Cholesterol lowering effect of dietary weight loss and orlistat treatment - Efficacy and limitations

Department of Internal Medicine II, Technical University of Munich, Munich, Germany.
Alimentary Pharmacology & Therapeutics (Impact Factor: 5.73). 07/2004; 19(11):1173-9. DOI: 10.1111/j.1365-2036.2004.01966.x
Source: PubMed


Orlistat reduces energy uptake by the impairment of fat digestion and some evidence indicates it also lowers plasma cholesterol.
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.
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.
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%.
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.

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Available from: Gerald Klose, Nov 07, 2014
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    • "Clinical studies in obese patients acknowledged the contribution of an additional, yet to be identified, mechanism(s) to the decreased levels of plasma cholesterol. Erdmann and colleagues have reported that orlistat prevents the digestion of approximately 30% of the ingested fat (Erdmann et al., 2004), which is associated with 15–25% reduction in cholesterol plasma levels (Erdmann et al., 2004; Mittendorfer et al., 2001). The authors of these studies concluded that orlistat lowers plasma cholesterol beyond its effect on weight loss associated with digestion inhibition. "
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    ABSTRACT: The known mechanism by which orlistat decreases the absorption of dietary cholesterol is by inhibition of intestinal lipases. The aim of this study was to investigate the ability of orlistat to limit cholesterol absorption by inhibition of the cholesterol transport protein Niemann-Pick C1-like 1 (NPC1L1) as another mechanism of action. In situ rat intestinal perfusion studies were conducted to study the effect of orlistat on jejunal cholesterol absorption. Inhibition kinetic parameters were calculated from in vitro inhibition studies using Caco2 and NPC1L1 transfected cell lines. The in situ studies demonstrated that intestinal perfusion of orlistat (100µM) was able to reduce cholesterol absorption by three-fold when compared to control (i.e. in the absence of orlistat, P<0.01). In vitro studies using Caco2 cells demonstrated orlistat to reduce the cellular uptake of cholesterol by 30%. Additionally, orlistat reduced the cellular uptake of cholesterol in dose dependent manner in NPC1L1 transfected cell line with an IC50=1.2µM. Lineweaver-Burk plot indicated a noncompetitive inhibition of NPC1L1 by orlistat. Beside the already established mechanism by which orlistat reduces the absorption of cholesterol, we demonstrated for the first time that orlistat limits cholesterol absorption by the inhibition of NPC1L1 transport protein. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jun 2015 · European journal of pharmacology
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  • Article: Orlistat
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    ABSTRACT: Orlistat is an inhibitor of gastrointestinal lipases and, therefore, prevents the absorption of dietary fat. This agent reduces weight in obese adults and adolescents with or without comorbidities (including type 2 diabetes mellitus, hypercholesterolaemia, hypertension, metabolic syndrome) who received up to 4 years of therapy in conjunction with a hypocaloric diet. In obese patients, orlistat in combination with a hypocaloric diet improved metabolic risk factors and reduced the risk of developing type 2 diabetes. Furthermore, this agent was cost effective in patients with obesity, particularly those with type 2 diabetes. Orlistat is generally well tolerated, with gastrointestinal adverse events being most commonly reported. Orlistat, in addition to lifestyle and dietary intervention, is thus an attractive option for the treatment of patients with obesity, especially those with associated comorbidities or at risk of developing type 2 diabetes. Pharmacological Properties| Orlistat potently and selectively inhibits gastric and pancreatic lipases, thereby preventing the hydrolysis of dietary fat. Consequently, the absorption of dietary fat is inhibited, with increased faecal fat excretion. This agent also decreases postprandial gastric acid secretion, gastric emptying and cholecystokinin release in response to a meal. Orlistat has a beneficial effect on several metabolic parameters, including plasma lipid levels, measurements of glycaemic control, blood pressure, plasma leptin and haemostatic factors. It is not associated with significant changes in fat-free mass or resting energy expenditure. Orlistat prevents weight loss-induced reductions in biliary composition. Absorption of oral orlistat is minimal, with no evidence of accumulation after long-term administration. Orlistat is rapidly eliminated and excreted primarily in the faeces. With the exception of ciclosporin (cyclosporin), there are no clinically relevant drug interactions between orlistat and other commonly coadministered agents. Therapeutic Use| In obese patients treated with a mildly hypocaloric diet for the first year, bodyweight was reduced to a significantly greater extent with orlistat than placebo in large well designed trials (5–10% vs 2–7%). In the XENDOS (XENical in the prevention of Diabetes in Obese Subjects) trial (all patients received lifestyle and dietary intervention), the between-group difference in weight reduction was still significant after 4 years of treatment (5% vs 3%; p < 0.001). In this trial, orlistat also reduced the risk of developing type 2 diabetes by 37.3% compared with placebo; the risk reduction in patients with impaired glucose tolerance was 45%. In obese patients with type 2 diabetes, weight reduction was significantly greater with up to 1 year's treatment with orlistat (4–6%) than with placebo (1–4%). In obese and overweight adolescents, 1 year of orlistat treatment was significantly more effective than placebo in reducing body mass index, waist circumference and fat mass. Orlistat improved aspects of quality of life to a significantly greater extent than placebo in obese patients. Weight reduction of ≥5% after 12 weeks of orlistat treatment, but not weight reduction ≥2.5kg during a 4-week placebo plus hypocaloric diet lead-in period, was predictive of subsequent weight loss during long-term orlistat therapy. Orlistat was significantly more effective than placebo in improving metabolic risk factors in obese patients with one or several comorbidities (including type 2 diabetes, hypercholesterolaemia, hypertension or metabolic syndrome). Generally, orlistat, compared with placebo, significantly improved levels of total cholesterol, low-density lipoprotein-cholesterol, glycosylated haemoglobin, fasting and postprandial insulin, fasting and postprandial glucose and systolic and/or diastolic blood pressure in these patients. Orlistat was considered cost effective in the management of obese patients with type 2 diabetes, according to two long-term cost-effectiveness analyses. Incremental costs per event-free life year gained were €3462–19 986 (depending on level of complication) or $US8327. Tolerability| Orlistat was generally well tolerated in obese patients, with or without type 2 diabetes, in well controlled trials of up to 4 years' duration. The tolerability profile of orlistat in obese and overweight adolescents was similar to that in obese adults. Gastrointestinal adverse events were most commonly reported with orlistat therapy and were generally mild and transient. The incidence of mild-to-moderate hypoglycaemia was higher in obese patients with type 2 diabetes treated with orlistat than placebo; however, no patients required medical intervention. Decreases in plasma levels of fat-soluble vitamins occurred with orlistat therapy, although levels generally remained within the normal reference range.
    No preview · Article · Dec 2004 · Drugs
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