Use of orlistat in obese, dyslipidemic patients

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1 Future Lipidology ISSN: (Print) (Online) Journal homepage: Use of orlistat in obese, dyslipidemic patients Robert Nelson & John Miles To cite this article: Robert Nelson & John Miles (2006) Use of orlistat in obese, dyslipidemic patients, Future Lipidology, 1:3, To link to this article: Copyright 2006 Future Medicine Ltd Published online: 18 Jan Submit your article to this journal Article views: 139 Full Terms & Conditions of access and use can be found at

2 DRUG EVALUATION Use of orlistat in obese, dyslipidemic patients Robert H Nelson & John M Miles Author for correspondence Endocrine Research Unit, Jo 5 194, Mayo Clinic, 200 First St SW, MN, USA Tel.: ; Fax: ; miles.john@mayo.edu Keywords: dyslipidemia, orlistat, Type 2 diabetes, weight loss Obesity is associated with dyslipidemia, Type 2 diabetes and an increased risk of cardiovascular disease. Orlistat has been shown to be an effective adjunct to diet and exercise to promote weight loss. This article surveys recent literature regarding the effects of orlistat on lipids in obese, dyslipidemic patients. It is concluded that orlistat lowers total cholesterol, low-density lipoprotein cholesterol and triglycerides. Evidence that orlistat may have a pharmacological effect on lipids independent of weight loss is also discussed. Obesity has been linked to a number of chronic illnesses, including cardiovascular disease (CVD), Type 2 diabetes mellitus (DM), cancer and chronic respiratory disease. These conditions account for over 50% of all deaths worldwide [1]. Dyslipidemia is a comorbidity of obesity that is also linked independently to CVD and DM [2]. Obesity-related chronic diseases require a strategy of prevention, including efforts to reduce weight in overweight (body mass index [BMI] kg/m 2 ) and obese (BMI 30.0 kg/m 2 ) individuals. Multiple studies demonstrate that treating overweight and obesity by diet and exercise is usually unsuccessful in the long-term due to weight regain [3]. Using pharmacotherapy as an adjunct to conventional therapy has been shown to improve both total weight reduction and weight-loss maintenance. Considerable evidence demonstrates that even modest weight loss (5 10%) can have a positive impact on Type 2 DM as well as improving dyslipidemia [3]. Overview of the market The WHO estimates that over 1 billion adults in the world today are overweight, and at least 300 million are obese [101]. There has been considerable interest in identifying effective, safe and economical ways of achieving weight reduction and preventing weight regain. Currently, only two prescription drugs have been shown to be effective and are approved in the USA and Europe for use in treatment of overweight and obese individuals: Sibutramine (Meridia ) and orlistat (Xenical ). Orlistat has been approved in over 140 countries for weight management [103]. Other agents, including rimonabant and axokine, are in various stages of investigation [4]. Owing to side effects and a past history of market withdrawals, there has been poor acceptance of pharmacological agents for long-term use in the treatment of obesity [5]. Despite these obstacles, observers of the pharmaceutical industry believe that a safe and effective drug could be worth US$25 50 billion annually within 10 years [6]. Introduction to the compound Orlistat (tetrahydrolipstatin) is an inhibitor of gastrointestinal lipases. Multiple studies have demonstrated that it enhances weight loss achieved by lifestyle modification [5,7]. A longterm study over 4 years demonstrated that it is effective in helping individuals who have lost weight to maintain their target weight [8]. There is no evidence that it has major harmful effects, and its side effects (primarily gastrointestinal) have been well described. Chemistry Orlistat is known chemically as S-2formylamino- 4-methyl-pentanoic acid S-1-[[(2S,3S)-3-hexyl- 4-oxo-2-oxetanyl]methyl]-dodecyl ester. It is an off-white powder with a molecular weight of Da. The drug is insoluble in water but dissolves readily in organic solvents. It has no pka within physiological ph range [102]. Its structural formula is shown in Figure 1. Pharmacokinetics & metabolism Orlistat inhibits gastrointestinal lipase, resulting in reduced hydrolysis of dietary triglyceride (TG) and decreased dietary fat absorption. The recommended dose of orlistat is 120 mg given orally three-times daily in conjunction with meals. Fecal fat studies show a reduction in total fat absorption of approximately 30%. The drug is poorly absorbed systemically, with greater than 95% of a single dose recovered in feces and only 1 2% recovered in urine, primarily as inactive metabolites. Orlistat should be given as an adjunct to a low-fat (<30% of calories), reduced calorie diet and increased physical activity / Future Medicine Ltd ISSN Future Lipidol. (2006) 1(3),

