am), Em to Am ratio, myocardial relaxation time (RTm), deceleration time (DT) and isovolumic relaxation time (IVRT) were determined as diastolic measurements.

RESULTS: Subjects lost an average of 8.4+/-1.2 kg. LV mass decreased significantly after weight loss (p<0.001). In addition, IVRT decreased significantly (p=0.038). Only RTm decreased significantly (p=0.016), whereas other PWTDI parameters of LV remained the same. In the right ventricle, Sm velocity, IVA, Em, and Am velocities were similar. However, the PCTm to Am ratio decreased significantly (p=0.006), and the Em to Am ratio increased (p=0.04) and RTm decreased significantly (p=0.016) after weight loss.

CONCLUSIONS: In obese geriatric women, weight loss improves ventricular diastolic functions and decreases LV mass. It also contributes to partial improvement in right ventricular systolic function.

PMID: 20634644 [PubMed – indexed for MEDLINE]

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Biochim Biophys Acta. 2010 Jun;1801(6):665-73. Epub 2010 Mar 16.

Gelucire 44/14 improves fat absorption in rats with impaired lipolysis.

Lukovac S, Gooijert KE, Gregory PC, Shlieout G, Stellaard F, Rings EH, Verkade HJ.

Pediatric Gastroenterology, Department of Pediatrics, Beatrix Children’s Hospital, Groningen University Institute for Drug Exploration (GUIDE), Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Erratum in:

  • Biochim Biophys Acta. 2010 Sep;1801(9):1105.


Clinically relevant fat malabsorption is usually due to impaired intestinal fat digestion (lipolysis) and/or to impaired solubilization of the lipolytic metabolites. We hypothesized that Gelucire 44/14 – a semi-solid self-micro-emulsifying excipient – could increase fat absorption. In relevant rat models for impaired lipolysis or for impaired solubilization we tested whether administration of Gelucire 44/14 enhanced fat absorption. Rats with impaired lipolysis (lipase inhibitor Orlistat diet) and rats with reduced solubilization (permanent bile diversion) underwent a 72 h fat balance test to assess fat absorption. The absorption kinetics of a stable isotope-labeled fatty acid was assessed in rats with reduced solubilization, in the presence or absence of Gelucire 44/14. Gelucire 44/14 improved fat absorption in rats with impaired lipolysis (from 70% to 82%, p<0.001). In rats with reduced solubilization, Gelucire 44/14 did not increase fat absorption nor did it reconstitute the absorption kinetics of (13)C-labeled palmitate, compared with control rats administered buffer without Gelucire 44/14. The present data show that Gelucire 44/14 might enhance fat absorption under conditions of impaired lipolysis, but not during impaired solubilization. We speculate that, due to its self-micro-emulsification properties, Gelucire 44/14 stabilizes and improves residual lipolytic enzyme activity in vivo, which could be of therapeutic value in clinical conditions of fat malabsorption due to impaired lipolysis.

Copyright (c) 2010 Elsevier B.V. All rights reserved.

PMID: 20298808 [PubMed – indexed for MEDLINE]

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Diabetes Obes Metab. 2010 Jun;12(6):463-73.

Diabesity: therapeutic options.

Colagiuri S.

Boden Institute of Obesity, Nutrition and Exercise, University of Sydney, Sydney, NSW, Australia. scolagiuri@usyd.edu.au


A pathogenic relationship exists between type 2 diabetes and obesity. Over the last decade, the escalation in diabetes cases has paralleled the rapid increase in obesity rates, constituting a global health crisis. Environmental risk factors attributed to the global increase in obesity include the consumption of high-calorie, high-fat foods and inadequate physical activity. Obese individuals may also have a genetic predisposition for obesity. Both diabetes and obesity confer an elevated risk of developing a range of complications and comorbidities, including cardiovascular disease, hypertension and stroke, which can complicate disease management. This review examines the aetiology of the linkages between diabetes and obesity and the range of available therapies. Recent clinical evidence substantiating the efficacy and safety of incretin-based antidiabetic therapies is analysed, in addition to data on antiobesity therapeutic strategies, such as antiobesity agents, behaviour modification and bariatric surgery. Glucose control is often accompanied by weight-neutral or modest weight reduction effects with DPP-4 inhibitor treatment (sitagliptin, vildagliptin, saxagliptin) and weight loss with GLP-1 receptor agonist therapy (exenatide, liraglutide). Studies of antiobesity agents including orlistat, sibutramine and rimonabant have shown attrition rates of 30-40%, and the long-term effects of these agents remain unknown. Bariatric surgical procedures commonly performed are laparoscopic adjustable banding of the stomach and the Roux-en-Y gastric bypass, and have produced type 2 diabetes remission rates of up to 73%. Therapeutic strategies that integrate glycaemic control and weight loss will assume greater importance as the prevalence of diabetes and obesity increase.

PMID: 20518802 [PubMed – in process]

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Drugs Aging. 2010 Jun 1;27(6):497-506. doi: 10.2165/11536660-000000000-00000.

Long-term pharmacotherapy for obesity in elderly patients: a retrospective evaluation of medical records from a specialized obesity outpatient clinic.

Horie NC, Cercato C, Mancini MC, Halpern A.

Obesity Outpatient Clinic for the Elderly, Department of Geriatrics, Hospital das Clinicas, Faculdade de Medicina da Universidade de São Paulo (USP), São Paulo, Brazil. nidiachorie@yahoo.com.br


Obesity is a serious chronic disease and the prevalence of this condition is increasing among the elderly. Although the benefits of weight loss to improve control of associated diseases are well known in young adults, they are not in older patients. The use of anti-obesity drugs to promote weight loss is widespread in Brazil and other countries, and obesity specialists frequently prescribe medicines in doses and for durations previously unreported in the literature. Sibutramine, orlistat and amfepramone (diethylpropion) have been evaluated in clinical trials of more than 2 years’ duration in adults, demonstrating safety and efficacy, but long-term studies in obesity treatment are absent for other drugs. The efficacy and safety of obesity pharmacotherapy among the elderly is unknown. To describe the experience of obesity pharmacotherapy in the elderly in a specialized obesity care setting in Brazil, with a focus on efficacy and safety. A retrospective evaluation was conducted on medical charts from an outpatient clinic of a specialized tertiary centre for the treatment of obesity. We included patients who had had at least one consultation between January and December 2007, were aged > or =60 years at the beginning of the treatment, had had at least 6 months of follow-up and had received a prescription of at least one potential weight-loss drug. Diagnoses reported on medical records were documented. Age, weight, height and body mass index (BMI) were recorded at admission, after 6, 12, 18 and 24 months, and at the last available visit. The medicines prescribed, together with the dose, duration of use, adverse effects and reasons for discontinuation, were documented. The group consisted of 44 women (86%) and 7 men (14%), with a mean +/- SD age of 65.2 +/- 4.5 years, weight of 95.3 +/- 12.5 kg and BMI of 38.5 +/- 4.3 kg/m2. The mean +/- SD time of follow-up was 39.3 +/- 26.4 months, and the mean weight loss was 6.65 kg (p < 0.01). After the first 6 months, the mean +/- SD weight loss was 5.7 +/- 3.8 kg (p < 0.0001). A smaller weight loss was seen between the 6th and 12th months, with no statistically significant change in weight thereafter. A weight loss of > or =5% was achieved by 64.71%, 63.64%, 62.16% and 69.70% in the 6th, 12th, 18th and 24th months, respectively, and a weight loss of > or =10% was achieved by 17.65%, 34.09%, 32.43% and 39.39% in the 6th, 12th, 18th and 24th months, respectively. The medicines prescribed were sibutramine, orlistat, fluoxetine, sertraline, topiramate, fenproporex, mazindol and amfepramone, alone or in combinations, concomitantly or sequentially. The reasons for discontinuation were lack of response (n = 13), loss of response (development of tolerance) [n = 11], lack of adherence (n = 14) and adverse effects (n = 14). One episode of atrial flutter occurred in a patient taking fenproporex. The weight-loss medications were generally well tolerated, and only transient adverse events were reported. Long-term pharmacotherapy for obesity was effective and well tolerated by this group of elderly patients.

PMID: 20524709 [PubMed – indexed for MEDLINE]

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FASEB J. 2010 Jun;24(6):1893-903. Epub 2010 Jan 26.

Two cutinase-like proteins secreted by Mycobacterium tuberculosis show very different lipolytic activities reflecting their physiological function.

Schué M, Maurin D, Dhouib R, Bakala N’Goma JC, Delorme V, Lambeau G, Carrière F, Canaan S.

Centre National de la Recherche Scientifique, Aix-Marseille Université, Enzymologie Interfaciale et Physiologie de la Lipolyse UPR 9025, Marseille, France.


