Xenical

Int J Obes Relat Metab Disord. 2005 Apr 19;
Cost-effectiveness of orlistat for the treatment of overweight and obese patients in Ireland.
Lacey LA, Wolf A, O'shea D, Erny S, Ruof J.
1Lacey Solutions Ltd, Dublin, Ireland.

OBJECTIVE:: To assess the cost-effectiveness of orlistat plus a calorie-controlled diet compared with a calorie-controlled diet alone for the treatment of overweight and obese patients in Ireland. DESIGN:: Economic modelling techniques using published international efficacy data and Irish cost data were used to estimate the cost-effectiveness of orlistat in obese patients when only responders to treatment (ie achieve 5% weight loss after 3 months of treatment) continue orlistat after 3 months. The model incorporated known relationships between weight loss and quality of life (utility) gain, and weight loss and reduction in risk of type 2 diabetes (T2DM) to predict the impact of weight loss on quality-adjusted-life-years (QALYs) gained and on the onset of T2DM. The costs associated with each treatment arm included the acquisition cost of orlistat, cost of a calorie-controlled dietary programme and monitoring and treatment costs associated with T2DM. An Irish health-care perspective was taken for the analysis, based on 2003 costs. SUBJECTS:: Weight loss data on 1386 patients from five pivotal orlistat clinical trials with at least 12 months duration were pooled (two American and three primarily European studies). All the studies were randomized, placebo-controlled, multicentre trials with a similar design. The inclusion criteria were BMI >/=28 kg/m(2), age >/=18 y, no diagnosed T2DM and the ability to lose 2.5 kg in weight during the introductory period. MEASUREMENTS:: Cost effectiveness was modelled from these data and presented as incremental cost per QALY. RESULTS:: When orlistat treatment plus a calorie-controlled diet was compared with a calorie-controlled diet alone, the incremental cost per year was \[euro]478. The number needed to treat (NNT) to gain one QALY was estimated to be 35. The incremental cost per QALY gained was within the range considered cost-effective at \[euro]16 954. Sensitivity analysis demonstrated an incremental cost per QALY of \[euro]11 000-35 000 under a variety of assumptions. CONCLUSIONS:: Our model suggests that orlistat is effective and cost-effective in obese patients, if after 3 months of treatment, only treatment responders continue treatment.International Journal of Obesity advance online publication, 19 April 2005; doi:10.1038/sj.ijo.0802947.

Eur J Clin Pharmacol. 2005 May 14;
Press coverage and sales of Xenical in Sweden, 1998-2000.
Brouneus F, Dahlin A, Beermann B.
Medicines Information Unit, Medical Products Agency, P.O. Box 26, 751 03, Uppsala, Sweden, bjorn.beermann@mpa.se.

Objective: The anti-obesity drug Xenical (orlistat, Roche) was launched on the Swedish market in February 1999. The sales peaked in May 1999 and then declined. The purpose of this study was to investigate the press coverage of Xenical during the period 1998-2000 and, if possible, relate press attention to Xenical sales during this period.Methods: We analysed all articles published in Sweden's four biggest-selling newspapers mentioning Xenical during the period 1998-2000. Promotion activities aimed at healthcare professionals were measured by registering the number of advertisements in the Journal of the Swedish Medical Association. Sales figures for Xenical were obtained from the National Corporation of Swedish Pharmacies.Results: Approximately twice as many positive-effect messages were published than negative or neutral messages. Only six out of 42 positive messages referred to results from scientific studies. The initial high peaks for sales and positive-effect articles coincided with the launch of Xenical on the Swedish market.Conclusions: It is not possible to discern a causal relationship between press coverage and sales; however, it seems safe to say that the large number of positive articles published before and during the launch greatly increased public awareness of Xenical, thus promoting sales.

Diabet Med. 2005 May;22(5):612-8.
A randomized study of orlistat in combination with a weight management programme in obese patients with Type 2 diabetes treated with metformin.
Berne C; the Orlistat Swedish Type 2 diabetes Study Group.
Department of Medicine, University Hospital, Uppsala, Sweden. christian.berne@akademiska.se

AIMS: To assess the effects of orlistat vs. placebo, in combination with a weight management programme, on weight loss and metabolic control in obese patients with Type 2 diabetes. METHODS: Patients treated with either metformin alone or metformin in combination with sulphonylurea were randomized to double-blind treatment with orlistat or placebo (120 mg) three times daily, combined with a mildly reduced calorie diet and a weight management programme for 52 weeks. Changes in body weight, anthropometry, glycaemic control and lipid profile were assessed. RESULTS: After 52 weeks, orlistat-treated patients achieved an almost threefold greater reduction in weight compared with placebo recipients (-5.0% vs. -1.8%; P<0.0001). The decrease in waist circumference was significantly greater with orlistat than placebo (-4.8 cm vs. -2.8 cm; P=0.0022). Orlistat treatment was also associated with significantly greater reductions in haemoglobin A(1c) (-1.1% vs. -0.2%; P<0.0001), fasting plasma glucose (-1.9 mmol/l vs. -0.3 mmol/l; P<0.0001), total cholesterol (-0.2 mmol/l vs. 0.1 mmol/l; P=0.03) and apolipoprotein B (-0.08 g/l vs. 0.01 g/l; P=0.0085) and greater improvements in beta-cell function (P=0.031) and insulin resistance (P=0.001) assessed using the homeostasis model assessment (HOMA). Similar results were obtained for subgroups of patients treated with metformin alone or metformin in combination with sulphonylurea. Orlistat treatment reduced the requirement for anti-diabetic medication more than placebo. CONCLUSIONS: Orlistat, in combination with a reduced calorie diet and a weight management programme, promotes weight loss and clinically relevant improvements in glycaemic control and other cardiovascular risk factors in obese patients with Type 2 diabetes.

