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At least 19 recordsLinked to original sources
PubMed2000

Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group.

OBJECTIVE: To determine the effect of orlistat, a new lipase inhibitor, on long-term weight loss, to determine the extent to which orlistat treatment minimizes weight regain in a second year of treatment, and to assess the effects of orlistat on obesity-related risk factors. RESEARCH METHODS AND PROCEDURES: This was a 2-year, multicenter, randomized, double-blind, placebo-controlled study. Obese patients (body mass index 28 to 43 kg/m2) were randomized to placebo or orlistat (60 or 120 mg) three times a day, combined with a hypocaloric diet during the first year and a weight maintenance diet in the second year of treatment to prevent weight regain. Changes in body weight, lipid profile, glycemic control, blood pressure, quality of life, safety, and tolerability were measured. RESULTS: Orlistat-treated patients lost significantly more weight (p<0.001) than placebo-treated patients after Year 1 (6.6%, 8.6%, and 9.7% for the placebo, and orlistat 60 mg and 120 mg groups, respectively). During the second year, orlistat therapy produced less weight regain than placebo (p = 0.005 for orlistat 60 mg; p<0.001 for orlistat 120 mg). Several obesity-related risk factors improved significantly more with orlistat treatment than with placebo. Orlistat was generally well tolerated and only 6% of orlistat-treated patients withdrew because of adverse events. Orlistat leads to predictable gastrointestinal effects related to its mode of action, which were generally mild, transient, and self-limiting and usually occurred early during treatment. DISCUSSION: Orlistat administered for 2 years promotes weight loss and minimizes weight regain. Additionally, orlistat therapy improves lipid profile, blood pressure, and quality of life.

Adult↗
PubMed1998

Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group.

BACKGROUND: We undertook a randomised controlled trial to assess the efficacy and tolerability of orlistat, a gastrointestinal lipase inhibitor, in promoting weight loss and preventing weight regain in obese patients over a 2-year period. METHODS: 743 patients (body-mass index 28-47 kg/m2), recruited at 15 European centres, entered a 4-week, single-blind, placebo lead-in period on a slightly hypocaloric diet (600 kcal/day deficit). 688 patients who completed the lead-in were assigned double-blind treatment with orlistat 120 mg (three times a day) or placebo for 1 year in conjunction with the hypocaloric diet. In a second 52-week double-blind period patients were reassigned orlistat or placebo with a weight maintenance (eucaloric) diet. FINDINGS: From the start of lead-in to the end of year 1, the orlistat group lost, on average, more bodyweight than the placebo group (10.2% [10.3 kg] vs 6.1% [6.1 kg]; LSM difference 3.9 kg [p<0.001] from randomisation to the end of year 1). During year 2, patients who continued with orlistat regained, on average, half as much weight as those patients switched to placebo (p<0.001). Patients switched from placebo to orlistat lost an additional 0.9 kg during year 2, compared with a mean regain of 2.5 kg in patients who continued on placebo (p<0.001). Total cholesterol, low-density lipoprotein (LDL) cholesterol, LDL/high-density lipoprotein ratio, and concentrations of glucose and insulin decreased more in the orlistat group than in the placebo group. Gastrointestinal adverse events were more common in the orlistat group. Other adverse symptoms occurred at a similar frequency during both treatments. INTERPRETATION: Orlistat taken with an appropriate diet promotes clinically significant weight loss and reduces weight regain in obese patients over a 2-year period. The use of orlistat beyond 2 years needs careful monitoring with respect to efficacy and adverse events.

Adult↗
PubMed1998

Efficacy and tolerability of orlistat in the treatment of obesity: a 6-month dose-ranging study. Orlistat Dose-Ranging Study Group.

OBJECTIVE: To determine the weight-reducing efficacy of orlistat, a novel gastrointestinal lipase inhibitor, and to define the optimal dosage regimen and establish the tolerability of the drug when used for a 6-month treatment period. METHODS: The study was a multicentre randomised, double-blind, parallel group in design and involved 676 obese male and female subjects aged at least 18 years with a body mass index between 28 and 43 kg x m(-2) Following a 5-week placebo run-in period, subjects were randomised to receive orlistat 30 mg, 60 mg, 120 mg, 240 mg or matching placebo three times a day (tid) for 24 weeks during meals. Patients were maintained on a mildly hypocaloric diet throughout the study period. The primary efficacy parameter was body weight change over time. RESULTS: Orlistat resulted in a significantly greater mean loss of body weight than observed in the placebo group. In absolute terms, mean weight loss was greatest in the 120 mg group (9.8%). More orlistat- than placebo-treated patients lost > 10% of initial body weight (37% of the 120 mg group vs 19% of the placebo group). Orlistat was well tolerated. Predictably, in view of its known pharmacological effects, more orlistat-treated patients experienced gastrointestinal events. Mean levels of vitamins A, D and E, and beta-carotene remained within the clinical reference ranges in all treatment groups and rarely required supplementation. After 24 weeks, plasma concentrations of orlistat were either non-measurable or detected at the assay's limit of quantitation. CONCLUSION: Orlistat treatment results in a dose-dependent reduction in body weight in obese subjects and is well tolerated. Orlistat 120 mg tid represents the optimal dosage regimen.