Cutinases are extracellular enzymes that are able to degrade cutin, a polyester protecting plant leaves and many kinds of lipids. Although cutinases are mainly found in phytopathogenic fungi or bacteria, 7 genes related to the cutinase family have been predicted in the genome of Mycobacterium tuberculosis. These genes may encode proteins that are involved in the complex lipid metabolism of the bacterium. Here, we report on the biochemical characterization of two secreted proteins of M. tuberculosis, Rv1984c and Rv3452, belonging to the cutinase family. Although their amino acid sequence shows 50% identity with that of the well-characterized cutinase from Fusarium solani pisi, and a high level of homology has been found to exist between these two enzymes, they show distinct substrate specificities. Rv1984c preferentially hydrolyzes medium-chain carboxylic esters and monoacylglycerols, whereas Rv3452 behaves like a phospholipase A(2), and it is able to induce macrophage lysis. The tetrahydrolipstatin inhibitor, a specific lipase inhibitor, abolishes the activity of both enzymes. Site-directed mutagenesis was performed to identify the catalytic triad of Rv1984c. Structural models for Rv1984c and Rv3452 were built, based on the crystal structure of F. solani cutinase, with a view to investigating the contribution of specific residues to the substrate specificity. Our findings open new prospects for investigating the physiological roles of cutinase-like proteins in the lipid metabolism and virulence of M. tuberculosis.

PMID: 20103719 [PubMed – indexed for MEDLINE]

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Minerva Gastroenterol Dietol. 2010 Jun;56(2):159-67.

Weight loss: cornerstone in the treatment of non-alcoholic fatty liver disease.

Tilg H, Moschen A.

Christian Doppler Research Laboratory for Gut Inflammation, Innsbruck Medical University, Austria. Herbert.Tilg@i-med.ac.at


Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases worldwide, mostly due to the dramatic increase in obesity rates. This disease presents mainly as simple liver steatosis, whereas 10-20% of patients exhibit an inflammatory phenotype referred to as non-alcoholic steatohepatitis (NASH). Advanced liver disease affects a smaller group of patients including fibrosis, cirrhosis and hepatocellular carcinoma. Higher age, extensive overweight, and number of features of the metabolic syndrome are associated with NAFLD severity. In most cases, NAFLD is associated with insulin resistance and insulin resistance is therefore a major target for all NAFLD treatment modalities. Various treatments into this direction, such as the use of thiazolidinediones have recently failed and did not lead to an improvement in liver histology parameters. Successful weight loss either achieved via bariatric surgery or subsequent to lifestyle modification/behavior therapy, however, has been demonstrated to improve both metabolic parameters and liver histology including inflammatory changes. The first recently reported randomized controlled trial in NASH patients testing the effects of weight loss showed that a one year period of lifestyle adjustment resulted in a 7-10% weight loss with significant histological improvement of liver disease. Orlistat, the only available obesity drug treatment on the market, failed to improve insulin resistance or histopathology in NAFLD. Therefore, new weight-loss inducing agents are eagerly awaited to increase the percentage of obese people to benefit from weight reduction.

PMID: 20485253 [PubMed – indexed for MEDLINE]

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Neuropsychopharmacology. 2010 Jun;35(7):1520-30. Epub 2010 Mar 24.

Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis.

Maayan L, Vakhrusheva J, Correll CU.

Child Study Center, New York University School of Medicine, New York, NY, USA.


Antipsychotic-related weight gain and metabolic effects are a critical outcome for patients requiring these medications. A literature search using MEDLINE, Web of Science, PsycNET, and EMBASE for randomized, open and double-blind, placebo-controlled trials of medications targeting antipsychotic-induced weight gain was performed. Primary outcome measures were change and endpoint values in body weight and body mass index (BMI). Secondary outcomes included >or=7% weight gain, all-cause discontinuation, change in waist circumference, glucose and lipid metabolism parameters, and psychiatric symptoms. Sensitivity analyses were conducted to explain heterogeneity of the results. Across 32 studies including 1482 subjects, 15 different medications were tested: amantadine, dextroamphetamine, d-fenfluramine, famotidine, fluoxetine, fluvoxamine, metformin, nizatidine, orlistat, phenylpropanolamine, reboxetine, rosiglitazone, sibutramine, topiramate, and metformin+sibutramine. Compared with placebo, metformin had the greatest weight loss (N=7, n=334, -2.94 kg (confidence interval (CI:-4.89,-0.99)), followed by d-fenfluramine (N=1, n=16, -2.60 kg (CI:-5.14,-0.06)), sibutramine (N=2, n=55, -2.56 kg (CI:-3.91,-1.22)), topiramate (N=2, n=133, -2.52 kg (CI:-4.87,-0.16)), and reboxetine (N=2, n=79, -1.90 kg (CI:-3.07,-0.72)). Weight loss remained significant with metformin initiation after weight gain had occurred, but not when started concomitantly with antipsychotics. Nausea rates were not higher with any treatment compared with placebo. In all, 5 of 15 psychopharmacologic interventions aimed at ameliorating antipsychotic-induced weight gain outperformed placebo. Results were most robust for metformin, although these were modest and heterogeneous. Only one (negative) combination treatment study was available and head-to-head studies are absent. None of the agents were able to entirely reverse weight gain because of antipsychotics. At present, no treatment has sufficient evidence to recommend broad clinical usage. Antipsychotics with no or minimal cardiometabolic liability, as well as interventions that prevent or normalize adverse antipsychotic cardiometabolic effects are needed.

PMID: 20336059 [PubMed – indexed for MEDLINE]

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Nutr Res Rev. 2010 Jun;23(1):146-54. Epub 2010 Mar 1.

Physiological parameters governing the action of pancreatic lipase.

Brownlee IA, Forster DJ, Wilcox MD, Dettmar PW, Seal CJ, Pearson JP.

Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne, UK. i.a.brownlee@ncl.ac.uk


The most widely used pharmacological therapies for obesity and weight management are based on inhibition of gastrointestinal lipases, resulting in a reduced energy yield of ingested foods by reducing dietary lipid absorption. Colipase-dependent pancreatic lipase is believed to be the major gastrointestinal enzyme involved in catalysis of lipid ester bonds. There is scant literature on the action of pancreatic lipase under the range of physiological conditions that occur within the human small intestine, and the literature that does exist is often contradictory. Due to the importance of pancreatic lipase activity to nutrition and weight management, the present review aims to assess the current body of knowledge with regards to the physiology behind the action of this unique gastrointestinal enzyme system. Existing data would suggest that pancreatic lipase activity is affected by intestinal pH, the presence of colipase and bile salts, but not by the physiological range of Ca ion concentration (as is commonly assumed). The control of secretion of pancreatic lipase and its associated factors appears to be driven by gastrointestinal luminal content, particularly the presence of acid or digested proteins and fats in the duodenal lumen. Secretion of colipase, bile acids and pancreatic lipase is driven by cholecystokinin and secretin release.

PMID: 20193096 [PubMed – indexed for MEDLINE]

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Diabetes Obes Metab. 2010 May;12(5):365-83.

The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease.

Polyzos SA, Kountouras J, Zavos C, Tsiaousi E.

Second Medical Clinic, Medical School, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece. stergios@endo.gr


Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries and the leading cause of cryptogenic cirrhosis. Insulin resistance (IR) is a key factor in the pathogenesis of NAFLD, the latter being considered as the hepatic component of IR or metabolic syndrome (MetS). Although the pathogenesis of NAFLD is not fully elucidated, a complex interaction between adipokines and cytokines produced by adipocytes and/or inflammatory cells infiltrating adipose tissue appears to play a crucial role in MetS and NAFLD. Adiponectin is the most abundant and adipose-specific adipokine. In the liver, adiponectin acts through the activation of 5-AMP-activated protein kinase and peroxisome proliferator-activated receptor-alpha pathways and inhibition of toll-like receptor-4 mediated signalling. There is an evidence that adiponectin decreases hepatic and systematic IR and attenuates liver inflammation and fibrosis. Adiponectin generally predicts steatosis grade and severity of NAFLD, but it remains to be addressed to what extent this is a direct effect or related to the presence of more severe IR. Although there is no proven pharmacotherapy for the treatment of NAFLD, recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications. Weight loss, through diet, lifestyle changes and/or medications including orlistat, sibutramine, rimonabant or bariatric surgery, increase adiponectin and may improve liver histology. Insulin sensitizers, including pioglitazone and rosiglitazone, and lipid-lowering agents, including statins and fibrates, also upregulate adiponectin and ameliorate liver histology. The wider use of new treatment approaches appears to signal the dawn of a new era in the management of NAFLD. In this adiponectin-focused review, the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are systematically analysed.

PMID: 20415685 [PubMed – in process]

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Diabetologia. 2010 May;53(5):875-81. Epub 2010 Feb 5.

Assessing the cost-effectiveness of drug and lifestyle intervention following opportunistic screening for pre-diabetes in primary care.

Bertram MY, Lim SS, Barendregt JJ, Vos T.

Centre for Burden of Disease and Cost-Effectiveness, School of Population Health, The University of Queensland, Herston Rd, Herston, Queensland 4006, Australia. m.bertram@sph.uq.edu.au


AIMS/HYPOTHESIS: This study aims to evaluate the cost-effectiveness of a screening programme for pre-diabetes, which was followed up by treatment with pharmaceutical interventions (acarbose, metformin, orlistat) or lifestyle interventions (diet, exercise, diet and exercise) in order to prevent or slow the onset of diabetes in those at high risk.

