Recent Advances in the Use of Orlistat in the ...

Download PDF
2 downloads 0 Views 162KB Size Report
Comment
to cetilistat, a novel inhibitor of gastrointestinal and pan- creatic lipases. In that study, there was a 4.4 cm decrease in waist circumference after 12 weeks in the ...
JOURNAL OF CLINICAL METABOLISM & DIABETES

REVIEW ARTICLE

Recent Advances in the Use of Orlistat in the Treatment of Abdominal Obesity and Associated Cardiometabolic Risk Factors Kaj Stenlo¨ f Affiliation: Department for Clinical Research, The Sahlgrenska University Hospital, Gothenburg, Sweden

A B S T R A C T Obesity is a serious health concern in several parts of the world. During the last few years, the prevalence of abdominal obesity has attracted specific attention, as abdominal obesity and visceral obesity are associated with several important metabolic disturbances and explain most of the increased risk for cardiovascular disease (CVD) associated with obesity. Thus, in the clinical evaluation of obese patients with an increased risk for CVD, it is important to aim to reduce abdominal fat. Lifestyle interventions, including diet and physical activity, should be first-line treatments; however, pharmaceutical agents might also be considered. Not surprisingly, abdominal and visceral obesity are important targets for drug development. Orlistat is an existing pharmacological agent available for the long-term treatment of obesity. This drug inhibits gastric and pancreatic lipase degradation of triglycerides in the intestine, such that ingested triglycerides cannot be hydrolyzed or absorbed. Orlistat has been investigated in several large studies that demonstrated its efficacy and safety, and is currently available in more than 120 countries, with more than 20 million doses having been distributed worldwide. The purpose of this report is to provide a short review of the available data regarding the effects of orlistat on abdominal obesity and associated metabolic disturbances. Keywords: abdominal obesity, orlistat, hyperglycemia, dyslipidemia, hypertension, atherosclerosis, cardiovascular disease Correspondence: Kaj Stenlo¨ f, Department for Clinical Research, The Sahlgrenska University Hospital, Gro¨na stra˚ket 12, SE-413 45 Gothenburg, Sweden. Tel: 46 31 342 10 00; Fax: 46 31 41 93 68; e-mail: [email protected]

Three different mechanisms have been proposed to explain how increased intra-abdominal fat is related to an increased risk for metabolic abnormalities [5]. (1) The insulin-resistant, hypertrophic fat in the visceral region could increase the exposure of the liver to free fatty acids, leading to hyperinsulinemia, glucose intolerance, and hypertriglyceridemia. (2) Intra-abdominal fat could function as an endocrine organ that produces several factors to generate an insulinresistant, pro-inflammatory, pro-thrombotic, and pro-hypertensive milieu. (3) Intra-abdominal fat could be a marker of dysfunctional or absent subcutaneous fat, indicating an increase in ectopic fat deposition in several locations.

INTRODUCTION A large proportion of the population in western society today has a sedentary lifestyle and easy access to energy-dense food that can be consumed in large amounts. This environment leads to a positive energy balance and an increased risk for the development of obesity. Obesity (defined as a body mass index (BMI) above 30 kg/m2) has become a major health problem in several parts of the world and has overtaken smoking as the leading preventable cause of premature death [1]. Even though BMI has been a useful measurement in defining obesity, it has become increasingly obvious that it is insufficiently precise in identifying the cardiovascular risk of obese patients. Recent large epidemiological studies in the US and Europe have pointed out the importance of body composition measurements, and specifically the evaluation of abdominal obesity. In these studies, measurements of obesity, such as waist circumference, have been more strongly associated with cardiovascular events and death than BMI [2, 3]. Furthermore, intra-abdominal obesity is more closely associated with major metabolic complications including the key components of the metabolic syndrome: dyslipidemia, hypertriglyceridemia, and hypertension. When the International Diabetes Foundation presented their revised definition of the metabolic syndrome, abdominal obesity was included as a prominent component [4].