Adult↗
PubMed2004

Comparison of the effect of orlistat vs orlistat plus metformin on weight loss and insulin resistance in obese women.

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.

Adult↗
PubMed2006

Total synthesis and comparative analysis of orlistat, valilactone, and a transposed orlistat derivative: Inhibitors of fatty acid synthase.

Concise syntheses of orlistat (Xenical), a two-carbon transposed orlistat derivative, and valilactone are described that employ the tandem Mukaiyama aldol-lactonization (TMAL) process as a key step. This process allows facile modification of the alpha-side chain. Versatile strategies for modifying the delta-side chain are described, involving cuprate addition and olefin metathesis. Comparative antagonistic activity of these derivatives toward a recombinant form of the thioesterase domain of fatty acid synthase is reported along with comparative activity-based profiling.

Anti-Obesity Agents↗
PubMed2005

Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene.

BACKGROUND: Orlistat (Xenicaltrade mark), a US Food and Drug Administration (FDA)-approved drug for bodyweight loss, has recently been demonstrated to exhibit antitumor properties towards prostate cancer cells by virtue of its ability to block the lipogenic activity of fatty acid synthase (FAS). FAS (oncogenic antigen-519) is up-regulated in about 50% of breast cancers, is an indicator of poor prognosis, and has recently been functionally associated with the Her2/neu (erbB-2) oncogene. MATERIALS AND METHODS: We assessed the antitumoral effects of orlistat against the human breast cancer cell line SK-Br3, an in vitro paradigm of FAS and Her2/neu overexpression in breast cancer. RESULTS: Cell cycle analyses revealed that micromolar concentrations of orlistat induced, in a time- and dose-dependent manner, significant changes in the distribution of cell populations including a complete loss of G2-M phase, S-phase accumulation and a concomitant increase in the emerging sub-G1 (apoptotic) cells. Poly (ADP-ribose) polymerase (PARP) cleavage, an early event required for cells committed to apoptosis, was more predominant in orlistat-treated G1 phase cells. When we characterized signaling molecules participating in the cellular events following orlistat-induced inhibition of FAS activity and preceded inhibition of breast cancer cell proliferation, a dramatic down-regulation of Her2/neu-coded p185(Her2/neu) oncoprotein was found in orlistat-treated SK-Br3 cells (>90% reduction). Interestingly, a significant accumulation of the DNA-binding protein PEA3, a member of the Ets transcription factor family that specifically targets a PEA3-binding motif present on the Her2/neu gene promoter and down-regulates its activity, was observed in orlistat-treated SK-Br3 cells. When a Luciferase reporter gene driven by the Her2/neu promoter was transiently transfected in SK-Br3 cells, orlistat exposure was found to dramatically repress the promoter activity of Her2/neu gene, whereas a Her2/neu promoter bearing a mutated binding DNA sequence was not subject to negative regulation by orlistat, thus demonstrating that the intact PEA3 binding site on the Her2/neu promoter is required for the orlistat-induced transcriptional repression of Her2/neu overexpression. RNA interference (RNAi)-mediated silencing of FAS gene expression similarly repressed Her2/neu gene expression in a PEA3-dependent manner, thus ruling out a role for non-FAS orlistat-mediated effects. When the combination of orlistat and the anti-Her2/neu antibody trastuzumab (Herceptintrade mark) in either concurrent (orlistat + trastuzumab) or sequential (orlistat --> trastuzumab; trastuzumab --> orlistat) schedules was tested for synergism, addition or antagonism using the combination index (CI) method of Chou-Talalay, co-exposure of orlistat and trastuzumab demonstrated strong synergistic effects (CI10-90 = 0.110-0.847), whereas sequential exposure to orlistat followed by trastuzumab (CI10-90 = 0.380-1.210) and trastuzumab followed by orlistat (CI10-90 = 0.605-1.278) mainly showed additive or antagonistic interactions. Indeed, orlistat-induced FAS inhibition synergistically promoted apoptotic cell death when concurrently combined with trastuzumab as determined by an ELISA for histone-associated DNA fragments. Importantly, the degree of FAS expression in a panel of human breast cancer cell lines was predictive of sensitivity to orlistat-induced anti-proliferative effects as determined by a MTT-based characterization of metabolically viable breast cancer cells. Moreover, hypersensitivity to orlistat-induced cytotoxicity was observed in MCF-7 breast cancer cells engineered to overexpress Her2/neu (MCF-7/Her2-18 cells), which exhibit a significant up-regulation of FAS expression and activity. CONCLUSIONS: These findings reveal that the development of more potent and/or bioavailable orlistat's variants targeting the lipogenic activity of FAS may open a novel therapeutic avenue for treating Her2/neu-overexpressing breast carcinomas.