BMC Fam Pract. 2005 Jan 29;6(1):5.
Influence of intense multidisciplinary follow-up and orlistat on weight reduction in a primary care setting.
Feigenbaum A, Pasternak S, Zusk E, Sarid M, Vinker S.
Department of Family Medicine, Sackler School of Medicine, Tel Aviv University; Tel Aviv, Israel. vinker01@inter.net.il.

BACKGROUND: Obesity is the most common health problem in developed countries. Recently, several physicians' organizations have issued recommendations for treating obesity to family physicians, including instructions in nutrition, physical activity and medications. The aim of this study was to examine if effective weight-reducing treatment can be given by a family physician. It compares regular treatment with intensive treatment that include close follow-up and orlistat treatment. METHODS: The study was conducted in three primary care clinics. 225 patients were divided into three groups according to their choice. Group A received a personal diet with fortnightly meetings with the family physician and dietitian and orlistat treatment. Group B received a general diet, monthly meetings with the family physician only and orlistat treatment. Group C received a personal diet, monthly meetings with the dietitian only and no drug treatment. The primary endpoint was reduction of at least 5% of the initial weight during the study period. RESULTS: A greater percentage of patients in group A achieved their weight reduction goals than in other groups (51%, 13% and 9% in groups A, B and C, respectively, p < 0.001). There was a significant reduction in triglycerides in all groups, a significant reduction of low density lipids (LDL) in groups A and B and no significant difference in high density lipids (HDL) in any group. CONCLUSIONS: Significant weight reduction was obtained in a family physician setting. Further research is needed to evaluate if, by providing the family physician with the proper tools, similar success can be achieved in more clinics.

Int J Obes Relat Metab Disord. 2005 Mar 01;
Orlistat in responding obese type 2 diabetic patients: meta-analysis findings and cost-effectiveness as rationales for reimbursement in Sweden and Switzerland.
Ruof J, Golay A, Berne C, Collin C, Lentz J, Maetzel A.
[1] 1Health Services Research Unit, Division of Rheumatology, Center of Internal Medicine, Hannover Medical School, Hannover, Germany [2] 2Global Health Economics Department, Roche Pharmaceuticals, Basel, Switzerland.

OBJECTIVE:: The aim of this study is to review the clinical and economic rationale for the reimbursement of orlistat in responding obese patients with type 2 diabetes. METHODS:: Data from seven randomized controlled clinical trials of orlistat in overweight and obese patients with type 2 diabetes were pooled. A subgroup analysis involving patients who achieved a response (defined as a weight loss of >/=5% after 12 weeks of treatment) was conducted. The outcomes of the pooled analysis were then used to construct a Markov health economic model covering an 11-y period. The incidences of diabetes-related micro- and macrovascular complications were derived from the United Kingdom Prospective Diabetes Study. The effects of changes in body mass index, and the impact of micro- and macrovascular complications on utilities were derived from published sources. Publicly available cost data were used and are presented here in 2001 Euros. Discounting of 3% was applied. A probabilistic sensitivity analysis was conducted to examine the robustness of results. RESULTS:: A total of 1249 patients treated with orlistat and 1230 given placebo were eligible for the intent-to-treat analysis. At the end of the study period, 23% of orlistat patients achieved a weight reduction of >/=5%. These patients showed a mean decrease in HbA1C of 1.16%, a weight reduction of 8.6 kg, a reduction in total cholesterol of 5.3% and a reduction in systolic blood pressure of 5.2 mmHg. The base-case economic analysis revealed costs per quality-adjusted life year gained of \[euro]14 000 in Sweden and \[euro]13 600 in Switzerland. CONCLUSION:: The data presented here support the utilization and reimbursement of orlistat in overweight and obese diabetic patients who respond to the treatment.International Journal of Obesity advance online publication, 1 March 2005; doi:10.1038/sj.ijo.0802925.

Int J Obes Relat Metab Disord. 2004 Aug;28(8):1059-63.
Comparison of the effect of orlistat vs orlistat plus metformin on weight loss and insulin resistance in obese women.
Sari R, Balci MK, Coban E, Yazicioglu G.
Division of Endocrinology & Metabolism, School of Medicine, Akdeniz University, Turkey. drsari@hotmail.com
BACKGROUND AND AIM: Orlistat and metformin are the currently used drugs for weight loss. We aimed to compare the effect of orlistat and orlistat plus metformin combination therapy on weight loss and insulin resistance in obese women. PATIENTS AND METHODS: In all, 57 obese women (body mass index >/=30 kg/m(2) and normal glucose tolerance) were included. All subjects took the same content and caloric diet therapy during the study. After a month of diet period, each individual was randomly assigned to receive 360 mg orlistat per day (group 1; n=30) or 360 mg orlistat plus 1700 mg metformin per day (group 2; n=27) during the next 3 months. Body weight and insulin resistance by the homeostasis model assessment model (HOMA-IR) was measured at baseline, first month and fourth month. RESULTS: The mean weight loss in groups 1 and 2 was 1.36+/-0.8 kg (1.4+/-0.7%) and 1.11+/-0.7 kg (1.1+/-0.7%) from baseline to first month; 4.8+/-2.9 kg (5.28+/-3.0%) and 5.77+/-2.5 kg (6.17+/-2.9%) from first month to fourth month. Body weight was decreased in groups 1 (P< 0.001) and 2 (P< 0.001), but there was no statistically significant difference between groups. Change of HOMA-IR in groups 1 and 2 was 0.41+/-0.4 (14.9+/-10.1%) and 0.23+/-0.7 (8.16+/-12.3%) from baseline to first month; 0.49+/-0.77 (22.0+/-26%) and 0.95+/-0.88 (34.8+/-29.1%) from first month to fourth month. HOMA-IR value was decreased in groups 1 (P< 0.001) and 2 (P< 0.001) but was not different between groups during the study period. CONCLUSIONS: Combination of orlistat with metformin did not result in an additional effect on weight loss and insulin resistance when compared to orlistat alone in our study. However, new studies which have more sample sizes and the longer study period are necessary for this purpose.