METHODS: To approximate the experience of individuals with pre-diabetes in the Australian population, we used a microsimulation approach, following patient progression through diabetes, cardiovascular disease and renal failure. The model compares costs and disability-adjusted life years lived in people identified through an opportunistic screening programme for each intervention compared with a ‘do nothing’ scenario, which is representative of current practice. It is assumed that the effect of a lifestyle change will decay by 10% per year, while the effect of a pharmaceutical intervention remains constant throughout use.

RESULTS: The most cost-effective intervention options are diet and exercise combined, with a cost-effectiveness ratio of AUD 22,500 per disability-adjusted life year (DALY) averted, and metformin with a cost-effectiveness ratio of AUD 21,500 per DALY averted. The incremental addition of one intervention to the other is not cost-effective.

CONCLUSIONS/INTERPRETATION: Screening for pre-diabetes followed by diet and exercise, or metformin treatment is cost-effective and should be considered for incorporation into current practice. The number of dietitians and exercise physiologists needed to deliver such lifestyle change interventions will need to be increased to appropriately support the intervention.

PMID: 20135088 [PubMed – indexed for MEDLINE]

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Int J Oncol. 2010 May;36(5):1309-14.

Fatty acid synthesis is a therapeutic target in human liposarcoma.

Olsen AM, Eisenberg BL, Kuemmerle NB, Flanagan AJ, Morganelli PM, Lombardo PS, Swinnen JV, Kinlaw WB.

Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.


Liposarcomas (LS) are mesenchymal tumors that can recur after surgical resection and often do not respond to presently available medical therapies. This study demonstrates the dependence of LS on de novo long-chain fatty acid synthesis for growth. Lipogenesis can be impaired by inhibiting the activities of lipogenic enzymes, including acetyl CoA-carboxylase (ACC) and fatty acid synthase (FASN), or by suppressing the expression of key genes involved in the pathway and its regulation. The FASN inhibitors cerulenin and orlistat reduced the growth of two LS cell lines (LiSa2, SW872), as did inhibition of ACC with soraphen A. CDDO-Me, a synthetic triterpenoid, suppressed expression of Spot 14 and FASN genes and likewise inhibited LS cell growth. Importantly, the anti-proliferative effect of each agent was prevented by the co-administration of palmitate, the major product of cellular long-chain fatty acid synthesis. In stark contrast to LS cells, these compounds had no effect on the growth of fibroblasts. Four biochemically distinct agents that target critical points in the fatty acid synthetic pathway exert anti-proliferative effects on LS cells, and rescue of cell growth by palmitic acid suggests that reduced tumor cell lipogenesis mediates the growth inhibition. These findings warrant further studies aimed at the clinical exploitation of the dependence of LS cell growth on fatty acids.

PMID: 20372807 [PubMed – indexed for MEDLINE]

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J Ren Care. 2010 May;36 Suppl 1:163-71.

Weight loss in obese patients with chronic kidney disease: who and how?

Teta D.

Department of Nephrology, University Hospital (CHUV), Lausanne, Switzerland. daniel.teta@chuv.ch


Obesity has adverse consequences in the general population. In patients with chronic kidney disease (CKD), it is associated with increased inflammation, insulin resistance, hypertension and dyslipidaemia, which are important risk factors for CKD progression and death. In adults with CKD stages 1-4, weight loss should be encouraged, it reduces proteinuria and glomerular hyperfiltration, which are frequent in obese patients. Proposals for modifications of lifestyle, physical activity and calorie restriction are the first measures. Pharmacological treatments are generally unsafe in these patients, except orlistat, but that has modest efficacy. Bariatric surgery may be the only option in severe obesity, if all other measures fail. For obese patients on dialysis treatment, who are eligible for kidney transplantation, weight loss is mandatory to prevent obesity-related surgical complications and improve patient and graft survival after transplantation. Interventions should place an emphasis on exercise to increase muscle mass, and calorie but not protein restriction. Bariatric surgery should be carried out by experienced surgeons due to the high risk of complications. For obese patients who are not considered transplant candidates the benefits of weight loss remain uncertain.

PMID: 20586912 [PubMed – indexed for MEDLINE]

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Lipids. 2010 May;45(5):445-50. Epub 2010 Apr 9.

The effects of ezetimibe and/or orlistat on triglyceride-rich lipoprotein metabolism in obese hypercholesterolemic patients.

Nakou ES, Filippatos TD, Agouridis AP, Kostara C, Bairaktari ET, Elisaf MS.

Department of Internal Medicine, School of Medicine, University of Ioannina, 45 110 Ioannina, Greece.


We investigated the factors influencing triglycerides (TG) reduction during ezetimibe, alone or combined with orlistat, administration. Eighty-six obese hypercholesterolemic subjects were prescribed a low-fat diet and were randomized to ezetimibe (E group), orlistat (O group), or both (OE group) for 6 months. Plasma TG and apolipoprotein (apo) C-III reduction was significantly greater in the combination group compared with monotherapy. Multivariate analysis showed that in E group apoC-III reduction and baseline TG levels were independently positively correlated, whereas baseline apoC-II levels were negatively correlated, with TG lowering. In OE group apoC-III reduction was the only independent contributor to TG reduction.

PMID: 20379853 [PubMed – indexed for MEDLINE]

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Postgrad Med. 2010 May;122(3):106-17.

Managing type 2 diabetes: balancing HbA1c and body weight.

Mavian AA, Miller S, Henry RR.

Division of Endocrinology, Diabetes and Metabolism, University of California San Diego, San Diego, CA 92103, USA.


Most patients with type 2 diabetes present with comorbid overweight or obesity. Reaching and maintaining acceptable glycemic control is more difficult in overweight and obese patients, and these conditions are associated with increased risk for cardiovascular and other diseases. Glycemic management for these patients is complicated by the fact that insulin and many of the oral medications available to treat type 2 diabetes produce additional weight gain. However, an increasing number of therapeutic options are available that are weight neutral or lead to weight loss in addition to their glycemic benefits. This article evaluates the evidence from clinical trials regarding the relative glycemic benefits, measured in terms of glycated hemoglobin change, versus the impact on body weight of each medication currently approved for type 2 diabetes. In general, the sulfonylureas, thiazolidinediones, and D-phenylalanine derivatives have been shown to promote weight gain. The dipeptidyl peptidase-4 inhibitors are weight neutral, while the biguanides, incretin mimetics, and amylin mimetics promote weight loss. Trials examining the glycemic benefits of the weight loss agents orlistat and sibutramine are also examined. Awareness of this evidence base can be used to inform medication selection in support of weight management goals for patients with type 2 diabetes.

PMID: 20463420 [PubMed – indexed for MEDLINE]

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World J Hepatol. 2010 Apr 27;2(4):139-42.

Combination drug treatment in patients with non-alcoholic fatty liver disease.

Filippatos TD, Elisaf MS.

Theodosios D Filippatos, Moses S Elisaf, Department of Internal Medicine, University of Ioannina, Ioannina 45110, Greece.


Non-alcoholic fatty liver disease (NAFLD) includes simple steatosis, a benign condition, and non-alcoholic steatohepatitis, a condition that beyond TG accumulation also includes necroinflammation and fibrosis. An association between NAFLD and cardiovascular disease (CVD) has been recently suggested. NAFLD patients usually have an increased CVD risk profile. NAFLD is also associated with metabolic syndrome (MetS) and is considered as the hepatic component of MetS by some authors. Currently, the only established treatment of NAFLD is gradual weight loss. However, multifactorial treatment of NAFLD risk factors may be needed to reduce the increased CVD risk of NALFD patients. Drug combinations that include antiobesity drugs (such as orlistat and sibutramine) and target CVD risk factors may be a good approach to NAFLD patients. Our group has investigated the orlistat-fenofibrate combination treatment in obese patients with MetS and the orlistat-ezetimibe and sibutramine-antihypertensive combination treatment in obese patients with hyperlipidaemia with promising results in CVD risk factor reduction and improvement of liver function tests. Small studies give promising results but double-blind, randomized trials examining the effects of such multifactorial treatment in hard CVD endpoints in NAFLD patients are missing.

PMID: 21160985 [PubMed – in process]PMCID: PMC2999276Free PMC Article

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Org Lett. 2010 Apr 2;12(7):1556-9.

A concise, phosphate-mediated approach to the total synthesis of (-)-tetrahydrolipstatin.

Venukadasula PK, Chegondi R, Maitra S, Hanson PR.

Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582, USA.


An efficient synthesis of (-)-tetrahydrolipstatin (THL) is reported. This method takes advantage of a phosphate tether-mediated, one-pot, sequential RCM/CM/hydrogenation protocol to deliver THL in eight total steps from a readily prepared (S,S)-triene. The strategy incorporates selective cross-metathesis, regioselective hydrogenation, regio- and diastereoselective cuprate addition, and Mitsunobu inversion for installation of the C5 formamide ester subunit.

PMID: 20196547 [PubMed – indexed for MEDLINE]PMCID: PMC2888003 [Available on 2011/4/2]

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Curr Diab Rep. 2010 Apr;10(2):108-15.

Combination drugs for treating obesity.