Anti-Obesity Agents↗
PubMedDate not supplied

The interaction of the lipase inhibitor orlistat with ethanol in healthy volunteers.

OBJECTIVES: The primary objective was to investigate the possible interference of ethanol on the orlistat effect on inhibition of dietary fat absorption and the possible interference of orlistat on the pharmacokinetics of ethanol. Secondary objectives were to assess the tolerability during concomitant dosing of orlistat and ethanol and to determine the ethanol effect on plasma levels of orlistat. METHODS: This was a double-blind, placebo-controlled, parallel, randomized study performed in 30 (three parallel groups of ten subjects each) healthy normal weight male subjects between the ages of 20 and 30 years. A 5-day run-in period to accustom subjects to a standardized diet of 2500 kcal/day (30% fat) and to establish baseline fecal fat excretion was followed by a 6-day treatment period. Subjects were randomly assigned to one of three treatment groups (A = orlistat 120 mg t.i.d. and ethanol placebo, B = orlistat 120 mg t.i.d. and 40 g ethanol qd on days -1 and 6, and 40 g bid on days 1-5, and C = orlistat placebo tid and 40 g ethanol qd on days -1 and 6, and 40 g b.i.d. on days 1 5). Serial blood samples were collected for determination of ethanol serum concentrations at specified times over 5 h after each dose of ethanol on days -1 and 6, and for determination of orlistat plasma concentrations on days 1, 3, 5, and 6. Feces were collected quantitatively on days -5 through 8 for analysis of fecal fat. RESULTS: The means of baseline-corrected fecal fat excretion values were comparable: 23.7 g for group A (orlistat) and 22.7 g for group B (orlistat and ethanol). No significant difference was found regarding ethanol pharmacokinetic parameters between treatments with orlistat and placebo. No apparent differences existed between the number of plasma samples with measurable orlistat concentrations in groups A and B. CONCLUSION: Concomitant ingestion of social amounts of ethanol did not alter the inhibitory effect of orlistat on dietary fat absorption during short-term treatment (6 days) with orlistat. Short-term treatment with orlistat had no significant influence on ethanol pharmacokinetics.

Adult↗
PubMed2006

Orlistat reduces gallbladder emptying by inhibition of CCK release in response to a test meal.

BACKGROUND AND AIMS: Orlistat is a covalent inhibitor of digestive lipase derived from lipstatin, the natural product of Streptomyces toxytricini. By blocking the active site of intestinal lipase, orlistat inhibits hydrolysis of dietary triglycerides and thus reduces the intestinal lipid absorption. It is uncertain whether intestinal inhibition of lipase by orlistat also interferes with nutrient-induced CCK release from intestinal I-cells. The aim of the present study was therefore to assess whether oral administration of orlistat inhibits CCK release in response to a test meal and thus causes impaired gallbladder emptying. METHODS: 22 healthy volunteers were given a test meal consisting of 200 ml dairy cream and two teaspoons of chocolate powder (552 kcal=2328 kJ; 56.0 g fat; 5.2 g proteins, 6.6 g carbohydrates), with and without oral application of 120 mg orlistat. Gallbladder volume was determined by ultrasound before and 5, 10, 20, 30 and 40 min after meal ingestion. In parallel, a venous blood sample was collected for the measurement of bioactive CCK. CCK activity was assessed using a bioassay with isolated rat pancreatic acini cells. RESULTS: Oral administration of orlistat significantly impairs gallbladder emptying. After ingestion of the test meal the gallbladder contracted by 78.5% in the control group, whereas the test group with orlistat only showed a contraction of 45.7% (p<0.01). Maximal contraction was reached after 35 to 40 min, the maximal gallbladder emptying was delayed up to 10 min by orlistat. Orlistat induced a significant reduction of bioactive CCK levels in response to a test meal (CCK(max) with orlistat=4.1 pmol/l; CCK(max) without orlistat=7.8 pmol/l). CCK levels were reduced by 47% and the onset of maximal CCK secretion was delayed up to 10 min. CONCLUSION: The inhibition of intestinal lipolytic activity by orlistat results in reduced gallbladder emptying through inhibition of meal-mediated CCK release. We therefore hypothesize that impaired gallbladder motility may represent a risk factor in chronic treatment of severe obesity using orlistat.