Kidney Int. 2004 Aug;66(2):676-82.
Fat malabsorption induced by gastrointestinal lipase inhibitor leads to an increase in urinary oxalate excretion.
Ferraz RR, Tiselius HG, Heiberg IP.
Nephrology Division, Universidade Federal de Sao Paulo, UNIFESP, Sao Paulo, Brazil.
BACKGROUND: Unabsorbed fat and bile acids may react with calcium in the intestinal lumen, limiting the amount of free calcium binding with oxalate and thereby raising intestinal oxalate absorption leading to hyperoxaluria. The aim of the present study was to determine whether orlistat (Xenical), a gastrointestinal lipase inhibitor, might increase urinary oxalate in an experimental rat model. METHODS: Thirty-nine male adult Wistar rats were fed a standard diet alone (controls) or supplemented with either 2% sodium oxalate (NaOx) or 3.2 mL of soy oil, or with both (NaOx + soy oil) for 4 weeks (diet period). Orlistat (16 mg/day) was added to the diet from the 5th to the 8th week (diet + orlistat period). Urinary oxalate (uOx), calcium (uCa), magnesium (uMg), and citrate (uCit) were determined and the ion-activity product of calcium oxalate [AP (CaOx) index(rat)] was estimated. RESULTS: Compared to baseline uOx significantly increased after diet + orlistat in controls (0.64 +/- 0.1 mg/24 hours vs. 0.56 +/-0.1 mg/24 hours), soy oil (0.80 +/- 0.3 mg/24 hours vs. 0.49 +/-0.2 mg/24 hours), and NaOx (2.48 +/- 0.8 mg/24 hours vs. 0.57 +/- 0.2 mg/24 hours), but the most marked increase occurred in NaOx + soy oil (3.87 +/- 0.7 mg/24 hours vs. 0.47 +/- 0.1 mg/24 hours). All groups except controls presented a significant reduction in uCa and uMg. Orlistat induced a significant increase in AP (CaOx) index(rat) compared, respectively, to baseline and to the diet period in NaOx (4.52 +/- 2.34 mg/24 hours vs. 0.94 +/- 0.86 and 1.53 +/- 0.93 mg/24 hours) and NaOx + soy oil (6.49 +/- 4.03 mg/24 hours vs. 0.54 +/- 0.17 and 1.76 +/- 1.32 mg/24 hours). CONCLUSION: These data suggest that the use of lipase inhibitors, especially under a diet rich in oxalate alone or associated with fat, leads to a significant and marked increase in urinary oxalate and a slight reduction in uCa and uMg that, taken together, resulted in an increase in AP (CaOx) index(rat), elevating the risk of stone formation.

J Biol Chem. 2004 Jul 16;279(29):30540-5. Epub 2004 May 11.
A fatty acid synthase blockade induces tumor cell-cycle arrest by down-regulating Skp2.
Knowles LM, Axelrod F, Browne CD, Smith JW.Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.
In eukaryotes, fatty acid synthase (FAS) is the enzyme responsible for synthesis of palmitate, the precursor of long-chain nonessential fatty acids. FAS is up-regulated in a wide range of cancers and has been suggested as a relevant drug target. Here, two independent approaches are taken toward knocking down FAS and then probing its connection to tumor cell proliferation. In one approach, Orlistat, a drug approved for treating obesity, is used as a potent inhibitor of the thioesterase function of FAS. In a separate strategy, the expression of FAS is suppressed by targeted knock-down with small interfering RNA. In both circumstances, the ablation of FAS activity causes a dramatic down-regulation of Skp2, a component of the E3 ubiquitin ligase that controls the turnover of p27Kip1. These effects ultimately tie into the retinoblastoma protein pathway and lead to a cell-cycle arrest at the G1/S boundary. Altogether, the findings of the study reveal unappreciated links between fatty acid synthase and ubiquitin-dependent proteolysis of cell-cycle regulatory proteins.