Greenway FL, Bray GA.

Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, 70808, USA. frank.greenway@pbrc.edu


Although obesity is a chronic disease like hypertension and diabetes, obesity is not treated with drug combinations as are other chronic diseases. This is because orlistat and sibutramine, the two drugs approved for long-term treatment of obesity, do not result in additive weight loss when combined. This article discusses the history of combination drug therapy for treating obesity, the lessons learned from that experience, and describes the drug combinations now in development. One combination of two standardized dietary herbal supplements that result in clinically significant weight loss is also described. Obesity is poised to enter the era of combination drug therapy, as is now the routine in the treatment of other chronic diseases like hypertension and diabetes. The advent of combination drug therapy for obesity treatment offers hope for increasing the efficacy of obesity pharmacotherapy.

PMID: 20425569 [PubMed – indexed for MEDLINE]

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Diabet Med. 2010 Apr;27(4):485-6.

Pancreatitis associated with the use of sitagliptin and orlistat combination: a case report.

Garg R, Hussey C, Ibrahim S.

PMID: 20536524 [PubMed – indexed for MEDLINE]

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Future Oncol. 2010 Apr;6(4):551-62.

Fatty acid synthase as a potential therapeutic target in cancer.

Flavin R, Peluso S, Nguyen PL, Loda M.

Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Harvard Medical School, Brigham & Women’s Hospital, Boston, MA, USA.


Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis. Overexpression of FASN is common in many cancers, and accumulating evidence suggests that it is a metabolic oncogene with an important role in tumor growth and survival, making it an attractive target for cancer therapy. Early small-molecule FASN inhibitors such as cerulenin, C75 and orlistat have been shown to induce apoptosis in several cancer cell lines and to induce tumor growth delay in several cancer xenograft models but their mechanism is still not well understood. These molecules suffer from pharmacological limitations and weight loss as a side effect that prevent their development as systemic drugs. Several potent inhibitors have recently been reported that may help to unravel and exploit the full potential of FASN as a target for cancer therapy in the near future. Furthermore, novel sources of FASN inhibitors, such as green tea and dietary soy, make both dietary manipulation and chemoprevention potential alternative modes of therapy in the future.

PMID: 20373869 [PubMed – indexed for MEDLINE]

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Horm Metab Res. 2010 Apr;42 Suppl 1:S3-36. Epub 2010 Apr 13.

A European evidence-based guideline for the prevention of type 2 diabetes.

Paulweber B, Valensi P, Lindström J, Lalic NM, Greaves CJ, McKee M, Kissimova-Skarbek K, Liatis S, Cosson E, Szendroedi J, Sheppard KE, Charlesworth K, Felton AM, Hall M, Rissanen A, Tuomilehto J, Schwarz PE, Roden M, Paulweber M, Stadlmayr A, Kedenko L, Katsilambros N, Makrilakis K, Kamenov Z, Evans P, Gilis-Januszewska A, Lalic K, Jotic A, Djordevic P, Dimitrijevic-Sreckovic V, Hühmer U, Kulzer B, Puhl S, Lee-Barkey YH, AlKerwi A, Abraham C, Hardeman W, Acosta T, Adler M, AlKerwi A, Barengo N, Barengo R, Boavida JM, Charlesworth K, Christov V, Claussen B, Cos X, Cosson E, Deceukelier S, Dimitrijevic-Sreckovic V, Djordjevic P, Evans P, Felton AM, Fischer M, Gabriel-Sanchez R, Gilis-Januszewska A, Goldfracht M, Gomez JL, Greaves CJ, Hall M, Handke U, Hauner H, Herbst J, Hermanns N, Herrebrugh L, Huber C, Hühmer U, Huttunen J, Jotic A, Kamenov Z, Karadeniz S, Katsilambros N, Khalangot M, Kissimova-Skarbek K, Köhler D, Kopp V, Kronsbein P, Kulzer B, Kyne-Grzebalski D, Lalic K, Lalic N, Landgraf R, Lee-Barkey YH, Liatis S, Lindström J, Makrilakis K, McIntosh C, McKee M, Mesquita AC, Misina D, Muylle F, Neumann A, Paiva AC, Pajunen P, Paulweber B, Peltonen M, Perrenoud L, Pfeiffer A, Pölönen A, Puhl S, Raposo F, Reinehr T, Rissanen A, Robinson C, Roden M, Rothe U, Saaristo T, Scholl J, Schwarz PE, Sheppard KE, Spiers S, Stemper T, Stratmann B, Szendroedi J, Szybinski Z, Tankova T, Telle-Hjellset V, Terry G, Tolks D, Toti F, Tuomilehto J, Undeutsch A, Valadas C, Valensi P, Velickiene D, Vermunt P, Weiss R, Wens J, Yilmaz T.

Paracelsus Medical University, Salzburg, Austria.


BACKGROUND: The prevalence and socioeconomic burden of type 2 diabetes (T2DM) and associated co-morbidities are rising worldwide.

AIMS: This guideline provides evidence-based recommendations for preventing T2DM.

METHODS: A European multidisciplinary consortium systematically reviewed the evidence on the effectiveness of screening and interventions for T2DM prevention using SIGN criteria.

RESULTS: Obesity and sedentary lifestyle are the main modifiable risk factors. Age and ethnicity are non-modifiable risk factors. Case-finding should follow a step-wise procedure using risk questionnaires and oral glucose tolerance testing. Persons with impaired glucose tolerance and/or fasting glucose are at high-risk and should be prioritized for intensive intervention. Interventions supporting lifestyle changes delay the onset of T2DM in high-risk adults (number-needed-to-treat: 6.4 over 1.8-4.6 years). These should be supported by inter-sectoral strategies that create health promoting environments. Sustained body weight reduction by >or= 5 % lowers risk. Currently metformin, acarbose and orlistat can be considered as second-line prevention options. The population approach should use organized measures to raise awareness and change lifestyle with specific approaches for adolescents, minorities and disadvantaged people. Interventions promoting lifestyle changes are more effective if they target both diet and physical activity, mobilize social support, involve the planned use of established behaviour change techniques, and provide frequent contacts. Cost-effectiveness analysis should take a societal perspective.

CONCLUSIONS: Prevention using lifestyle modifications in high-risk individuals is cost-effective and should be embedded in evaluated models of care. Effective prevention plans are predicated upon sustained government initiatives comprising advocacy, community support, fiscal and legislative changes, private sector engagement and continuous media communication.

Georg Thieme Verlag KG Stuttgart-New York.

PMID: 20391306 [PubMed – indexed for MEDLINE]

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Int J Obes (Lond). 2010 Apr;34(4):712-9. Epub 2010 Jan 12.

Bifidobacterium as an oral delivery carrier of oxyntomodulin for obesity therapy: inhibitory effects on food intake and body weight in overweight mice.

Long RT, Zeng WS, Chen LY, Guo J, Lin YZ, Huang QS, Luo SQ.

Department of Cell Biology, Southern Medical University, Guangdong Province, PR China.


INTRODUCTION: Oxyntomodulin (OXM) is a gut hormone released from intestinal L cell. Synthetic OXM and its analog reduce food intake and body weight in both rodents and human beings by being administered intravenously. However, people find intravenous administration difficult because of its side effects and inconvenience. The aim of this study is to develop a novel oral delivery system for OXM and its analog using genetically engineered Bifidobacterium as the carrier.

METHODS: An OXM gene expression vector pBBADs-OXM for the Bifidobacterium genus was constructed. Human OXM sequence was fused with extracellular exo-xylanase (XynF) signal peptide (Xs) from Bifidobacterium longum under the control of the pBAD promoter. B. longum NCC2705 was transformed with the recombinant plasmid pBBADs-OXM by electroporation, and the transformed B. longum was selected using MRS plates containing 60 microg ml(-1) ampicillin. The OXM expression in vitro was identified by western blot and enzyme-linked immunosorbent assay (ELISA) assay after L-arabinose induction. Overweight BALB/c mice were treated with B. longum transformed with OXM after 0.2% L-arabinose induction every day for 4 weeks to investigate the effects of OXM-transformed B. longum on food intake and body weight by oral administration. The B. longum transformed with the green fluorescent protein (GFP) gene was used as negative control; orlistat, a gastrointestinal lipase inhibitor, was used as positive control; Normal saline (NS, 0.9% saline) was used as blank control. The food intakes of each group were measured every day, and body weights were measured once a week. Normal BALB/c (2 months old) mice were treated with OXM-transformed B. longum after induction by intragastric administration every day for 6 days to reveal the mechanism of transformed B. longum, with OXM exerting its biological function by oral administration. Plasma OXM, plasma ghrelin and the OXM of intestinal contents were detected by the ELISA method. Plasma glucose and triglyceride levels were analyzed using the Automatic Biochemistry Analyzer.