JCMD 2010; 000:(000). Month 2010

In the clinical evaluation of obese patients with an increased risk for cardiovascular disease, it is important to aim to reduce intra-abdominal fat. Lifestyle interventions, including diet and physical activity, should be first-line treatments; however, weight-loss drugs might also be considered as valuable additional treatment options. Orlistat (tetrahydrolipstatin) is a pharmacological agent available for the long-term treatment of obesity. It is a derivative of lipstatin and inhibits gastric and pancreatic lipase degradation of triglycerides in the intestine. Due to this inhibition, triglycerides cannot be hydrolyzed and absorbed as free fatty acids, causing them to be excreted unmetabolized through the gastrointestinal channel. The effect of the drug, therefore, is to both reduce the uptake and increase the excretion of fat. Orlistat is

1

www.slm-jcmd.com

Journal of Clinical Metabolism & Diabetes

prescribed at a dose of 120 mg tid (blocking approximately 30% of ingested fat from being absorbed) or sold over-thecounter at a dose of 60 mg tid (blocking approximately 25% of ingested fat from being absorbed). Orlistat has been investigated in several large studies that have demonstrated its efficacy and safety, and it is currently available in more than 120 countries, with more than 40 million doses having been distributed worldwide (www.fda.gov/Drugs/, May 2010). The purpose of the present report is to provide a short review of the available data regarding the effects of orlistat on abdominal obesity and associated metabolic disturbances.

orlistat at 120 mg tid, while a decrease of 3.2 cm was observed in the placebo group [7]. In a Cochrane review [8] of nine studies with a total of 2457 treated subjects, orlistat significantly reduced waist circumference by 2.1 cm more than the placebo (2.9 to 1.3 cm). All studies, apart from one, included subjects with abdominal obesity based on waist circumference and at least one additional known cardiovascular risk factor (eg, dyslipidemia, hypertension, type 2 diabetes, or impaired glucose tolerance (IGT)). In the larger Xendos study, 21% of the patients had IGT. All of the studies included used a dosage regimen of 120 mg tid.

MATERIALS AND METHODS

In a recently published separate meta-analysis by Jacob et al [9] that evaluated long-term orlistat treatment in subjects with pharmacological treatment for type 2 diabetes, the reduction in waist circumference was significantly larger (by 2.2 cm) in the orlistat-treated group compared to the placebo group.

In this meta-analysis, review articles and randomized clinical trials were identified in MEDLINE and Cochrane database searches. These searches were performed to identify publications describing the effects of orlistat. All reference lists of the identified publications were also evaluated to identify additional publications of interest. One person (KS) selected the publications included, and the validity of the selected publications was determined based on group size, study design, and generalizability. When available, data from the metaanalysis are presented as weighted mean differences and 95% confidence intervals. All studies reported are for orlistat 120 mg unless otherwise noted.

One large controlled study by Chanoine et al [10] evaluated the effects of orlistat treatment on abdominal obesity in adolescents. In that study, 539 obese adolescents aged 1216 years were treated with orlistat for 54 weeks. Despite an increase in BMI, waist circumference was reduced by 1.3 cm in the orlistat-treated group and increased by 0.1 cm in the placebo-treated group. Two studies evaluated the effects of orlistat on maintaining a reduced waist circumference. In one maintenance study, 479 subjects on placebo or orlistat at 120 mg tid were studied during a 1-year maintenance diet after a 1-year period of weight loss. During the maintenance period, there was a 1.6and 1.1-cm regain in waist circumference in the placebo and orlistat groups, respectively. After 2 years, waist circumference was significantly lower (by 2 cm) in the orlistat-treated group compared to the placebo-treated group [11].

RESULTS Abdominal obesity The effects of orlistat on abdominal obesity have mostly been studied by exploring anthropometric measurements such as waist circumference. Imaging techniques such as computed tomography have only been used in a few studies. Short-term studies are available that show a decrease in waist circumference after just 12 weeks of orlistat treatment. Furthermore, the long-term effects have been evaluated in several large clinical trials showing that orlistat reduces waist circumference by approximately 2 cm more than placebo. Orlistat treatment is effective in reducing abdominal obesity in both adults and adolescents, and maintenance studies using either regular or low-energy diets have shown that the reduction in abdominal obesity is better maintained with orlistat treatment than with placebo.

In a randomized trial including subjects with abdominal obesity and at least one cardiovascular risk factor who had lost 5% or more of their initial body weight during an 8-week period of a very low energy diet (VLED) (600800 kcal/day), patients (309 of 383) were randomized to receive orlistat or placebo during a 3-year maintenance period [12]. After one year, waist circumference remained unchanged in the orlistat group, while it had increased by 3 cm in the placebo group. After 3 years, the orlistat-treated group had regained 4.3 cm, while the placebo group had regained 3.6 cm, and the maintained waist circumference was 2.3 cm lower in the orlistat group than in the placebo group.

The short-term effects of orlistat treatment on waist circumference have been examined in two studies. In one randomized, open-label study by Aydin et al [6], the observed decrease in waist circumference was strongly associated with a decrease in BMI, and orlistat treatment was associated with a larger decrease in waist circumference per decrease in BMI units than comparable treatments (diet or sibutramine).