Arch Intern Med. 2004 Jul 12;164(13):1395-404.
Efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes mellitus: a meta-analysis.
Norris SL, Zhang X, Avenell A, Gregg E, Schmid CH, Kim C, Lau J.
Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA. scn5@cdc.gov
BACKGROUND: Obesity is closely related to type 2 diabetes mellitus, and weight reduction is an important part of the care delivered to obese persons with diabetes. The objective of this review was to assess the efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes. METHODS: A systematic review of the literature was performed, and studies were included if pharmacotherapy was used as the primary strategy for weight loss among adults with type 2 diabetes. Published and unpublished studies with any design were included. A random effects model was used to combine outcomes from randomized controlled trials. RESULTS: Sufficient data for the meta-analysis were available for fluoxetine, orlistat, and sibutramine. Fourteen randomized, placebo-controlled trials were included in the review, with a total of 2231 patients. Pharmacotherapy produced modest reductions in weight for fluoxetine (3.4 kg [95% confidence interval (CI), 1.7-5.2 kg] at 8-16 weeks of follow-up; 5.1 kg [95% CI, 3.3-6.9 kg] at 24-30 weeks; and 5.8 kg [ 95% CI, 0.8-10.8 kg] at 52 weeks); orlistat (2.6 kg [95% CI, 2.1-3.2 kg] [2.6% loss] at 52 weeks); and sibutramine (4.5 kg [95% CI, 1.8-7.2 kg] [3.3% loss] at up to 26 weeks). Glycated hemoglobin was also modestly reduced: fluoxetine (1.0% [95% CI, 0.4%-1.5%] at 8-16 weeks; 1.0% [95% 0.6%-1.4%] at 24-30 weeks; and 1.8% [95% CI, -0.2%-3.8%] at 52 weeks); orlistat (0.4% [95% CI, 0.3%-0.5%]); and sibutramine (0.7% [95% CI, -0.5%-1.9%]). Gastrointestinal adverse effects were common with orlistat; tremor, somnolence, and sweating with fluoxetine; and palpitations with sibutramine. CONCLUSIONS: Fluoxetine, orlistat, and sibutramine can achieve statistically significant weight loss over 26 to 52 weeks. However, the magnitude of weight loss was modest, and the long-term health benefits and safety remain unclear. Interventions that combine pharmacologic therapy with intensive behavioral interventions may be more effective but need additional research.

Indian J Gastroenterol. 2004 Jul-Aug;23(4):131-4.
Efficacy of omega-3 fatty acids, atorvastatin and orlistat in non-alcoholic fatty liver disease with dyslipidemia.
Hatzitolios A, Savopoulos C, Lazaraki G, Sidiropoulos I, Haritanti P, Lefkopoulos A, Karagiannopoulou G, Tzioufa V, Dimitrios K.
First Propaedeutic Department of Internal Medicine, Ahepa General Hospital, Aristotelion University of Thessaloniki, Greece. aee@med.auth.gr
AIM: To evaluate the efficacy and safety of three hypolipidemic agents in patients with non-alcoholic fatty liver disease associated with hyperlipidemia. METHODS: Patients with dyslipidemia (Fredrickson type IIb), asymptomatic persistent transaminasemia lasting 24 weeks, and evidence of hepatic fat infiltration on ultrasonography and liver biopsy were studied. Those with predominant hypertriglyceridemia received omega-3 fatty acids (5 mL thrice daily) (Group A), those with predominant hypercholesterolemia received atorvastatin 20 mg/daily (Group B), and overweight patients received orlistat 120 mg thrice daily before meals (Group C). After 24 weeks of treatment, serum transaminase and lipid levels and liver ultrasonography were repeated. RESULTS: Serum transaminase levels decreased significantly (p< 0.001) in all groups but the decrease was more marked in Group C (AST 75 [16] to 31 [7] IU/L; ALT 120 [38] to 41 [10] IU/L) than in Group A (AST 70 [14] to 41 [6]; ALT 110 [20] to 68 [12]) or Group B (AST 68 [13] to 46 [9]; ALT 115 [22] to 76.6 [13]). After treatment, ultrasonography showed resolution of fatty liver in 35% of patients in Group A, 61% in Group B, and in 86% in Group C (p< 0.001, Group C vs. A). CONCLUSIONS: A decline in transaminase levels and normalization of ultrasonographic evidence of fatty liver were observed on treatment with omega-3 fatty acids in patients with hypertriglyceridemia, with atorvastatin in those with hypercholesterolemia, and orlistat in overweight patients with hyperlipidemia.

Kardiol. 2004 Jul;93(7):503-13.
Obesity and cardiovascular diseases-theoretical background and therapeutic consequences
Voller H, Schmailzl KJ, Bjarnason-Wehrens B.
Klinik am See, Fachklinik fur kardiovaskulare Erkrankungen, Kardiologie, Seebad 84, 15562 Rudersdorf/Berlin, Germany. heinz.voeller@klinikamsee.com
In the normal population, the prevalence of obesity is almost 20%. It is a condition influenced by genetic factors, so that individual behavior cannot be regarded as its sole cause. The amount of food is essentially determined by the hormone leptin, the feedback regulation of which can be disturbed by a modification of the molecule or a mutation of the receptor. A further important determinant is energy consumption, which is subject to large individual variations, which partly result from thermogenesis. With regard to the fat distribution, it is concentrated on the trunk in the android form as compared to the hips in the gynecoid form. The android form is subject to a higher incidence of cardiovascular morbidity and mortality. The indirect determination of body fat by measuring the body mass index (weight [kg]/body weight [m(2)]) is hence less reliable than measuring the waist (women > 80 cm, men > 94 cm).The effects of generalized obesity on cardiovascular function are chiefly an increase of blood volume and an eccentric left ventricular hypertrophy. This first of all results in diastolic dysfunction, which can give rise to a disturbance of systolic function in left ventricular dilatation. Concentric hypertrophy develops in the presence of arterial hypertension. This is twice as frequent in obese patients than in the normal population, which is due to increased activity of the sympathetic nervous system and stimulation of the renin-angiotensin system. A disturbance of lipid metabolism is observed four to six times more frequently. The qualitative change in LDL fraction with a raised concentration of low density LDL particles appears to be of crucial importance. With increasing fat mass, the sensitivity to insulin is lowered, so that in obesity the risk of developing diabetes mellitus type 2 is tripled.Since there has been a dramatic increase in the numbers of overweight children and adolescents (from 10.5% to 15.5% within the past five years), prevention programs should be started in good time. A reduction in calorie intake and an altered dietary composition (55% complex carbohydrates, 30% fat and 15% to 20% protein) on the one hand, and increased physical activity on the other hand continue to be the central components. The latter is especially effective when it regularly gives rise to an increased turnover of fatty acids as a result of an increased energy metabolism at moderate intensity. This leads to adaptation, i. e. an increase in the activity of lipoprotein lipase.If prevention programs and/or changes in lifestyle do not give rise to the desired weight reduction, medication is indicated in some adults. Sibutramine (Reductil and orlistate (Xenical) lead to an additional weight loss of up to 10%. However, consistent treatment of any cardiovascular risk factors present is more important. Treatment of arterial hypertension is of greatest prognostic significance, especially in concomitant diabetes mellitus. In individual cases and after thorough discussion of indication surgical options should be considered.