Administration, Oral↗
PubMed2001

A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity.

BACKGROUND: The prevalence of obesity in developed societies is increasing. Obesity is associated with an increased risk of co-morbidity, including cardiovascular disease and diabetes. Following the withdrawal of fenfluramine and dexfenfluramine, interest has focused on a novel anti-obesity drug orlistat. OBJECTIVE: To systematically assess the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity. METHODS - SEARCH STRATEGY: Nineteen electronic databases were searched from inception to June 2000. Additionally, Internet searches were carried out, bibliographies of retrieved articles were examined and submissions were received from the manufacturer of orlistat. METHODS - INCLUSION AND EXCLUSION CRITERIA: Randomised controlled trials (RCTs) evaluating the effectiveness of orlistat used for weight loss or maintenance of weight loss in overweight or obese patients were eligible for inclusion. Primary outcome measures were changes in body weight, fat content or fat distribution. Secondary outcomes were changes in obesity-related risk-factor profiles, such as lipid levels, indicators of glycaemic control and blood pressure. Studies recruiting people with eating disorders such as anorexia nervosa and bulimia nervosa were excluded. METHODS - PROCESS OF STUDY SELECTION: Assessment of titles and abstracts was performed independently by two reviewers. If either reviewer considered a reference to be relevant, the full paper was retrieved. Full papers were assessed against the review selection criteria by two independent reviewers, and disagreements were resolved through discussion. METHODS - DATA EXTRACTION: Data were extracted by one reviewer into structured summary tables and checked by a second reviewer. Any disagreements about data were resolved by discussion. METHODS - QUALITY ASSESSMENT: Each included trial was assessed against a comprehensive checklist for methodological quality. Quality assessment was performed independently by two reviewers with disagreements resolved by discussion. METHODS - METHODS OF ANALYSIS/SYNTHESIS: This report is a narrative summary, with results grouped according to study endpoint. Statistical pooling was undertaken in groups of trials that were considered to be sufficiently similar. METHODS - ESTIMATION OF QUALITY OF LIFE, COSTS AND COST-EFFECTIVENESS AND/OR COST PER QUALITY-ADJUSTED LIFE-YEAR: Relevant economic evaluations were identified from the search strategy described above. Assessment of methodological quality was undertaken using principles outlined in published guidelines. METHODS - COMPANY SUBMISSIONS: Data from company submissions were subject to the same selection and appraisal processes as other studies considered for inclusion in the review, except that only RCTs with a duration of at least 1 year were selected. RESULTS - RESULTS OF THE SEARCH STRATEGY: Fourteen RCTs (including three company submissions) and two economic evaluations (including one company submission) were included in the review. RESULTS - RESULTS OF THE QUALITY ASSESSMENT: Methodological quality of trials was moderate to good. The main problems were lack of detail on methods used to produce true randomisation, small sample sizes in some cases and failure to use intention-to-treat analysis. It is likely that maintenance of blinding was difficult due to adverse effects associated with the study medication. RESULTS - EVIDENCE OF CLINICAL EFFECTIVENESS AND COST-EFFECTIVENESS: Most of the trials showed greater weight loss and better weight maintenance with orlistat compared to placebo at all endpoints (statistically significant differences for both outcomes). Orlistat 120 mg three times daily was the optimum regimen in terms of weight loss. Most trials showed significant improvement in at least some lipid concentration parameters, and, in three RCTs, orlistat produced statistically significant reductions in blood pressure relative to placebo. In obese patients with type 2 diabetes, orlistat resulted in a significantly greater weight loss at 1 year compared with placebo, and some parameters of glycaemic control and lipid concentration also showed significantly greater improvements compared with placebo. The incidence of gastrointestinal adverse events was consistently higher in orlistat groups compared with placebo, and orlistat use was associated with lower serum levels of fat-soluble vitamins. The cost per quality-adjusted life-year for orlistat was 45,881 UK pounds. CONCLUSIONS - IMPLICATIONS FOR CLINICAL PRACTICE: Although many trials have demonstrated statistically significant differences between groups in terms of weight loss in favour of orlistat versus placebo, the differences may not always be of clinical significance. The clinical significance of between-group differences for secondary outcomes may also be debatable. Possible adverse effects should be taken into account when prescribing orlistat, particularly gastrointestinal effects. (ABSTRACT TRUNCATED)

Anti-Obesity Agents↗
PubMed2000

One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor.