RESULTS: Transformed B. longum with OXM was selected and identified without biological and morphological alteration. An approximately 4-5 kDa OXM peptide was detected in both the supernatant and the cell pellet of transformed B. longum after L-arabinose induction in vitro. The food intake, body weight and blood triglyceride level of overweight mice treated with OXM-transformed B. longum were all significantly reduced compared with that of the GFP negative control group and NS control group (P<0.01). Interestingly, the plasma triglyceride level of the GFP group was significantly decreased compared with that of the NS control group (P<0.01). The OXM level in the intestinal contents of the OXM group was significantly increased compared with that of the GFP negative control group and the NS group (P<0.05). The plasma ghrelin level of the OXM group was significantly decreased compared with that of the GFP and NS groups (P<0.01). Unexpectedly, the ghrelin level of the GFP group was significantly increased compared with that of the NS control group (P<0.01).

CONCLUSION: A novel oral delivery system of Bifidobacterium for human OXM has been successfully established. The expression of recombinant OXM can be detected in the supernatant and cell pellet of transformed B. longum. OXM-transformed B. longum reduces food intake, body weight and plasma lipid level in overweight mice by oral administration.

PMID: 20065960 [PubMed – indexed for MEDLINE]

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Isr Med Assoc J. 2010 Apr;12(4):199-202.

Computed tomography study of the effect of orlistat on visceral adipose tissue volume in obese subjects.

Dicker D, Herskovitz P, Katz M, Atar E, Bachar GN.

Department of Internal Medicine D, Rabin Medical Center (Golda Campus), Petah Tikva, Israel.

Comment in:


BACKGROUND: Obesity has become a major public health problem worldwide.

OBJECTIVES: To examine the effect of orlistat in promoting weight loss and its specific effect on visceral adipose tissue and subcutaneous adipose tissue as evaluated by computed tomography.

METHODS: A prospective case series study of 10 obese subjects was conducted. The 6 women and 4 men, age 50-67 years (mean 59 +/- 8 years), had a mean body mass index of 34.1 +/- 3.2 kg/m2. All subjects were prescribed a mildly hypocaloric diet (600 kcal/day deficit). In addition, all subjects were treated with orlistat 120 mg 3 times a day for 20.1 +/- 7 weeks.

RESULTS: The subjects had lost approximately 8.2 kg each, or 8.4% of their initial body weight. Mean body weight decreased from 98 +/- 13 to 89.8 +/- 13.6 kg at the last followup visit (P = 0.0001); mean BMI decreased from 34.1 +/- 3.2 to 30.3 +/- 3.9 kg/m2 (P = 0.0001), and mean waist circumference from 113.8 +/- 11.4 to 107.6 +/- 10 cm (P = 0.0006). Mean total abdominal adipose tissue volume, evaluated by computed tomography, decreased from 426 +/- 104.3 to 369.8 +/- 99.6 mm3 (P = 0.0001). Mean abdominal SAT volume decreased from 251.1 +/- 78.8 to 224 +/- 81.1 mm3 (P = 0.006), and mean abdominal VAT volume decreased from 176 +/- 76.7 to 141.6 +/- 67 mm3 (P = 0.0001). Thus, the total abdominal adipose tissue volume for the whole group decreased by 15.4%, and most of this decrease was attributable to the reduction in VAT (24.8%) as opposed to SAT (only 12% reduction) (P = 0.03). The weight reduction that occurred during the study was accompanied by a statistically significant reduction in levels of total cholesterol, low density lipoprotein-cholesterol, triglycerides, and fasting blood glucose.

CONCLUSIONS: Our results demonstrate the effect of orlistat in reducing human visceral adipose tissue as evaluated by CT. The benefit of the treatment is further supported by the statistically significant reduction in cardiovascular risk factors.

PMID: 20803876 [PubMed – indexed for MEDLINE]Free Article

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J Med Food. 2010 Apr;13(2):406-14.

Ethanolic extracts of Brassica campestris spp. rapa roots prevent high-fat diet-induced obesity via beta(3)-adrenergic regulation of white adipocyte lipolytic activity.

An S, Han JI, Kim MJ, Park JS, Han JM, Baek NI, Chung HG, Choi MS, Lee KT, Jeong TS.

National Research Laboratory of Lipid Metabolism & Atherosclerosis, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.


The influence of ethanolic extracts of Brassica campestris spp. rapa roots (EBR) on obesity was examined in imprinting control region (ICR) mice fed a high-fat diet (HFD) and in 3T3-L1 adipocytes. The ICR mice used were divided into regular diet, HFD, EBR (50 mg/kg/day EBR administered orally), and orlistat (10 mg/kg/day orlistat administered orally) groups. The molecular mechanism of the anti-obesity effect of EBR was investigated in 3T3-L1 adipocytes as well as in HFD-fed ICR mice. In the obese mouse model, both weight gain and epididymal fat accumulation were highly suppressed by the daily oral administration of 50 mg/kg EBR for 8 weeks, whereas the overall amount of food intake was not affected. EBR treatment induced the expression in white adipocytes of lipolysis-related genes, including beta(3)-adrenergic receptor (beta(3)-AR), hormone-sensitive lipase (HSL), adipose triglyceride lipase, and uncoupling protein 2. Furthermore, the activation of cyclic AMP-dependent protein kinase, HSL, and extracellular signal-regulated kinase was induced in EBR-treated 3T3-L1 cells. The lipolytic effect of EBR involved beta(3)-AR modulation, as inferred from the inhibition by the beta(3)-AR antagonist propranolol. These results suggest that EBR may have potential as a safe and effective anti-obesity agent via the inhibition of adipocyte lipid accumulation and the stimulation of beta(3)-AR-dependent lipolysis.

PMID: 20132043 [PubMed – indexed for MEDLINE]

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J Inflamm (Lond). 2010 Mar 30;7:15.

Elevated endotoxin levels in non-alcoholic fatty liver disease.

Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, Tripathi G, Ashour E, Abdalla MS, Sharada HM, Amin AI, Burt AD, Kumar S, Day CP, McTernan PG.

University of Warwick, Unit for Diabetes and Metabolism, Warwick Medical School, Clinical Sciences Research Institute, UHCW, Clifford Bridge Road, Coventry, CV2 2DX, UK. a.harte@warwick.ac.uk.



BACKGROUND: Emerging data indicate that gut-derived endotoxin may contribute to low-grade systemic inflammation in insulin resistant states. This study aimed to examine the importance of serum endotoxin and inflammatory markers in non-alcoholic fatty liver disease (NAFLD) patients, with and without type 2 diabetes mellitus (T2DM), and to explore the effect of treatment with a lipase inhibitor, Orlistat, on their inflammatory status.

METHODS: Fasted serum from 155 patients with biopsy proven NAFLD and 23 control subjects were analysed for endotoxin, soluble CD14 (sCD14), soluble tumour necrosis factor receptor II (sTNFRII) and various metabolic parameters. A subgroup of NAFLD patients were re-assessed 6 and 12 months after treatment with diet alone (n = 6) or diet plus Orlistat (n = 8).

RESULTS: Endotoxin levels were significantly higher in patients with NAFLD compared with controls (NAFLD: 10.6(7.8, 14.8) EU/mL; controls: 3.9(3.2, 5.2) EU/mL, p < 0.001); NAFLD alone produced comparable endotoxin levels to T2DM (NAFLD: T2DM: 10.6(5.6, 14.2) EU/mL; non-diabetic: 10.6(8.5, 15.2) EU/mL), whilst a significant correlation between insulin resistance and serum endotoxin was observed (r = 0.27, p = 0.008). Both sCD14 (p < 0.01) and sTNFRII (p < 0.001) increased with severity of fibrosis. A positive correlation was also noted between sTNFRII and sCD14 in the NAFLD subjects (r = 0.29, p = 0.004).Sub-cohort treatment with Orlistat in patients with NAFLD showed significant decreases in ALT (p = 0.006), weight (p = 0.005) and endotoxin (p = 0.004) compared with the NAFLD, non-Orlistat treated control cohort at 6 and 12 months post therapy, respectively.

CONCLUSIONS: Endotoxin levels were considerably increased in NAFLD patients, with marked increases noted in early stage fibrosis compared with controls. These results suggest elevated endotoxin may serve as an early indicator of potential liver damage, perhaps negating the need for invasive liver biopsy. As endotoxin may promote insulin resistance and inflammation, interventions aimed at reducing endotoxin levels in NAFLD patients may prove beneficial in reducing inflammatory burden.

PMID: 20353583 [PubMed – in process]PMCID: PMC2873499Free PMC Article

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Orv Hetil. 2010 Mar 21;151(12):501-4.

[Current treatment of obesity].

[Article in Hungarian]

Pados G.

Szent Imre Kórház, Kardiometabolikus Centrum, Lipidrészleg, Budapest, Tétényi út 12-16. 1115. lipidreszleg@gmail.com

PMID: 20231134 [PubMed – indexed for MEDLINE]

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Eat Weight Disord. 2010 Mar-Jun;15(1-2):e9-14.

A 2-year multifactor approach of weight loss maintenance.

Makoundou V, Bobbioni-Harsch E, Gachoud JP, Habicht F, Pataky Z, Golay A.

Service of Therapeutic Education for Chronic Diseases, Geneva University Hospital, Geneva, Switzerland.