Aliment Pharmacol Ther. 2004 Jun 15;19(12):1261-8.
Influence of a lipase inhibitor on gastric sensitivity and accommodation to an orally ingested meal.
Demarchi B, Vos R, Deprez P, Janssens J, Tack J.
Department of Internal Medicine, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium.
BACKGROUND: Intraduodenal administration of lipids, through lipid digestion and release of cholecystokinin (CCK), induces viscero-visceral reflexes that affect gastric tone and sensitivity. It is unclear whether the same mechanisms control gastric function after an orally ingested meal. AIM: To evaluate the effect of orlistat, a selective lipase inhibitor, on gastric response to an orally administered meal. METHODS: Eighteen healthy volunteers participated in this study. They were treated for 5 days with orlistat (120 mg) or placebo t.d.s. in a double-blind randomized crossover design. During treatment, all subjects underwent a gastric barostat study, measurement of plasma CCK levels and a satiety drinking test. RESULTS: Although CCK plasma levels were significantly decreased, pre-treatment with orlistat failed to affect gastric compliance (72 +/- 6 mL/mm Hg and 64 +/- 6 mL/mm Hg, NS), gastric sensitivity (discomfort threshold 12.2 +/- 0.6 mm Hg vs. 10.9 +/- 0.6 mm Hg above minimal distending pressure, NS) or gastric accommodation (172 +/- 41 mL vs. 206 +/- 49 mL, NS) to an orally ingested meal. Furthermore, orlistat pre-treatment had no significant effect on the amount of calories ingested during a satiety drinking test (1329 +/- 88 kcal vs. 1217 +/- 115 kcal, NS). CONCLUSION: Administration of a lipase inhibitor does not affect gastric compliance, sensitivity to distension and accommodation to an orally ingested meal, and does not influence meal-induced satiety.

Aliment Pharmacol Ther. 2004 Jun 1;19(11):1173-9.
Cholesterol lowering effect of dietary weight loss and orlistat treatment--efficacy and limitations.
Erdmann J, Lippl F, Klose G, Schusdziarra V.
Department of Internal Medicine II, Technical University of Munich, Munich, Germany. johannes.erdmann@lrz.tum.de
BACKGROUND: Orlistat reduces energy uptake by the impairment of fat digestion and some evidence indicates it also lowers plasma cholesterol. AIM: To examine total, low-density lipoprotein- and high-density lipoprotein cholesterol during a weight reducing regimen, and assess the effect of orlistat in lowering cholesterol levels independent of its weight reducing efficacy. METHODS: A total of 448 patients with elevated cholesterol according to cardiovascular risk factors entered a 2 week single-blind run-in period on a hypocaloric diet. Of 384 patients were subsequently assigned double-blind treatment with orlistat (3 x 120 mg/day) or placebo for 6 months in conjunction with the hypocaloric diet. RESULTS: Weight loss in the orlistat group was 7.4 kg vs. 4.9 kg with placebo. Total and low-density lipoprotein cholesterol decreased by 25-30 mg/dL vs. 10-15 mg/dL with placebo. Reduction of cholesterol with orlistat was significantly greater than anticipated from weight loss alone. In patients with cardiovascular risk factors entering the study with lower cholesterol values orlistat was also superior to placebo. On the contrary, reduction of cholesterol concentrations never exceeded 20%. CONCLUSION: Orlistat has a cholesterol lowering efficacy independent of its weight reducing effect. Because of the limited therapeutic effectiveness, patients at high cardiovascular risk should receive rather early additional cholesterol lowering medication during weight loss programmes.

Biochim Biophys Acta. 2004 Jun 1;1682(1-3):72-9.
Rapid exchange of pancreatic lipase between triacylglycerol droplets.
Haiker H, Lengsfeld H, Hadvary P, Carriere F.
F Hoffmann-La Roche, CH-4070 Basel, Switzerland.
Two types of experiments were performed to study the reversibility of interfacial adsorption of pancreatic lipase (PL) to fat droplets during lipolysis. Lipolysis was measured in olive oil/gum arabic emulsions containing radiolabeled triolein in the presence of bile salts and lecithin at rate-limiting concentrations of porcine PL (PPL) or human PL (HPL). The lipolysis rate in a labeled emulsion, i.e. release of [(14)C]oleic acid, was immediately reduced by around 50% upon dilution with an equal amount of an unlabeled emulsion. Further, lipolysis was rapidly and completely suppressed when a non-exchanging lipase inhibitor was present in the second emulsion. These results indicate hopping of lipase between emulsion droplets. Alternative explanations were excluded. Hopping of PL between triolein droplets stabilized with gum arabic at supramicellar bile salt concentrations was observed only in the presence, not in the absence, of lecithin. Displacement from a trioctanoin-water interface of active HPL by an inactive mutant (S152G) was studied in the presence of bile salts by measuring HPL distribution between the water phase and the oil-water interface. Colipase was limiting for HPL binding to the oil-water interface (colipase to lipase molar ratio: 0.5) and, thus, for lipolysis. Upon adding S152G, which has the same affinity for colipase, inactive and active HPL were found to compete for binding at the oil-water interface. When equal amounts of HPL and HPL S152G were used, the lipolysis rate dropped to half the maximum rate recorded with HPL alone, suggesting that half the active HPL was rapidly desorbed from the oil-water interface. Therefore, under various conditions, PL does not remain irreversibly adsorbed to the oil-water interface, but can exchange rapidly between oil droplets, via an equilibrium between soluble and lipid-bound PL.