OBJECTIVE: To assess the efficacy and tolerability of orlistat (Xenical) in producing and maintaining weight loss over a 12-month period. DESIGN: Patients were randomized to double-blind treatment with either orlistat 120 mg or placebo three times daily, in conjunction with a low-energy diet, for 12 months. SETTING: Five centres in the UK. SUBJECTS: 228 obese adult patients with body mass index between 30 and 43 kg/m2 and mean weight 97 kg (range 74-144 kg). INTERVENTIONS: All patients were prescribed a low-energy diet, providing 30% of energy from fat, designed to produce an individually tailored energy deficit of approximately 600 kcal/day, for a run-in period of 4 weeks and then 12 months, plus orlistat 120 mg or placebo three times daily. MAIN OUTCOME MEASURES: Change in body weight (the primary efficacy parameter), waist circumference and adverse events were reviewed regularly, together with serum lipids, insulin, glucose and plasma levels of fat-soluble vitamins and beta carotene. RESULTS: Based on an intent-to-treat analysis, after 1 y of treatment patients receiving orlistat had lost an average of 8.5% of their initial body weight compared with 5.4% for placebo-treated patients; 35% of the orlistat group lost at least 5% of body weight compared with 21% of the placebo group (P < 0.05), and 28% and 17%, respectively (P = 0.04) lost at least 10% of body weight. Orlistat-treated patients showed significant decreases (P < 0.05) in serum levels of total cholesterol, low density lipoprotein cholesterol, and in the low density lipoprotein: high density lipoprotein ratio in comparison with placebo. Both groups had similar adverse-event profiles, except for gastrointestinal events, which were 26% more frequent in the orlistat group but were mostly mild and transient. To maintain normal plasma levels of fat-soluble vitamins, supplements of vitamins A, D and E were given to 1.8%, 8.0% and 3.6%, respectively, of orlistat-treated patients, compared with 0.9% of placebo-treated patients for each vitamin type. After 1 y, the decrease in vitamin E and beta carotene was significantly greater in orlistat-treated patients compared with those receiving placebo (P < 0.001). No significant change was found in the mean vitamin E:total cholesterol ratio in either group after 52 weeks. CONCLUSIONS: Orlistat, in conjunction with a low-energy diet, produced greater and more frequent significant weight loss than placebo during 1 y of treatment. One-third of orlistat-treated patients achieved clinically relevant weight loss (> or = 5% initial body weight). There was also an improvement in relevant serum lipid parameters. Fat-soluble vitamin supplements may be required during chronic therapy. Orlistat was well tolerated and offers a promising new approach to the long-term management of obesity.

Adult↗
PubMed2001

The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled, multicentre study.

OBJECTIVE: Assessment of the effects of orlistat 120 mg three times daily vs placebo on weight loss and serum lipids in obese hypercholesterolemic patients. DESIGN: A 24 week multicentre, double-blind, randomized, placebo-controlled trial. After a 2-week single-blind run-in period (placebo+diet (-600 kcal/day; < or =30% of calories as fat)), 294 patients were submitted to the hypocaloric diet and randomly assigned to either orlistat 120 mg or placebo three times daily. Patients who completed the double-blind study (n=255) were eligible for participation in a subsequent 24 week open-label orlistat extension phase. SUBJECTS: Patients with body mass index (BMI) 27-40 kg/m2 and hypercholesterolemia (low-density-lipoprotein cholesterol, LDL-C, 4.1-6.7 mmol/l). MEASUREMENTS: Efficacy assessments included weight loss, lipid levels, other cardiovascular risk factors and anthropometric parameters. Safety assessments. RESULTS: Weight loss during run-in was similar in both groups. After randomization, orlistat-treated patients lost significantly more weight than placebo recipients: mean percentage weight loss from start of run-in to week 24 was-6.8% in the orlistat group and -3.8% in the placebo group (P<0.001). Moreover, more patients in the orlistat group than in the placebo group achieved clinically meaningful weight loss of > or =5% (64 vs 39%) or > or =10% (23 vs 13%) at week 24. Treatment with orlistat was associated with significantly greater changes in total cholesterol (-11.9% vs -4.0%; P<0.001) and LDL-C (-17.6 vs -7.6%; P<0.001). For any category of weight loss during the double-blind treatment period, change in LDL-C was more pronounced in orlistat-treated patients than in placebo recipients, indicating that orlistat had a direct cholesterol-lowering effect that was independent of weight reduction (P<0.001). Adjunction of orlistat during the extension phase in patients who initially received placebo induced a further decrease in weight, total cholesterol and LDL-C. Orlistat was generally well tolerated with a safety profile comparable to placebo, with the exception of a higher incidence of gastrointestinal events (> or =1 event in 64 vs 38% of patients). CONCLUSION: Orlistat as an adjunct to dietary intervention promotes weight loss and reduces LDL-C beyond the effect of weight loss in overweight or obese patients with concomitant hypercholesterolemia.