The effects of orlistat on abdominal obesity without a hypocaloric diet were evaluated in a recently published openlabel, prospective cohort study in which 60 obese Chinese subjects with or without diabetes were treated with orlistat at 120 mg tid. Despite only a 2-kg weight loss at 6 months, waist circumference decreased by 5.4 cm in the non-diabetic group and by 3.8 cm in the diabetic group [13].

In another recent double-blind, randomized short-term clinical trial, orlistat was included as an active comparator to cetilistat, a novel inhibitor of gastrointestinal and pancreatic lipases. In that study, there was a 4.4 cm decrease in waist circumference after 12 weeks in the group treated with JCMD 2010; 000:(000). Month 2010

Few controlled studies have evaluated the effects of orlistat on abdominal obesity using imaging techniques. Tiikkainen 2

www.slm-jcmd.com

Orlistat in the treatment of abdominal obesity and cardiometabolic risk factors

et al analyzed the effects of orlistat on abdominal obesity using magnetic resonance imaging in 47 female subjects [14]. Despite similar weight changes in the two groups, the ratio of intra-abdominal fat to subcutaneous fat decreased significantly more in the orlistat-treated group compared to the placebo group.

treatment reduced the incidence of type 2 diabetes by 5.7% compared to placebo treatment (10.9 vs. 5.2%) during the observation period.

Hypertension The long-term effects of orlistat on blood pressure in hypertensive patients were reviewed in a recently published Cochrane publication that included unpublished subgroup analysis of hypertensive patients from the Xendos study (diastolic blood pressure ]90 mmHg at baseline), and three other randomized, placebo-controlled trials (total n 2058) [17]. Orlistat treatment was shown to reduce systolic and diastolic blood pressure by 2.5 mmHg (4.0 to 0.9 mmHg) and 1.9 mmHg ( 3.0 to 0.9 mmHg) more than the placebo, respectively.

ASSOCIATED METABOLIC DISTURBANCES Insulin resistance and type 2 diabetes The effects of orlistat on glycemic control in type 2 diabetes were recently evaluated in a meta-analysis presenting pooled data from seven large, double-blind, multicenter trials [9]. In total, 2550 subjects with type 2 diabetes treated with orlistat at 120 mg tid or placebo from 6 to 12 months were included in the analysis. Patients were treated with various combinations of anti-diabetic treatments, including metformin, sulfonylureas, and insulin. Treatment with orlistat significantly reduced the fasting plasma glucose by 0.92 mmol/L more than the placebo. Orlistat also provided significantly larger mean decreases in HbA1c compared to the placebo (0.74% vs. 0.31%). For patients (n 375) with minimal weight loss (51% of baseline body weight), orlistat provided a significantly greater decrease in both fasting plasma glucose (FPG) (0.81 mmol/L) and HbA1c (0.15%). In the orlistat group, 6.8% more patients were able to improve or reduce their anti-diabetic medication, and 10.3% fewer patients needed new anti-diabetic treatments compared to the placebo group. Orlistat improved FPG within just the first 4 weeks, and this effect was maintained throughout the study period. Body weight gradually decreased during the total study period, with only minimal change during the first 4 weeks. Based on these results, orlistat treatment was suggested to improve glycemic control independent of weight loss.

Dyslipidemia The beneficial effects of orlistat on fasting and postprandial blood lipids have been demonstrated in several large clinical trials. The acute effects of a single dose of orlistat at 120 mg were evaluated in a study of 63 overweight subjects with type 2 diabetes. Orlistat was shown to have a positive effect on postprandial lipidemia (ie, lower plasma triglycerides, total cholesterol, and free fatty acids) [18]. A separate study showed that this postprandial effect was maintained through at least 6 months of follow-up [19]. The long-term effects of orlistat on fasting serum lipid fractions were described in a Cochrane review [8], which found that orlistat reduced total cholesterol by 0.32 mmol/L (0.28 to 0.37 mmol/L, 13 studies), LDL cholesterol by 0.26 mmol/L (0.22 to 0.30 mmol/L, 13 studies), and HDL cholesterol by 0.03 mmol/L (0.02 to 0.04 mmol/L, 11 studies). The reduction in triglycerides ( 0.03 mmol/L, 11 studies) was not significant compared to placebo.