Wien Med Wochenschr. 2004 Jun;154(11-12):282-8.
Modification of conventional risk factors in coronary artery disease
Voller H.
Kardiologie, Klinik am See, Rudersdorf bei Berlin, Berlin, Deutschland. heinz.voeller@klinikamsee.com
The conventional cardiovascular risk factors such as smoking, hyperlipoproteinemia, arterial hypertension and diabetes are responsible for nearly 75% of myocardial infarction events. Since obesity is associated with a two- or threefold increased risk for arterial hypertension and diabetes, the reduction of body weight presents a basic and causal approach. Indeed 60% of the German population is overweight, and every fifth person has obesity. A low-calorie diet and higher quality nutrition as well as increased physical activity is the main therapeutic strategy. The maximum fat supply in a 1200 kcal/d diet should be less than 70 g. Training should be of low intensity, below the anaerobic threshold (50-70% of VO2max), in order to obtain optimal metabolic effect in combination with maximal fat reduction. Should the newly adopted lifestyle not result in a satisfactory loss of weight, medication can be applied in addition. Sibutramin (Reductil) or Orlistat (Xenical) can in individual cases be of help and lead to a further weight loss of up to 10%. It has been demonstrated that such weight loss can evoke the same positive effects of glucose metabolism in patients with impaired glucose tolerance as can metformin. Nevertheless, from a prognostic point of view, in patients with coronary artery disease and manifest diabetes, insulin therapy is required. Although arterial hypertension carries with it four times the risk of stroke and twice that of myocardial infarction, the majority of the population does not receive adequate treatment. Even after an acute cardiac event, in every second patient, an elevated blood pressure of > 140/90 mm Hg at the beginning of the rehabilitation period is found. In approximately 80% of the patients, a guideline-based therapy can be achieved during the follow-up phase. Comparable results apply to LDL-cholesterol patients as well. For patients with chronic coronary artery disease, it is highly important that medication and change in lifestyle be continued. Patients need to receive standardized information and ongoing medical care.

Health Technol Assess. 2004 May;8(21):iii-iv, 1-182.
Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.
Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, Smith WC, Jung RT, Campbell MK, Grant AM.
Heath Services Unit, University of Aberdeen, UK.
OBJECTIVES: To undertake a systematic review of the long-term effects of obesity treatments on body weight, risk factors for disease, and disease. METHODS: The study encompassed three systematic reviews that examined different aspects of obesity treatments. (1) A systematic review of obesity treatments in adults where the methods of the Cochrane Collaboration were applied and randomised controlled trials (RCTs) with a follow-up of at least 1 year were evaluated. (2) A systematic epidemiological review, where studies were sought on long-term effects of weight loss on morbidity and/or mortality, and examined through epidemiological modelling. (3) A systematic economic review that sought reports with both costs and outcomes of treatment, including recent reports that assessed the cost-effectiveness of pharmaceutical and surgical interventions. A Markov model was also adopted to examine the cost-effectiveness of a low-fat diet and exercise intervention in adults with obesity and impaired glucose tolerance. RESULTS: The addition of the drugs orlistat or sibutramine was associated with weight loss and generally improved risk factors, apart from diastolic blood pressure for sibutramine. Metformin was associated with decreased mortality after 10 years in obese people with type 2 diabetes. Low-fat diets were associated with continuing weight loss for 3 years and improvements in risk factors, as well as prevention of type 2 diabetes and improved control of hypertension. Insufficient evidence was available to demonstrate the benefits of low calorie or very low calorie diets. The addition of an exercise or behaviour programme to diet was associated with improved weight loss and risk factors for at least 1 year. Studies combining low-fat diets, exercise and behaviour therapy suggested improved hypertension and cardiovascular disease. Family therapy was associated with improved weight loss for 2 years compared to individual therapy. There was insufficient evidence to conclude that individual therapy was more beneficial than group therapy. Weight lost more quickly (within 1 year), from the epidemiology review, may be more beneficial with respect to the risk of mortality. The effects of intentional weight loss need further investigation. Weight loss from surgical and non-surgical interventions for people suffering from obesity was associated with decreased risk of development of diabetes, and a reduction in low-density lipoprotein cholesterol, total cholesterol and blood pressure, in the long term. Targeting high-risk individuals with drugs or surgery was likely to result in a cost per additional life-year or quality-adjusted life-year (QALY) of no more than 13,000 British pounds. There was also suggestive evidence of cost saving from treatment of people with type 2 diabetes with metformin. Targeting surgery on people with severe obesity and impaired glucose tolerance was likely to be more cost-effective at 2329 British pounds per additional life-year. Economic modelling over 6 years for diet and exercise for people with impaired glucose tolerance was associated with a high initial cost per additional QALY, but by the sixth year the cost per QALY was 13,389 British pounds. Results did not include cost savings from diseases other than diabetes, and therefore may be conservative. CONCLUSIONS: The drugs orlistat and sibutramine appear beneficial for the treatment of adults with obesity, and metformin for obese patients with type 2 diabetes. Exercise and/or behaviour therapy appear to improve weight loss when added to diet. Low-fat diets with exercise, or with exercise and behaviour therapy are associated with the prevention of type 2 diabetes and hypertension. Long-term weight loss in epidemiological studies was associated with reduced risk of type 2 diabetes, and may be beneficial for cardiovascular disease. Low-fat diets and exercise interventions in individuals at risk of obesity-related illness are of comparable cost to drug treatments. Long-term pragmatic RCTs of obesity treatments in populations with obesity-related illness or at high risk of developing such illness are needed (to include an evaluation of risk factors, morbidity, quality of life and economic evaluations). Drug trials that include dietary advice, plus exercise and/or behaviour therapy are also needed. Research exploring effective types of exercise, diet or behaviour and also interventions to prevent obesity in adults is required.