Adolescent↗
PubMed2005

Efficacy and safety comparative evaluation of orlistat and sibutramine treatment in hypertensive obese patients.

AIM: The aim of our study was to comparatively evaluate the efficacy and safety of orlistat and sibutramine treatment in obese hypertensive patients, with a specific attention to cardiovascular effects and to side effects because of this treatment. METHODS: Patients were enrolled, evaluated and followed at three Italian Centres of Internal Medicine. We evaluated 115 obese and hypertensive patients. (55 males and 60 females; 26 males and 29 females, aged 50 +/- 4 with orlistat; 28 males and 30 females, aged 51 +/- 5 with sibutramine). All patients took antihypertensive therapy for at least 6 months before the study. We administered orlistat or sibutramine in a randomized, controlled, double-blind clinical study. We evaluated anthropometric variables, blood pressure and heart rate (HR) during 12 months of this treatment. RESULTS: A total of 113 completed the 4 weeks with controlled energy diet and were randomized to double-blind treatment with orlistat (n = 55) or sibutramine (n = 58). Significant body mass index (BMI) improvement was present after 6 (p < 0.05), 9 (p < 0.02), and 12 (p < 0.01) months in both groups, and body weight (BW) improvement was obtained after 9 (p < 0.05) and 12 (p < 0.02) months in both groups. Significant waist circumference (WC), hip circumference (HC) and waist/hip ratio (W/H ratio) improvement was observed after 12 months (p < 0.05, respectively) in both groups. Significant systolic blood pressure (SBP) and diastolic blood pressure (DBP) improvement (p < 0.05) was present in orlistat group after 12 months. Lipid profile [total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and triglycerides] reduction (p < 0.05, respectively) was observed in orlistat group and triglyceride reduction (p < 0.05) in sibutramine group after 12 months. No significant change was observed in sibutramine group during the study. No significant HR variation was obtained during the study in both groups. Of the 109 patients who completed the study, 48.1% of patients in the orlistat group and 17.5% of patients in the sibutramine group had side effects (p < 0.05 vs. orlistat group). Side-effect profiles were different in the two treatment groups. All orlistat side effects were gastrointestinal events. Sibutramine caused an increase in blood pressure (both SBP and DBP) in two patients, but it has been controlled by antihypertensive treatment. The vitamin changes were small and all mean vitamin and beta-carotene values stayed within reference ranges. No patients required vitamin supplementation. CONCLUSIONS: Both orlistat and sibutramine are effective on anthropometric variables during the 12-month treatment; in our sample, orlistat has been associated to a mild reduction in blood pressure, while sibutramine assumption has not be associated to any cardiovascular effect and was generically better tolerated than orlistat.

Analysis of Variance↗
PubMed1999

Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial.

CONTEXT: Orlistat, a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, may promote weight loss and reduce cardiovascular risk factors. OBJECTIVE: To test the hypothesis that orlistat combined with dietary intervention is more effective than placebo plus diet for weight loss and maintenance over 2 years. DESIGN: Randomized, double-blind, placebo-controlled study conducted from October 1992 to October 1995. SETTING AND PARTICIPANTS: Obese adults (body mass index [weight in kilograms divided by the square of height in meters], 30-43 kg/m2) evaluated at 18 US research centers. INTERVENTION: Subjects received placebo plus a controlled-energy diet during a 4-week lead-in. On study day 1, the diet was continued and subjects were randomized to receive placebo 3 times a day or orlistat, 120 mg 3 times a day, for 52 weeks. After 52 weeks, subjects began a weight-maintenance diet, and the placebo group (n = 133) continued to receive placebo and orlistat-treated subjects were rerandomized to receive placebo 3 times a day (n = 138), orlistat, 60 mg (n = 152) or 120 mg (n = 153) 3 times a day, for an additional 52 weeks. MAIN OUTCOME MEASURES: Body weight change and changes in blood pressure and serum lipid, glucose, and insulin levels. RESULTS: A total of 1187 subjects entered the protocol, and 892 were randomly assigned on day 1 to double-blind treatment. For intent-to-treat analysis, 223 placebo-treated subjects and 657 orlistat-treated subjects were evaluated. During the first year orlistat-treated subjects lost more weight (mean +/- SEM, 8.76+/-0.37 kg) than placebo-treated subjects (5.81+/-0.67 kg) (P<.001). Subjects treated with orlistat, 120 mg 3 times a day, during year 1 and year 2 regained less weight during year 2 (3.2+/-0.45 kg; 35.2% regain) than those who received orlistat, 60 mg (4.26+/-0.57 kg; 51.3% regain), or placebo (5.63+/-0.42 kg; 63.4% regain) in year 2 (P<.001). Treatment with orlistat, 120 mg 3 times a day, was associated with improvements in fasting low-density lipoprotein cholesterol and insulin levels. CONCLUSIONS: Two-year treatment with orlistat plus diet significantly promotes weight loss, lessens weight regain, and improves some obesity-related disease risk factors.