The overarching problem in the treatment of obesity is the consistency with which weight in treatment is regained. The aim of this study is to follow-up the patient using a multifactor approach (cognitive-behavioral therapies, diet and physical activity counselling, an “on-off” prescription of orlistat) during 4 years in order to assess the efficacy of this specific long-term weight loss maintenance programme. Weight maintenance is defined as a weight change of <2.5% of the study entry body weight. Fifty obese patients having previously lost at least 10% of their weight by any weight loss programme before entering the maintenance multifactor approach were enrolled. Ninety percent of the patients maintained more than 10% weight loss after 2 years. All the physical characteristics remained similar between study entry and 2 years after the weight loss maintenance programme. Waist and hip as well as fat mass did not show any significant differences and the mean fat mass remained stable 2 years later. In addition, all the psychological parameters analysed remained stable and in a normal range. In conclusion, this multifactor approach shows promising interim results at year-2. The multifactor approach with an “on-off” prescription of orlistat seems to be appropriate for the long term weight loss maintenance. But considering the clinical and psychological diversity of the patients, this approach has to be individually adapted for patients presenting eating behavior disorders which need a particular follow-up.

PMID: 20571327 [PubMed – indexed for MEDLINE]

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FEBS J. 2010 Mar;277(6):1481-93. Epub 2010 Feb 8.

Peptides from purified soybean beta-conglycinin inhibit fatty acid synthase by interaction with the thioesterase catalytic domain.

Martinez-Villaluenga C, Rupasinghe SG, Schuler MA, Gonzalez de Mejia E.

Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, IL, USA.


Fatty acid synthase (FAS) is uniquely expressed at high levels in cancer cells and adipose tissue. The objectives of this study were to identify, purify and validate soy FAS inhibitory peptides and to predict their binding modes. Soy peptides were isolated from hydrolysates of purified beta-conglycinin by co-immunoprecipitation and identified using LC-MS/MS. Three peptides, KNPQLR, EITPEKNPQLR and RKQEEDEDEEQQRE, inhibited FAS. The biological activity of these peptides was confirmed by their inhibitory activity against purified chicken FAS (IC(50) = 79, 27 and 16 mum, respectively) and a high correlation (r = -0.7) with lipid accumulation in 3T3-L1 adipocytes. The FAS inhibitory potency of soy peptides also correlated with their molecular mass, pI value and the number of negatively charged and hydrophilic residues. Molecular modeling predicted that the large FAS inhibitory peptides (EITPEKNPQLR and RKQEEDEDEEQQRE) bond to the thioesterase domain of human FAS with lower interaction energies (-442 and -353 kcal.mol(-1), respectively) than classical thioesterase inhibitors (Orlistat, -91 kcal.mol(-1) and C75, -51 kcal.mol(-1)). Docking studies suggested that soy peptides blocked the active site through interactions within the catalytic triad, the interface cavity and the hydrophobic groove in the human FAS thioesterase domain. FAS thioesterase inhibitory activities displayed by the synthetic soy peptides EITPEKNPQLR and RKQEEDEDEEQQRE (IC(50) = 10.1 +/- 1.6 and 10.7 +/- 4.4 mum, respectively) were higher than C75 (58.7 mum) but lower than Orlistat (0.9 mum). This is the first study to identify FAS inhibitory peptides from purified beta-conglycinin hydrolysates and predict their binding modes at the molecular level, leading to their possible use as nutraceuticals.

PMID: 20148945 [PubMed – indexed for MEDLINE]

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Gastroenterol Clin North Am. 2010 Mar;39(1):69-79.

Pharmacologic therapies for obesity.

Kaplan LM.

MGH Weight Center and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, 50 Staniford Street, Boston, MA 02114, USA. LMKaplan@partners.org


This article examines the transitions in pharmacological therapy for obesity. It reviews the current options approved by the Food and Drug Administration and several drugs approved for other indications that can be used to treat obesity as well. Because weight regulation is complex and redundant systems protect against perceived starvation, optimal treatment of obesity in individual patients will likely require different combinations of behavioral, nutritional, pharmacologic, endoscopic, and surgical therapies.

Copyright (c) 2010 Elsevier Inc. All rights reserved.

PMID: 20202580 [PubMed – indexed for MEDLINE]

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Hypertens Res. 2010 Mar;33(3):195-6. Epub 2010 Jan 15.

Weight loss and blood pressure normalization: the relevance of early interventions in hypertension.

Cicero AF.

Hypertension Research Unit, Internal Medicine, Aging and Kidney Disease Department, University of Bologna, Via Albertoni 15, Bologna, Italy. afgcicero@cardionet.it

Comment on:

PMID: 20075935 [PubMed – indexed for MEDLINE]

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Pharmacoepidemiol Drug Saf. 2010 Mar;19(3):273-9.

Use of psychotropic drugs and analgesics among users of antiobesity drugs–a population based study.

Amundsen MO, Engdahl B, Berg C, Nordeng H.

Department of Pharmacy, School of Pharmacy, University of Oslo, N-0316 Blindern, Norway.


AIM: The aim of the present study was to investigate to what extent patients using prescription antiobesity drugs (orlistat, sibutramine and rimonabant) concomitantly or concurrently used psychotropic drugs and analgesics and the association between this drug use and the patients’ gender and age. An additional aim was to investigate the sequence of drug therapy among users of both antiobesity drugs and antidepressants or antipsychotics, respectively.

METHODS: Data were retrieved from the Norwegian Prescription Database (NorPD). All patients who had an antiobesity drug (ATC code A08A) dispensed from a Norwegian pharmacy between January 2004 and December 2007 were included in the study.

RESULTS: One in four patients using antiobesity drugs had at least on one occasion used a psychotropic drug concomitantly. The most commonly used psychotropic drugs were anxiolytics/hypnotics/sedatives (17.7%) and antidepressants (14.7%). Analgesics were used by 36.2%. A significantly higher percentage of women used anxiolytics/hypnotics/sedatives (18.8% vs. 14.0%, p < 0.0005), antidepressants (16.1% vs. 9.5%, p < 0.0005), antipsychotics (4.0% vs. 2.9%, p < 0.0005) and analgesics (37.8% vs. 30.5%, p < 0.0005) concomitantly with antiobesity drugs when compared to men. One out of ten patients using sibutramine had at least on one occasion used an interacting drug concomitantly.

CONCLUSION: Use of psychotropic drugs and analgesics among patients using antiobesity drugs is extensive, especially among women. Clinicians prescribing sibutramine should be more aware of drug interactions with other prescribed drugs. There is still insufficient information on psychiatric disorders among these patients.

PMID: 20014050 [PubMed – indexed for MEDLINE]

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Drugs. 2010 Feb 12;70(3):335-46. doi: 10.2165/11319210-000000000-00000.

Pharmacotherapy and weight-loss supplements for treatment of paediatric obesity.

Rogovik AL, Chanoine JP, Goldman RD.

Pediatric Research in Emergency Therapeutics Program, BC Children’s Hospital, Vancouver, British Columbia, and The Hospital for Sick Children, Toronto, Ontario, Canada.


Childhood obesity has become the most common paediatric disorder in the developed world. Treatment of obesity in children may include lifestyle interventions, pharmacotherapy and weight-loss supplements. The outcome of lifestyle interventions, which classically include dietary modifications, increased activity and behavioural modifications, remains insufficient and the adjuvant role of pharmacological agents has been proposed. Among the group of weight-loss medications, orlistat is the only pharmaceutical approved by the US FDA for the treatment of overweight and obese adolescents. The role of metformin needs to be established in larger studies and sibutramine remains an experimental product because of its potential adverse events. Weight-loss supplements lack sufficient data supporting their efficacy and safety, even in adults, and cannot be recommended at this time for adolescents. Preliminary data suggest that the use of fibre supplements, such as glucomannan, provides additional weight loss in individuals receiving a lifestyle intervention. No single approach will successfully treat obesity, and lifestyle modification presently remains the main pillar of any intervention aiming at decreasing bodyweight.

PMID: 20166770 [PubMed – indexed for MEDLINE]

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J Clin Endocrinol Metab. 2010 Feb;95(2):879-86. Epub 2009 Oct 16.

Role of fat hydrolysis in regulating glucagon-like Peptide-1 secretion.

Beglinger S, Drewe J, Schirra J, Göke B, D’Amato M, Beglinger C.

Division of Gastroenterology, University Hospital, CH-4031 Basel, Switzerland. beglinger@tmr.ch


Context: Glucagon-like peptide-1 (GLP-1) is produced by specialized cells in the gut and secreted in response to carbohydrates and lipids. The mechanisms regulating fat-stimulated GLP-1 release have, however, not been clarified in detail. Aim: We aimed to investigate the effect of intraduodenal (ID) fat hydrolysis on GLP-1 release and test whether the signal is mediated through cholecystokinin (CCK)-1 receptors. Design and Setting: Thirty-four healthy, male ambulatory volunteers were studied in three consecutive, randomized, double blind, crossover studies. Intervention: There were three interventions: 1) 12 subjects received an ID fat infusion with or without orlistat, an irreversible inhibitor of gastrointestinal lipases, in comparison with vehicle; 2) 12 subjects received ID sodium oleate (C18:1), ID sodium caprylate (C8:0), or ID vehicle; and 3) 10 subjects received ID sodium oleate with and without the CCK-1 receptor antagonist dexloxiglumide or ID vehicle plus iv saline (placebo). The effect of these treatments on GLP-1 concentrations and CCK release was quantified. Results: The following results were reached: 1) ID fat induced significant increase in GLP-1 concentrations (P < 0.004), and inhibition of fat hydrolysis by orlistat abolished this effect; 2) sodium oleate significantly stimulated GLP-1 release (P < 0.008), whereas sodium caprylate was ineffective compared with controls; and 3) dexloxiglumide administration abolished the effect of sodium oleate on GLP-1. ID fat or sodium oleate significantly stimulated plasma CCK (P < 0.006 and P < 0.004) compared with saline, whereas sodium caprylate did not. Conclusion: Generation of long-chain fatty acids through hydrolysis of fat is a critical step for fat-induced stimulation of GLP-1 in humans; the signal is mediated via CCK release and CCK-1 receptors.