Am J Cardiol. 2004 Apr 15;93(8):1012-6.
Effect of short-term weight loss on the metabolic syndrome and conduit vascular endothelial function in overweight adults.
Brook RD, Bard RL, Glazewski L, Kehrer C, Bodary PF, Eitzman DL, Rajagopalan S.
Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. robdbrok@umich.edu
Impaired vascular endothelial function may be an important mechanism linking obesity to increased cardiovascular risk. We investigated whether short-term weight loss improves conduit artery endothelial dysfunction in overweight adults. Forty-three otherwise healthy overweight patients with a body mass index > or =27 kg/m(2) completed an open-label 3-month trial consisting of a calorie-restricted diet and 120 mg of orlistat taken 3 times daily with meals. Endothelial function and parameters of the metabolic syndrome were measured before and after intervention. Subjects lost 6.6 +/- 3.4% of their body weight. Low-density lipoprotein cholesterol, low-density lipoprotein concentration, fasting insulin, and leptin decreased significantly (all p <0.009), and C-reactive protein decreased (p = 0.22). Conduit vascular function did not change as assessed by flow-mediated dilation (3.86 +/- 3.54 vs 3.74 +/- 3.78%, p = 0.86) and nitroglycerin-mediated dilation (17.18 +/- 5.89 vs 18.87 +/- 7.11%, p = 0.13) of the brachial artery. A moderate degree of weight reduction over 3 months improved the metabolic syndrome profile but not the vascular dysfunction associated with uncomplicated obesity

Diabetes Care. 2004 Jan;27(1):155-61.
XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study: A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.
Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L.
Department of Body Composition and Metabolism, Sahlgrenska University Hospital, Goteborg, Sweden. Hoffmann-La Roche, Nutley, New Jersey.
OBJECTIVE:-It is well established that the risk of developing type 2 diabetes is closely linked to the presence and duration of overweight and obesity. A reduction in the incidence of type 2 diabetes with lifestyle changes has previously been demonstrated. We hypothesized that adding a weight-reducing agent to lifestyle changes may lead to an even greater decrease in body weight, and thus the incidence of type 2 diabetes, in obese patients. RESEARCH DESIGN AND METHODS-In a 4-year, double-blind, prospective study, we randomized 3,305 patients to lifestyle changes plus either orlistat 120 mg or placebo, three times daily. Participants had a BMI >/==" BORDER="0">30 kg/m(2) and normal (79%) or impaired (21%) glucose tolerance (IGT). Primary endpoints were time to onset of type 2 diabetes and change in body weight. Analyses were by intention to treat. RESULTS:-Of orlistat-treated patients, 52% completed treatment compared with 34% of placebo recipients (P < 0.0001). After 4 years' treatment, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P = 0.0032). Exploratory analyses indicated that the preventive effect was explained by the difference in subjects with IGT. Mean weight loss after 4 years was significantly greater with orlistat (5.8 vs. 3.0 kg with placebo; P < 0.001) and similar between orlistat recipients with impaired (5.7 kg) or normal glucose tolerance (NGT) (5.8 kg) at baseline. A second analysis in which the baseline weights of subjects who dropped out of the study was carried forward also demonstrated greater weight loss in the orlistat group (3.6 vs. 1.4 kg; P < 0.001). CONCLUSIONS:-Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced greater weight loss in a clinically representative obese population. Difference in diabetes incidence was detectable only in the IGT subgroup; weight loss was similar in subjects with IGT and or NGT.

Rom J Gastroenterol. 2003 Sep;12(3):189-92.
The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis.
Sabuncu T, Nazligul Y, Karaoglanoglu M, Ucar E, Kilic FB.
Department of Endocrinology and Metabolism, University of Harran, Faculty of Medicine, Sanliurfa, Turkey.
OBJECTIVE: Non-alcoholic steatohepatitis (NASH) is frequent in obese subjects and has a relatively benign course; however, it may progress to cirrhosis. Weight loss in these patients may alleviate the findings of NASH. The aim of this study was to investigate the effects of pharmacological anti-obesity therapies on the findings of NASH. SUBJECTS: There were thirteen patients (9 women, 4 men) in sibutramine group and 12 patients (8 women, 4 men) in orlistat group. The mean ages and body-mass indexes of the two groups were 42.5 years, 37.3 kg/m2 and 43.2 years, 36.1 kg/m2, respectively. METHOD: The obese subjects with NASH were given sibutramine or orlistat for six months. Additionally, all patients were given a low caloric diet. Liver enzymes (AST, ALT, GGT and ALP), insulin resistance (analysed by HOMA) and hepatic ultrasound (US) findings were assessed at baseline and after 6 months. RESULTS: Both sibutramine and orlistat significantly reduced body weight (10.2 and 8.4%, respectively), insulin resistance (47 and 40%, respectively), AST (41 and 39%, respectively), ALT (59 and 58%, respectively), and GGT serum levels (27 and 25%, respectively). The ultrasonographic regression in steatosis was observed in 11 patients who received sibutramine and 8 patients who received orlistat. During the treatment, unexpectedly significant increases in total alkaline phosphatase levels were found in both sibutramine and orlistat groups (9 and 14%, respectively). CONCLUSION: The present study shows that both sibutramine-induced and orlistat-induced weight losses result in reduction of insulin resistance, and improvements in biochemical markers and US findings of NASH. Because the GGT levels decreased in both groups, the increased ALP levels might have another source.