3 DRUG EVALUATION Nelson & Miles Figure 1. Orlistat. H 3 C Taken from [102]. Proper patient selection and education are necessary to prevent excessive side effects and poor adherence (Box 1) [102]. Clinical efficacy All published studies that investigate the efficacy of orlistat include a low-fat, calorie-restricted diet in both the active treatment and the placebo groups. A recent systematic review and metaanalysis summarizes the evidence for orlistat s effectiveness in this context [7]. More recent studies address its effects on the clinical lipid profile TG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and LDL-C:HDL-C ratio. These studies have been conducted in both nondiabetic and diabetic subjects. A meta-analysis of randomized clinical trials of orlistat identified 11 studies that included changes in TC and LDL-C as secondary end points, nine that included HDL-C and eight that included TG [9]. Analysis of pooled data was performed by dividing study subjects into three groups: obese patients with low CV risk, obese patients with high CV risk and diabetic patients. The significant treatment effects favoring orlistat over placebo in the three groups are displayed in Table 1. Analysis of the pooled data showed that orlistat-assisted weight loss of 5 10% helps improve the serum lipid profile. Box 1. Pharmacokinetics and metabolism of orlistat. Mechanism of action Systemic absorption Dose response relationship Recommended dose H 3 C O CH 3 H N H OH O O Inhibits gastrointestinal lipase resulting in decreased fat absorption by ~30% <5%, no evidence of systemic lipase inhibition [30] Nonlinear with maximum effect at 360 mg/day [31] 120 mg three-times a daily O CH 3 A study by Muls and colleagues supports a pharmacological lipid-lowering effect of orlistat independent of weight loss [10]. This was a 6-month, multicenter, randomized, placebocontrolled trial (RCT) of obese patients with hypercholesterolemia. Subjects were randomized to placebo (n = 147) or orlistat (n = 147). A total of 255 subjects completed the study (127 on placebo, 128 on orlistat). At 24 weeks, the orlistat group showed a significantly greater decrease in plasma concentrations of TC (-5.5 vs +2.8%) and LDL-C (-10.7 vs -0.7%) compared with placebo (both p < 0.001). The placebo group had a significant increase in HDL-C compared with the orlistat-treated patients (+12.0 vs +5.1%, p < 0.001), whereas there was no significant difference between orlistat and placebo in change in TG or LDL-C:HDL-C ratio. Analysis of LDL-C change by weight change category (changes ranging from weight gain to >10% weight loss) demonstrated a greater decrease in orlistat patients compared with placebo-treated patients (Figure 2), suggesting that orlistat has a direct LDL-C-lowering effect, independent of weight loss. Another study examined the effects of orlistat on cholesterol absorption in 18 subjects with abdominal obesity using a dual stable isotope tracer technique [11]. Orlistat treatment caused a 25% reduction in cholesterol absorption (p <0.01). The exact mechanism responsible for this effect is unclear. However, the findings suggest that reduced cholesterol absorption may contribute to beneficial effects on lipoprotein metabolism in obese subjects treated with orlistat that are independent of weight loss by itself. Derosa and colleagues conducted a 1-year, double-blind RCT of 99 obese patients with hypercholesterolemia [12]. Subjects were assigned randomly to placebo, orlistat, fluvastatin or orlistat with fluvastatin. At 1 year, there were significant reductions from baseline in TC, LDL-C and TG in the active treatment groups. Also at 1 year, HDL-C was significantly higher than baseline in the fluvastatin and orlistat/fluvastatin groups. Between-group analysis using analysis of variance and two-sample t-tests showed significant reduction of TC and LDL-C in the orlistat/fluvastatin group (p < 0.01 vs placebo, p < 0.02 vs orlistat and p < 0.05 vs fluvastatin) at 1 year. These results indicate that orlistat has synergistic, beneficial effects on lipids when used in combination with fluvastatin. A recent study examined the effect of orlistat on postprandial lipemia, nuclear magnetic resonance 268 Future Lipidol. (2006) 1(3)