PMID: 19837920 [PubMed – indexed for MEDLINE]

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Nutr Res. 2010 Feb;30(2):134-40.

Lipase inhibitor orlistat decreases incorporation of eicosapentaenoic and docosahexaenoic acids in rat tissues.

Cruz-Hernandez C, Oliveira M, Pescia G, Moulin J, Masserey-Elmelegy I, Dionisi F, Destaillats F.

Nestlé Research Center, Vers-chez-les-Blanc, Lausanne, Switzerland.


Orlistat is a gastric and pancreatic lipases inhibitor that is often prescribed to obese subjects. Orlistat has been shown to decrease the absorption of biologically important lipophilic micronutrients such as liposoluble vitamins. We hypothesized that long-term administration of orlistat may lower the incorporation of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) in blood lipids and tissues. This hypothesis was tested in rats fed a diet supplemented with fish oil as a source of n-3 LC-PUFA. Male Wistar rats (n = 18) were divided into 3 groups and fed experimental high-fat diets containing fish oil (control diet) or fish oil plus orlistat (200 and 400 mg/kg of diet) over the course of 3 weeks. Fat absorption and the level of eicosapentaenoic acid (EPA) and docosahexaenoic acid, among other fatty acids, in red blood cells, plasma, liver, and spleen, were measured at the end of the experimental period. The results show that at 200 mg and 400 mg/kg of diet orlistat lowers fat absorption by 9% (P = .008) and 54% (P = .008). Orlistat given at the higher level induced a reduction of the incorporation of EPA in red blood cell (-45%; P = .006) and in plasma (-34%; P = .026) compared to the control group. Our results confirmed that administration of orlistat reduces incorporation of n-3 LC-PUFA in blood lipids and tissues in a rat model.

Copyright 2010 Elsevier Inc. All rights reserved.

PMID: 20226999 [PubMed – indexed for MEDLINE]

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Obes Rev. 2010 Feb;11(2):150-8. Epub 2009 Jul 1.

Efficacy of weight loss drugs on obesity and cardiovascular risk factors in obese adolescents: a meta-analysis of randomized controlled trials.

Czernichow S, Lee CM, Barzi F, Greenfield JR, Baur LA, Chalmers J, Woodward M, Huxley RR.

The George Institute for International Health, the University of Sydney, Sydney, NSW, Australia. czernichow@uren.smbh.univ-paris13.fr


Weight loss drugs have been developed to reduce the comorbidities associated with excess weight. We conducted a meta-analysis of the efficacy of orlistat and sibutramine on weight, body mass index, waist circumference and cardiovascular risk factors in overweight adolescents. MEDLINE and the Cochrane Library were searched for relevant articles using MESH terms and keywords. Studies were included if they had reported quantitative estimates and standard deviations of the association between each weight loss drug and weight, with information on at least one cardiovascular risk factor. A total of eight trials (three orlistat and five sibutramine) with information on 1391 individuals was included in the present analysis. The mean decrease in weight between the intervention and control groups was 5.25 kg (95% confidence interval: 3.03-7.48) after a minimum follow-up of 6 months. There was evidence of statistical heterogeneity between the studies (I(2) = 76%) that was no longer apparent after exclusion of trials of orlistat (mean weight decrease = 5.32 kg; I(2) = 38%). There was little evidence that treatment was associated with adverse effects on cardiovascular risk factors but this requires verification from future large trials with longer study follow-up.

PMID: 19573052 [PubMed – indexed for MEDLINE]

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Pediatrics. 2010 Feb;125(2):e396-418. Epub 2010 Jan 18.

Effectiveness of weight management interventions in children: a targeted systematic review for the USPSTF.

Whitlock EP, O’Connor EA, Williams SB, Beil TL, Lutz KW.

Center for Health Research, Kaiser Permanente, 3800 N Interstate Ave, Portland, OR 97227, USA. evelyn.whitlock@kpchr.org

Comment in:


CONTEXT: Targeted systematic review to support the updated US Preventive Services Task Force (USPSTF) recommendation on screening for obesity in children and adolescents.

OBJECTIVES: To examine the benefits and harms of behavioral and pharmacologic weight-management interventions for overweight and obese children and adolescents.

METHODS: Our data sources were Ovid Medline, PsycINFO, the Education Resources Information Center, the Database of Abstracts of Reviews of Effects, the Cochrane databases, reference lists of other reviews and trials, and expert recommendations. After 2 investigators reviewed 2786 abstracts and 369 articles against inclusion/exclusion criteria, we included 15 fair- to good-quality trials in which the effects of treatment on weight, weight-related comorbidities, and harms were evaluated. Studies were quality rated by 2 investigators using established criteria. Investigators abstracted data into standard evidence tables.

RESULTS: In the available research, obese (or overweight) children and adolescents aged 4 to 18 years were enrolled, and no studies targeted those younger than 4 years. Comprehensive behavioral interventions of medium-to-high intensity were the most effective behavioral approach with 1.9 to 3.3 kg/m(2) difference favoring intervention groups at 12 months. More limited evidence suggests that these improvements can be maintained over the 12 months after the end of treatments and that there are few harms with behavioral interventions. Two medications combined with behavioral interventions resulted in small (0.85 kg/m(2) for orlistat) or moderate (2.6 kg/m(2) for sibutramine) BMI reduction in obese adolescents on active medication; however, no studies followed weight changes after medication use ended. Potential adverse effects were greater than for behavioral interventions alone and varied in severity. Only 1 medication (orlistat) has been approved by the US Food and Drug Administration for prescription use in those aged > or =12 years.

CONCLUSIONS: Over the past several years, research into weight management in obese children and adolescents has improved in quality and quantity. Despite important gaps, available research supports at least short-term benefits of comprehensive medium- to high-intensity behavioral interventions in obese children and adolescents.

PMID: 20083531 [PubMed – indexed for MEDLINE]

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Arch Intern Med. 2010 Jan 25;170(2):146-54.

Nonsurgical weight loss for extreme obesity in primary care settings: results of the Louisiana Obese Subjects Study.

Ryan DH, Johnson WD, Myers VH, Prather TL, McGlone MM, Rood J, Brantley PJ, Bray GA, Gupta AK, Broussard AP, Barootes BG, Elkins BL, Gaudin DE, Savory RL, Brock RD, Datz G, Pothakamuri SR, McKnight GT, Stenlof K, Sjöström LV.

Pennington Biomedical Research Center of Louisiana State University System, Baton Rouge, LA 70808, USA. ryandh@pbrc.edu

Comment in:


BACKGROUND: Effective primary care practice (PCP) treatments are needed for extreme obesity. The Louisiana Obese Subjects Study (LOSS) tested whether, with brief training, PCPs could effectively implement weight loss for individuals with a body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 40 to 60.

METHODS: The LOSS, a 2-year (July 5, 2005, through January 30, 2008) randomized, controlled, “pragmatic clinical trial” trained 7 PCPs and 1 research clinic in obesity management. Primary outcome measure was year-2 percentage change from baseline weight. Volunteers (597) were screened and randomized to intensive medical intervention (IMI) (n = 200) or usual care condition (UCC) (n = 190). The UCC group had instruction in an Internet weight management program. The IMI group recommendations included a 900-kcal liquid diet for 12 weeks or less, group behavioral counseling, structured diet, and choice of pharmacotherapy (sibutramine hydrochloride, orlistat, or diethylpropion hydrochloride) during months 3 to 7 and continued use of medications and maintenance strategies for months 8 to 24.

RESULTS: The mean age of participants was 47 years; 83% were women, and 75% were white. Retention rates were 51% for the IMI group and 46% for the UCC group (P = .30). After 2 years, the results were as follows: (1) among 390 randomized participants, 31% in the IMI group achieved a 5% or more weight loss and 7% achieved a 20% weight loss or more, compared with 9% and 1% of those in the UCC group. (2) The mean +/- SEM baseline observation carried forward analysis showed a weight loss of -4.9% +/- 0.8% in IMI and -0.2 +/- 0.3% in UCC. (3) Last observation carried forward analysis showed a weight loss of -8.3% +/- 0.79% for IMI, whereas UCC was -0.0% +/- 0.4%. (4) A total of 101 IMI completers lost -9.7% +/- 1.3% (-12.7 +/- 1.7 kg), whereas 89 UCC completers lost -0.4% +/- 0.7% (-0.5 +/- 0.9 kg); (P < .001 for all group differences). Many metabolic parameters improved.