J Clin Endocrinol Metab. 2003 Aug;88(8):3829-34.
Effect of lipase inhibition on gastric emptying of, and the glycemic and incretin responses to, an oil/aqueous drink in type 2 diabetes mellitus.
Pilichiewicz A, O'Donovan D, Feinle C, Lei Y, Wishart JM, Bryant L, Meyer JH, Horowitz M, Jones KL.
University of Adelaide, Department of Medicine, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia.
This study examined the effects of the lipase inhibitor, orlistat, on gastric emptying of, and the glycemic and incretin hormone responses to, a drink containing oil and glucose components in patients with type 2 diabetes. Seven patients (aged 58 +/- 5 yr), managed by diet alone, consumed 60 ml olive oil (labeled with 20 MBq (99m)Tc-V-thiocyanate) and 300 ml water containing 75 g glucose (labeled with 6 MBq (67)Ga-EDTA), on two occasions, with and without 120 mg orlistat, positioned in the left lateral decubitus position with their back against a gamma camera. Venous blood samples, for measurement of blood glucose and plasma insulin, glucagon-like peptide-1 and glucose-dependent insulintropic polypeptide were obtained immediately before, and after, the drink. Gastric emptying of both oil (P < 0.001) and glucose (P < 0.0005) was faster after orlistat compared with control. Postprandial blood glucose (P < 0.001) and plasma insulin (P < 0.05) were substantially greater after orlistat compared with control. In contrast, plasma glucagon-like peptide-1 (P < 0.005) and glucose-dependent insulintropic polypeptide (P < 0.05) were less after orlistat. In conclusion, inhibition of fat digestion, by orlistat, may exacerbate postprandial glycemia, as a result of more rapid gastric emptying and a diminished incretin response.

Nutr Clin Care. 2003 Jan-Apr;6(1):27-37.
Pharmacotherapy of obesity: an update.
Schurgin S, Siegel RD.
Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Tufts-New England Medical Center, Boston, MA 02111, USA.
There has been an epidemic of obesity in the last decade. In spite of the rising numbers of people who are overweight and obese, medical treatment of obesity is currently where medical treatment of hypertension was in the 1950s with only two Food and Drug Administration-approved medications for chronic weight loss and maintenance, sibutramine and orlistat. This article reviews these medications and others currently being used for weight loss and weight maintenance. Available medications for obesity include drugs that affect caloric intake and appetite and alter energy expenditure and nutrient absorption, as well as some with an unclear mechanism of action at present. Dozens of drugs in different phases of clinical investigation could be available in the next decade.

Rev Med Liege. 2003 Apr;58(4):206-10.
Prevention of type 2 diabetes: lifestyle changes or pharmacological interventions?
Scheen AJ, Letiexhe MR, Ernest P.
Service de Diabetologie, Nutrition et Maladies metaboliques, Service de Medecine interne generale, Unite de Pharmacologie clinique, Departement de Medecine, Universite de Liege.
The World Health Organisation strongly recommends strategies for the prevention of type 2 diabetes, knowing the epidemics of the disease and its strong association with that of obesity. Several intervention studies, in China ("Da-Qing Study"), in Europe ("Malmo study", "Finnish Diabetes Prevention Study") and in the United States ("Diabetes Prevention Program"), showed that lifestyle change are able to reduce by around 50% the incidence of type 2 diabetes in at risk individuals. Various pharmacological approaches have also proven their efficacy in preventing type 2 diabetes, but in most cases with less impressive reductions, between 25% and 35%. It is the case for metformin, acarbose, orlistat (xenical) or various inhibitors of the renin-angiotensin system. After the report of promising results with troglitazone, large prospective studies are ongoing to test the efficacy of rosiglitazone and pioglitazone in such an indication, two insulinsensitizers of the thiazolidinedione family. We will briefly described the main results of intervention studies to prevent type 2 diabetes in at risk subjects, because of the presence of obesity, impaired glucose tolerance and/or arterial hypertension.

Int J Clin Pharmacol Res. 2002;22(3-4):85-8.
Orlistat (xenical) use in overweight women with mild hypercholesterolemia.
Petrogiannopoulos C, Kalogeropoulos S, Latsios GS, Hartzoulakis G, Kalogeropoulos G, Zaharof A.
Hellenic Red Cross Hospital, Athens, Greece.
In the present study, we investigated the effects of a 6-month treatment with orlistat on body weight and lipid profile in 27 overweight women (mean body mass index [BMI]: 27.5 kg/m2; median age: 38.4 years) with mild hypercholesterolemia (total cholesterol: 225 mg/dl; low-density lipoprotein cholesterol [LDL-C]: 162 mg/dl). Orlistat was administered three times per day in conjunction with a hypocaloric diet After 6 months of treatment, body weight decreased by 17.71% and BMI decreased by 18.54%, whereas there was a significant (p < 0.01) improvement in serum lipid levels (total cholesterol: -25.33% LDL-C: -30.86%, high-density lipoprotein cholesterol: +9.37%, triglycerides: -35.97%). In conclusion, orlistat in combination with a low-energy diet seems to have a beneficial effect on body weight and lipid profile in overweight women with mild hypercholesterolemia.