4 Orlistat DRUG EVALUATION Table 1. Significant difference between orlistat and placebo in change from baseline at 1 year. Lipid parameter Nondiabetic Diabetic subjects Low risk High risk Total cholesterol LDL-C HDL-C LDL-C:HDL-C Triglycerides : p < 0.05; -: NS. HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol. Data taken from [9]. lipoprotein subclass profiles and particle size [13]. The investigators studied ten healthy males under three conditions: orlistat with a high-fat meal, orlistat with a medium-fat meal and placebo with a high-fat meal. They found that the 8 h mean TG area under the curve was significantly lower in both orlistat groups compared with placebo (p = 0.02). Analysis of particle size also showed significant differences. The study demonstrated that orlistat lowers postprandial TG, shortens the time of postprandial lipemia, lowers the concentration of large TG-rich particles and decreases the size of very-low-density lipoprotein (VLDL) particles. These findings are important due to the effect these parameters have on the risk of atherosclerosis [14 16]. A recent study by Hsieh and colleagues examined the effects of orlistat compared with placebo on parameters associated with the metabolic syndrome [17]. They randomized 106 obese men and women who had satisfactorily completed a 1-year weight reduction program to orlistat (n = 51) or placebo (n = 55). After 1 year, the orlistat group had significantly greater improvements in BMI, percentage body fat, waist circumference, insulin resistance and high-sensitivity C-reactive protein as compared with placebo. Significant changes were found in serum leptin (p = 0.001) and adiponectin (p = 0.027), independent of changes in percentage body fat and waist circumference. Tan and colleagues conducted a singledose study of the effects of orlistat (120 mg) on postprandial glucose, lipids, remnant lipoproteins and free fatty acids (FFA) [18]. The study involved 63 overweight patients with Type 2 DM and utilized a randomized, double-blind, placebo-controlled crossover design. There was a significantly greater reduction in postprandial plasma TG (p < ), remnant lipoprotein cholesterol (p = 0.003) and FFA (p < ) with orlistat compared with placebo. A group of double-blind, randomized, controlled clinical trials of at least 1 year duemonstrated a beneficial effect of orlistat in obese diabetic subjects when used as an adjunct to a low-fat, reduced calorie diet and increased exercise. These trials included studies of patients taking sulfonylureas [19,20], metformin [21,22] and insulin [23]; all of them confirm favorable effects of orlistat on TC and LDL-C. Only one study showed significant change in TG [19]. The longest duration study to date is the XENical in the prevention of DM in Obese subjects Study (XENDOS), which randomized 1650 obese subjects with impaired fasting glucose to orlistat and 1655 to placebo and followed them for 4 years [8]. Orlistat reduced the incidence of new-onset DM and also Figure 2. Average percent change in LDL-C in six different weight loss categories among patients taking orlistat or placebo. LDL-C (Δ %) Placebo Orlistat *p < versus placebo. Estimated from data provided in [10]. LDL-C: Low-density lipoprotein cholesterol

5 DRUG EVALUATION Nelson & Miles Table 2. Orlistat studies in diabetic or glucose-intolerant subjects. Author Study length* (subjects, n ) Hollander weeks (322) Kelley weeks (550) Miles weeks (516) Hanefeld & Sachse weeks (383) Group Total cholesterol p-value LDL-C p-value # HDL-C p-value TG p-value # Treatment Placebo ± 0.06 < ± 0.06 < ± ± Sulfonylureas Orlistat ± ± ± ± 0.07 Placebo +2.6 ± 1.2% ± 1.9% ± 1.3% ± 3.7% Insulin Orlistat -4.7 ± 1.1% -9.1 ± 1.5% +4.0 ± 1.3% ± 3.4% Placebo +2.6 ± 1.0% < ± 2.7% ± 1.45% Orlistat -4.1 ± 0.9% -2.8 ± 2.3% ± 1.52% ± 3.6% Metformin ± sulfonylureas 0.8 ± 2.8% Placebo +1.8 ± 1.6% < ± 2.6% < ± 1.8 % <0.01 Values not reported NS Sulfonylureas or no drugs Berne weeks (220) Torgerson (XENDOS) Orlistat -2.3 ± 1.2% -2.0 ± 1.9% +0.6 ± 1.5% Placebo ± 0.11 (+1.9%) Orlistat ± 0.10 (-4.4%) ± 0.09 (+0.3%) ± 0.09 (-2.6%) NS ± 0.02 (+5.8%) ± 0.02 (-0.8%) ± 0.23 (-1.4%) 0.12 ± 0.10 ( 4.6%) NS Metformin ± sulfonylureas 4 years (3305) Placebo -2.3% < % < % < % NS No treatment (IGT) Orlistat -7.9% -12.8% +6.5% +2.4% *Study length refers to placebo lead followed by randomization (x + y weeks). Subject number is total number of subjects randomized. Data are presented as % change from baseline except for the Hollander and Berne studies, which presented data in mmol/l. The % changes in the Berne study are estimated from mean baseline values. # p-values calculated from change from baseline, orlistat vs placebo. Studies presented are intent to treat analyses. HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; NS: Not significant; TG: Triglycerides. 270 Future Lipidol. (2006) 1(3)