Adult↗
PubMed2005

Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial.

CONTEXT: The prevalence of overweight and obesity in children and adolescents is increasing rapidly. In this population, behavioral therapy alone has had limited success in providing meaningful, sustained weight reduction, and pharmacological treatment has not been extensively studied. OBJECTIVE: To determine the efficacy and safety of orlistat in weight management of adolescents. DESIGN, SETTING, AND PATIENTS: Multicenter, 54-week (August 2000-October 2002), randomized, double-blind study of 539 obese adolescents (aged 12-16 years; body mass index [BMI] >or=2 units above the 95th percentile) at 32 centers in the United States and Canada. INTERVENTIONS: A 120-mg dose of orlistat (n = 357) or placebo (n = 182) 3 times daily for 1 year, plus a mildly hypocaloric diet (30% fat calories), exercise, and behavioral therapy. MAIN OUTCOME MEASURES: Change in BMI; secondary measures included changes in waist and hip circumference, weight loss, lipid measurements, and glucose and insulin responses to oral glucose challenge. RESULTS: There was a decrease in BMI in both treatment groups up to week 12, thereafter stabilizing with orlistat but increasing beyond baseline with placebo. At the end of the study, BMI had decreased by 0.55 with orlistat but increased by 0.31 with placebo (P = .001). Compared with 15.7% of the placebo group, 26.5% of participants taking orlistat had a 5% or higher decrease in BMI (P = .005); 4.5% and 13.3%, respectively, had a 10% or higher decrease in BMI (P = .002). At study end, weight had increased 0.53 kg with orlistat and 3.14 kg with placebo (P<.001). Dual-energy x-ray absorptiometry showed that this difference was explained by changes in fat mass. Waist circumference decreased in the orlistat group but increased in the placebo group (-1.33 cm vs +0.12 cm; P<.05). Generally mild to moderate gastrointestinal tract adverse events occurred in 9% to 50% of the orlistat group and in 1% to 13% of the placebo group. CONCLUSIONS: In combination with diet, exercise, and behavioral modification, orlistat statistically significantly improved weight management in obese adolescents compared with placebo. The use of orlistat for 1 year in this adolescent population did not raise major safety issues although gastrointestinal adverse events were more common in the orlistat group.

Adolescent↗
PubMed2003

Weight management and current options in pharmacotherapy: orlistat and sibutramine.

BACKGROUND: Chronic obesity is associated with various cardiovascular disorders, including diabetes, dyslipidemia, and hypertension. Pharmacotherapy with antiobesity agents is an important management strategy in conjunction with lifestyle interventions. OBJECTIVE: This article describes the pharmacologic management of obesity, concentrating on orlistat and sibutramine. METHODS: Relevant articles were identified through a MEDLINE search (1966-February 2002) using the terms obesity, overweight, weight loss, antiobesity drugs, orlistat, and sibutramine. The search for efficacy trials was limited to randomized controlled studies of >6 months' duration. Also included in the review were relevant references cited in the bibliographies of identified articles, news reports, and the authors' own data. RESULTS: Orlistat reduces fat absorption by inhibiting gastrointestinal lipases. In randomized, controlled trials of up to 2 years' duration, orlistat plus a hypocaloric diet produced significantly greater weight loss than placebo (P < 0.001). In the maintenance phase, patients taking orlistat had less weight regain than did placebo recipients. The weight reduction with orlistat was also associated with a significant improvement in control of cardiovascular risk factors (P < 0.05). Unlike orlistat, sibutramine works by suppressing appetite; its efficacy, however, was similar to that of orlistat in the identified clinical trials. Orlistat was associated primarily with gastrointestinal side effects. Use of orlistat was associated with minimal drug interactions, except with cyclosporine, with which it should not be taken. Sibutramine was also well tolerated, although it may cause dry mouth, anorexia, and insomnia, and should be used with caution in patients at risk for cardiovascular disease. CONCLUSIONS: Orlistat and sibutramine demonstrated a favorable efficacy and safety profile in randomized controlled trials. Current evidence supports their use as adjuncts to lifestyle modifications in the treatment of obesity.

Anti-Obesity Agents↗
PubMed2001

Gastrointestinal side effects of orlistat may be prevented by concomitant prescription of natural fibers (psyllium mucilloid).