CONCLUSION: Primary care practices can initiate effective medical management for extreme obesity; future efforts must target improving retention and weight loss maintenance.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00115063.

PMID: 20101009 [PubMed – indexed for MEDLINE]Free Article

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Arch Intern Med. 2010 Jan 25;170(2):136-45.

A randomized trial of a low-carbohydrate diet vs orlistat plus a low-fat diet for weight loss.

Yancy WS Jr, Westman EC, McDuffie JR, Grambow SC, Jeffreys AS, Bolton J, Chalecki A, Oddone EZ.

Center for Health Services Research in Primary Care, Department of Veterans Affairs Medical Center, Durham, North Carolina, USA. yancy006@mc.duke.edu

Comment in:


BACKGROUND: Two potent weight loss therapies, a low-carbohydrate, ketogenic diet (LCKD) and orlistat therapy combined with a low-fat diet (O + LFD), are available to the public but, to our knowledge, have never been compared.

METHODS: Overweight or obese outpatients (n = 146) from the Department of Veterans Affairs primary care clinics in Durham, North Carolina, were randomized to either LCKD instruction (initially, <20 g of carbohydrate daily) or orlistat therapy, 120 mg orally 3 times daily, plus low-fat diet instruction (<30% energy from fat, 500-1000 kcal/d deficit) delivered at group meetings over 48 weeks. Main outcome measures were body weight, blood pressure, fasting serum lipid, and glycemic parameters.

RESULTS: The mean age was 52 years and mean body mass index was 39.3 (calculated as weight in kilograms divided by height in meters squared); 72% were men, 55% were black, and 32% had type 2 diabetes mellitus. Of the study participants, 57 of the LCKD group (79%) and 65 of the O + LFD group (88%) completed measurements at 48 weeks. Weight loss was similar for the LCKD (expected mean change, -9.5%) and the O + LFD (-8.5%) (P = .60 for comparison) groups. The LCKD had a more beneficial impact than O + LFD on systolic (-5.9 vs 1.5 mm Hg) and diastolic (-4.5 vs 0.4 mm Hg) blood pressures (P < .001 for both comparisons). High-density lipoprotein cholesterol and triglyceride levels improved similarly within both groups. Low-density lipoprotein cholesterol levels improved within the O + LFD group only, whereas glucose, insulin, and hemoglobin A(1c) levels improved within the LCKD group only; comparisons between groups, however, were not statistically significant.

CONCLUSION: In a sample of medical outpatients, an LCKD led to similar improvements as O + LFD for weight, serum lipid, and glycemic parameters and was more effective for lowering blood pressure.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00108524.

PMID: 20101008 [PubMed – indexed for MEDLINE]Free Article

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J Am Chem Soc. 2010 Jan 20;132(2):656-66.

Activity-based proteome profiling of potential cellular targets of Orlistat–an FDA-approved drug with anti-tumor activities.

Yang PY, Liu K, Ngai MH, Lear MJ, Wenk MR, Yao SQ.

Department of Chemistry, National University of Singapore, Singapore 117543.


Orlistat, or tetrahydrolipstatin (THL), is an FDA-approved antiobesity drug with potential antitumor activities. Cellular off-targets and potential side effects of Orlistat in cancer therapies, however, have not been extensively explored thus far. In this study, we report the total of synthesis of THL-like protein-reactive probes, in which extremely conservative modifications (i.e., an alkyne handle) were introduced in the parental THL structure to maintain the native biological properties of Orlistat, while providing the necessary functionality for target identification via the bio-orthogonal click chemistry. With these natural productlike, cell-permeable probes, we were able to demonstrate, for the first time, this chemical proteomic approach is suitable for the identification of previously unknown cellular targets of Orlistat. In addition to the expected fatty acid synthase (FAS), we identified a total of eight new targets, some of which were further validated by experiments including Western blotting, recombinant protein expression, and site-directed mutagenesis. Our findings have important implications in the consideration of Orlistat as a potential anticancer drug at its early stages of development for cancer therapy. Our strategy should be broadly useful for off-target identification against quite a number of existing drugs and/or candidates, which are also covalent modifiers of their biological targets.

PMID: 20028024 [PubMed – indexed for MEDLINE]

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J Psychopharmacol. 2010 Jan 15. [Epub ahead of print]

Metformin for weight reduction in non-diabetic patients on antipsychotic drugs: a systematic review and meta-analysis.

Björkhem-Bergman L, Asplund AB, Lindh JD.

Division of Clinical Pharmacology, Karolinska University Hospital, Huddinge, Karolinska Institutet.


Weight gain is a clinically important side effect of antipsychotic drug therapy. The aim of this study was to determine the effect of the antidiabetic drug metformin on antipsychotic-induced weight gain in non-diabetic patients. In a systematic literature review we identified 195 citations from which seven randomized, placebo-controlled studies (398 patients) were included in the final analysis. Studies in adults (n = 5) and in children (n = 2) were analysed separately. Compared with placebo, metformin treatment caused a significant body weight reduction in adult non-diabetic patients treated with atypical antipsychotics (4.8%, 95% CI 1.6 to 8.0) and in children (4.1%, 95% CI 2.2 to 6.0). There was evidence of substantial heterogeneity among studies, and when the analysis was restricted to patients with a manifest (>10%) body weight increase prior to randomisation metformin reduced weight by 7.5% (95% CI 2.9 to 12.0). The effect was larger in Asians (7.8%, 95% CI 4.4 to 11.2) than in Hispanics (2.0%, 95% CI 0.7 to 3.3). In conclusion, metformin has a pronounced weight-reducing effect in antipsychotic-treated patients, especially in those with a manifest weight gain. Although direct comparisons are lacking, the observed effect on body weight compares favourably with the effect of sibutramine and orlistat, approved for weight reduction. However, metformin is not approved for use in non-diabetic patients and it is still not generally advisable to recommend metformin to counteract antipsychotic-induced weight gain.

PMID: 20080925 [PubMed – as supplied by publisher]

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J Mol Biol. 2010 Jan 8;395(1):155-66. Epub 2009 Oct 20.

Evolution of stability in a cold-active enzyme elicits specificity relaxation and highlights substrate-related effects on temperature adaptation.

Gatti-Lafranconi P, Natalello A, Rehm S, Doglia SM, Pleiss J, Lotti M.

Department of Biotechnology and Biosciences, State University of Milano-Bicocca, Piazza della Scienza 2, I-20126 Milano, Italy.


Molecular aspects of thermal adaptation of proteins were studied by following the co-evolution of temperature dependence, conformational stability, and substrate specificity in a cold-active lipase modified via directed evolution. We found that the evolution of kinetic stability was accompanied by a relaxation in substrate specificity. Moreover, temperature dependence and selectivity turned out to be mutually dependent. While the wild-type protein was strictly specific for short-chain triglycerides (C4) in the temperature range 10-50 degrees C and displayed highest activity in the cold, its stabilized variant was able to accept C8 and C12 molecules and its selectivity was temperature dependent. We could not detect any improvement in the overall structural robustness of the mutant when the structure was challenged by temperature or chemical denaturants. There is, however, strong evidence for local stabilization effects in the active-site region provided by two independent approaches. Differential scanning fluorimetry revealed that the exposure of hydrophobic patches (as the active site is) precedes denaturation, and molecular dynamics simulations confirmed that stability was obtained by restriction of the mobility of the lid, a flexible structure that regulates the access to the enzyme active site and influences its stability. This reduction of lid movements is suggested to be accompanied by a concomitant increase in the mobility of other protein regions, thus accounting for the observed broadening of substrate specificity.

PMID: 19850050 [PubMed – indexed for MEDLINE]

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JOP. 2010 Jan 8;11(1):61-3.

Acute pancreatitis following orlistat therapy: report of two cases.

Ahmad FA, Mahmud S.

Department of General Surgery, Hairmyres Hospital, East Kilbride, G75 8RG, United Kingdom. faheem.ahmad@hotmail.co.uk


CONTEXT: Orlistat is a pancreatic lipase inhibitor licensed for the treatment of obesity. As obesity rates increase and non-prescription dispensing of orlistat increases, an awareness of its adverse effects is of crucial importance as complications arise more frequently from increased use. Orlistat induced pancreatitis has been described only once previously, but without a diagnostic increase in serum amylase.

CASE REPORT: We report the case of two patients who developed severe acute abdominal pain and elevated pancreatic enzymes at 2 and 10 days after starting orlistat. In one case no alterative precipitant was identified. In the other, a predisposing history of pancreatic injury was present. In both cases all other contributory causes were excluded.

CONCLUSIONS: Our reports suggest orlistat can trigger drug induced acute pancreatitis in certain patients. For patients presenting with abdominal pain soon after commencing orlistat, a diagnosis of pancreatitis must be considered. We also recommend cautious use of orlistat in patients at risk of pancreatic injury.

PMID: 20065556 [PubMed – indexed for MEDLINE]Free Article

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