6 Orlistat DRUG EVALUATION significantly decreased TC and LDL-C, proving consistency with other trials [19 23]. All of these studies found that orlistat treatment produces a significantly greater and sustained reduction in weight and in CV risk factors, including dyslipidemia, than treatment with lifestyle modification alone. Details of these studies are provided in Table 2. The difference in the change in apolipoprotein B concentrations was measured in one study [22], with significant differences between orlistat and placebo (-0.08 ± 0.02 vs ± 0.02 g/l, respectively; p = ). Swinburn and colleagues investigated the effect of orlistat on the predicted 10-year CV risk in obese subjects with one or more pre-existing risk factors who were randomized to orlistat (n = 170) or placebo (n = 169) [24]. Significant differences in TC (p = ) and LDL-C (p = 0.006) were observed favoring orlistat, whereas changes in TG and HDL-C were not significant. Despite significant improvements in TC and LDL-C, as well as in serum glucose, glycated hemoglobin and systolic blood pressure (BP), the 10-year risk of CVD calculated from the Framingham equation [25] was not statistically improved. It is possible that this discrepancy could be due to a lack of sensitivity of the Framingham equation to changes in modifiable risk factors due to the weight given to nonmodifiable risk factors, such as age and sex. Other risk algorithms, such as prospective cardiovascular Munster heart (PROCAM) and CUORE [26], were not utilized in the analysis. In the studies summarized above, orlistat consistently produced reductions in TC that were significantly greater than observed with placebo. Most studies also demonstrated a significantly greater reduction in LDL-C with orlistat. Although changes in HDL-C were inconsistent, changes in LDL-C:HDL-C ratio usually favored orlistat. Changes in TG were also inconsistent. There is a suggestion in some clinical trials and in single-dose fat absorption studies that the effects of orlistat on lipids may be to some extent independent of weight reduction. It is not known whether these improvements in lipids result in decreased morbidity and mortality from CVD. The only ongoing prospective studies of the effects of weight loss on CVD in obese individuals (other than studies of bariatric surgery patients) are the Look AHEAD trial [27] and a recently registered Phase III trial of the effects of sibutramine ( A long-term study of sibutramine and the role of obesity management in relation to cardiovascular disease in overweight and obese patients ) that will follow subjects to their first CVD event [104]. Regulatory affairs Orlistat was approved for use in Europe in 1998 and in the USA for adults in Since then, no significant problems have been identified. The only major change has been the approval of orlistat for use in obese adolescents of age 12 or greater. Safety & tolerability Orlistat has been a safe drug, with no reported problems other than its known gastrointestinal (GI) side effects (e.g., oily stools, staining of undergarments, flatulence). These side effects can be minimized by careful patient selection and formal instruction by a registered dietitian in the need to avoid excess dietary fat. When the side effects occur, they are generally the direct consequence of excessive fat intake. When a patient has difficulty with side effects, daily use of psyllium may be helpful [28]. The manufacturer s product information recommends multivitamin supplementation with orlistat due to the reduced absorption of some fat-soluble vitamins and β-carotene [102]. The frequency of abnormally low fat-soluble vitamin levels in orlistattreated adults who are not given vitamin supplementation is 2% for vitamin A and 8% for vitamin D [29]. A major drug interaction has been identified with cyclosporine, thus the drugs should not be used concurrently [102]. Judging long-term safety has been made more difficult by the high dropout rate seen in weight-loss studies of more than weeks in duration. However, careful analysis of dropout data reveals that, in many studies, the dropout rate was higher in placebo groups than in orlistat groups [8,19,21,23], possibly due to orlistat s enhanced weight-loss effect. It would therefore appear that, if a subject perceives value in study participation, that individual would be more likely to continue. Conclusion Orlistat has been shown to be an effective adjunct to treat obese and overweight patients along with diet and lifestyle modification. It has favorable effects on dyslipidemia, especially TC and LDL-C reduction. Its effect on TG has been variable, but there may be significant reduction of TG in patients with Type 2 DM. Whether or not these short-term beneficial effects will lead to reductions in long-term CVD mortality remains 271