OBJECTIVES: This placebo-controlled open study was designed to test the hypothesis that most of the gastrointestinal (GI) side events induced by treatment of obese patients with orlistat (a gastrointestinal lipase inhibitor) could be prevented or ameliorated by concomitant use of natural fibers (psyllium mucilloid). DESIGN: Two groups of obese women (BMI>27 kg/m(2)) were treated with orlistat 120 mg three times a day. One group (A, n=30) was randomized to receive orlistat and, approximately 6.0 g of orange-flavored psyllium mucilloid dissolved in water and the other group (B, n=30) received orlistat and orange-flavored placebo. At the end of 30 days and 2 weeks of washout, group A switched to placebo and group B received psyllium while continuing orlistat three times a day. SUBJECTS: Sixty professional women, more than 21-y-old with a body mass index (BMI) between 27.3 and 48.0 kg/m(2), who were not receiving any other medication. MEASUREMENTS: Assessments included weekly visits to attending physician, filling a form in which GI events were recorded, monthly measurements of body weight, blood pressure and serum lipids. The frequency and severity of GI events were evaluated by a score system, based on information provided by the patients. RESULTS: Both groups A and B significantly lost (P<0.01) weight after 60 days of orlistat (A=96.8 to 94.9 kg and B=98.7 to 96.5 kg). Similarly, BMI values declined significantly in both groups. While in the psyllium plus orlistat group (group A) the mean +/-s.e.m. of the scores reflecting GI events was 13.0+/-1.8, the placebo plus orlistat group (B) had a value of 35.9+/-2.7 (P<0.01). When the reverse situation was instituted the placebo and orlistat group presented a mean score of 36.1+/-3.6 and the psyllium plus orlistat a mean score of 8.9+/-1.5 (P<0.01). CONCLUSIONS: Psyllium hydrophilic mucilloid concomitantly prescribed to obese patients receiving 120 mg of orlistat three times a day is an effective and safe adjunct therapy that is helpful in controlling the GI side effects of this pancreatic lipase inhibitor.

Adult↗
PubMed2003

Latin-American trial of orlistat for weight loss and improvement in glycaemic profile in obese diabetic patients.

AIM: To determine if obese non-insulin-dependent diabetic patients lose more weight when treated for 24 weeks (6 months) with orlistat (120 mg t.i.d.), in conjunction with a hypocaloric diet plus behavioural counselling, than when treated by placebo (t.i.d.) plus similar instructions. The secondary objectives were to evaluate the effects on glucose profile and to determine the tolerability and safety of orlistat. DESIGN: Double-blind, parallel, randomized, placebo-controlled, multicentre study. SUBJECTS: Obese, non-insulin-dependent diabetic patients, aged 18-70 years old, with BMI > 27 kg/m2, evaluated at 10 Latin-American centres, in five countries. EFFICACY AND TOLERABILITY MEASUREMENTS: After screened, eligible patients passed by a 2-week placebo run-in period receiving a hypocaloric diet. On day 0, patients were randomized to orlistat or placebo for 24 weeks. At each visit, body weight, blood pressure and waist circumference were measured. At the screening visit, baseline visit (week 0), and at weeks 8, 16 and 24, a central laboratory was in charge of measuring fasting glucose and insulin, HbA1c, postprandial glucose and insulin, fasting total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and postprandial triglycerides. Other safety laboratory assessments were measured locally at the screening visit, baseline visit and at the end of the study. Adverse events were assessed at each visit from baseline. RESULTS: After 24 weeks of treatment, the orlistat group lost an average of 4.7% of initial body weight vs. 3.0% in the placebo group (p = 0.0003). A greater weight loss was achieved in the orlistat compared with the placebo group (4.24 +/- 0.23 vs. 2.58 +/- 1.46 kg, p = 0.0003). Almost twice as many patients receiving orlistat (30% vs. 17%) lost > or = 5% of initial body weight (p = 0.003). Orlistat treatment plus diet compared to placebo plus diet was associated with significant improvement in glycaemic control, as reflected in decreases in HbA1c (p = 0.04), fasting plasma glucose (p = 0.036) and postprandial glucose (p = 0.05). Orlistat-treated patients had a mean decrease in glucose levels of 1.00 +/- 0.34 mmol/l [3.7%] vs. 0.01 +/- 0.30 mmol/l for placebo group, at week 24 and an absolute decrease of HbA1c of 0.61 +/- 0.15 vs. a decrease of 0.22 +/- 0.14% in the placebo group. Orlistat therapy also resulted in significantly greater improvements than placebo in lipid profile, with reductions in total cholesterol (p = 0.0001) and LDL-cholesterol (p = 0.002). Mild to moderate transient gastrointestinal events were reported, mainly with orlistat treatment, but their association with withdrawal from the study was low. CONCLUSION: Orlistat is a useful and an effective therapy in obese diabetic patients, promoting clinically significant weight loss and improved glycaemic control and lipid profile.

Adolescent↗