7 DRUG EVALUATION Nelson & Miles to be demonstrated. Orlistat remains primarily a drug for weight loss and there is insufficient evidence to advocate its use for primary treatment of dyslipidemia. Future perspective Obesity is a worldwide epidemic. Owing to increased morbidity and mortality associated with obesity, especially CVD, there is an urgent requirement for treatments that result in beneficial (5 10%) weight loss sustainable for more than 3 5 years. This will necessitate creative thinking regarding obesity treatment, including public policy changes to encourage healthy eating and increased activity, and research into the biological mechanisms that promote obesity and obesity-related disease. Considering the difficulties in changing individual behaviors, new drugs, and more educated use of existing drugs, will be an important part of treatment. The overall strategy needs to include weight loss in those who are overweight or obese, treatment of obesity comorbidities and effective weight-gain prevention in those who are not overweight. Executive summary Mechanism of action Inhibition of gastrointestinal lipases, resulting in up to 30% reduction in fat absorption. Pharmacokinetic properties Minimal systemic absorption (<5%). No need to adjust dose in renal or hepatic disease. Significant drug interaction with cyclosporine. May inhibit vitamin K absorption; patients on warfarin should have close laboratory monitoring when initiating or stopping orlistat therapy. Clinical efficacy Significantly greater weight loss with orlistat compared with diet and lifestyle modification alone. Recent systematic review and meta-analysis of 11 studies that monitored change in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Nine studies assessed change in high-density lipoprotein cholesterol (HDL-C) and eight determined change in triglyceride (TG). Orlistat helps lower TC and LDL-C in all subjects and helps lower TG in diabetic patients. Five recent studies of obese, nondiabetic subjects have shown decreases in TC, four found lowered LDL-C, two reported increased HDL-C, three demonstrated decreased TG and one showed beneficial changes in adiponectin and leptin. Single-dose studies have shown decreased cholesterol absorption and decreased postprandial plasma TG, suggesting a drug effect independent of weight loss. Seven randomized, controlled trials in obese diabetic subjects all found improvement in TC and LDL-C. Safety & tolerability Main side effects are gastrointestinal and can be avoided if the drug is used in conjunction with a low-fat diet. Indicated in adults and in adolescents 12 years of age or more. Dosage & administration Use as adjunct to diet and exercise. 120 mg three-times daily during or up to 1 h after a meal Supplemental multivitamin containing fat-soluble vitamins and β-carotene. Should be given at least 2 h prior to taking orlistat. Bibliography Papers of special note have been highlighted as either of interest ( ) or of considerable interest ( ) to readers. 1. Yach D, Leeder S, Bell J, Kistnasam B: Global chronic diseases. Science 307, 317 (2005). 2. Poirier P, Giles TD, Bray GA et al.: Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 113, (2006). 3. Stern JS, Hirsch J, Blair SN et al.: Weighing the options: criteria for evaluating weightmanagement programs. The committee to develop criteria for evaluating the outcomes of approaches to prevent and treat obesity. Obes. Res. 3, (1995). 4. Bays HE: Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes. Res. 12, (2004). 5. Finer N: Pharmacotherapy of obesity. Best Pract. Res. Clin. Endocrinol. Metab. 16, (2002). 6. Orenstein S: The pill that will make you thin. Business 2.0 5, (2004). 7. Padwal R, Li SK, Lau DC: Long-term pharmacotherapy for overweight and obesity: a 272 Future Lipidol. (2006) 1(3)

8 Orlistat DRUG EVALUATION systematic review and meta-analysis of randomized controlled trials. Int. J. Obes. Relat. Metab. Disord. 27, (2003). Comprehensively reviews the evidence for orlistat s efficacy for weight reduction. 8. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L: 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. Diabetes Care 27, (2004). Landmark study in diabetes prevention and the longest study of orlistat. 9. Hutton B, Fergusson D: Changes in body weight and serum lipid profile in obese patients treated with orlistat in addition to a hypocaloric diet: a systematic review of randomized clinical trials. Am. J. Clin. Nutr. 80, (2004). Overviews evidence for the beneficial effects of orlistat in aiding lipid reduction. 10. 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Websites 101 Diet, nutrition and the prevention of chronic diseases: report of a joint WHO/FAO expert consultation whqlibdoc.who.int/trs/who_trs_916.pdf Excellent resource for those interested in the global scope of the obesity problem Orlisat (Xenical ) complete product information About Xenical a 104. A long-term study of sibutramine and the role of obesity management in relation to cardiovascular disease in overweight and obese patients Affiliations Robert H Nelson Endocrine Research Unit, Jo 5-194, Mayo Clinic, 200 First St. SW, MN, USA nelson.robert1@mayo.edu John M Miles Endocrine Research Unit, Jo 5-194, Mayo Clinic, 200 First St. SW, MN, USA Tel.: ; Fax: ; miles.john@mayo.edu 273