Recovery and prevention of type 2 diabetes in subjects with impaired glucose tolerance

In a separate Cochrane review of orlistat treatment in type 2 diabetes, orlistat was associated with significant improvements in total cholesterol, LDL, and triglycerides, and these effects were sustained after 52 weeks of follow-up [20].

The effects of a low calorie diet and orlistat were studied in pooled data from three 2-year clinical studies [15] (n 675). In an identified subgroup with IGT (n 120), glucose levels normalized in a larger proportion of subjects receiving orlistat treatment (71.6%) compared to placebo (49.1%). In addition, fewer subjects progressed to a diabetic status in the orlistat group (3.0%) compared to the placebo group (7.6%).

The effects of orlistat on dyslipidemia were further analyzed in another meta-analysis. In that report, Orlistat significantly reduced total cholesterol by 0.43 mmol/L (0.28 to 0.57 mmol/L, n 2679), LDL cholesterol by 0.34 mmol/L (0.32 to 0.36 mmol/L, n 2679), triglycerides by 0.08 mmol/L (0.06 to 0.10, n 1581), and HDL cholesterol by 0.06 mmol/L (0.01 to 0.11 mmol/L, n 1799). It was concluded that orlistat significantly improves serum lipid levels regardless of whether additional co-morbidities such as type 2 diabetes are present [21].

The prevention of type 2 diabetes was also studied in two additional studies. In the larger Xendos study, which included 3305 subjects with either normal orIGT, there was a 2.8% lower incidence of diabetes in the total group and a 5.9% lower incidence in the IGT group after 4 years of treatment with diet plus orlistat or placebo [16].

In a more recent meta-analysis of 5760 patients taking orlistat (14 years of treatment), it was confirmed that orlistat improves dyslipidemia and that the reduction in total cholesterol is independent of the percentage weight loss [22].

In a study by Richelsen et al, the prevention of type 2 diabetes in subjects with metabolic risk factors was studied over a 3-year diet restriction period after VLED [12]. Orlistat

www.slm-jcmd.com

3

JCMD 2010; 000:(000). Month 2010

Journal of Clinical Metabolism & Diabetes

In a study by Filippatos et al, the effects of orlistat on HDL subfractions and pre-beta HDL1 were examined in a small sample prescribed a low fat diet [23]. That study showed that orlistat significantly increased large HDL-C and pre-beta HDL1 levels and significantly decreased small HDL-C levels. In separate studies, it was also shown that orlistat decreased small dense LDL cholesterol (sdLDL-C) levels and the activity of lipoprotein-associated phospholipase A2 (Lp-PLA2) [24].

diet. Long-term studies, however, have failed to show a maintained effect of orlistat on eating behavior or dietary fat intake [33]. In contrast, some experimental studies have shown that orlistat can have negative effects on satiety. When orlistat was administrated during a test meal in healthy volunteers, accelerated gastric emptying and impaired gallbladder emptying were observed. Under those experimental conditions, orlistat increased prospective food consumption [34]. Taken together, it is unclear what long-term effects orlistat has on food intake.

Orlistat also provides additional benefits for blood lipids when combined with other lipid-lowering drugs such as ezetimibe [25] or fenofibrate [26]. The relevance of the lipidlowering effect of orlistat, however, might be less clear when orlistat is used in combination with LCD [12] or in subjects already on lipid-lowering therapy [7].

DISCUSSION As abdominal obesity increases, there is a graded increase in the risk of cardiovascular disease (CVD) and myocardial infarction [2]. Recently published results from large epidemiological studies have concluded that the risk assessment for cardiovascular disease should be based on measurements such as waist circumference rather than, or at least in addition to, measurements of general obesity [2, 3]. Central obesity is considered to be an essential component across ethnic groups and an early step in the cascade leading to fullblown metabolic syndrome [5].

Atherogenesis No study is available demonstrating the effects of orlistat treatment on cardiovascular morbidity and mortality. Over the last couple of years, however, multiple experimental and clinical trials have provided data supporting the idea that orlistat treatment reduces additional pro-inflammatory factors and improves overall cardiovascular risk. In the Xendos study, 4-year treatment with orlistat was associated with improvements in plasma fibrinogen and plasminogen activator inhibitor-1 [16]. Orlistat treatment has also been associated with a decrease in CRP and IL-6 and an increase in adiponectin [2729].

Few studies are available that directly examine the effects of visceral fat. Most have instead used anthropometric measurements such as waist circumference or visceral obesity. Although waist circumference has become an established and useful measure of abdominal obesity, it is clear that waist measurements are subject to significant inter-operator variability [35]. Better training could improve the accuracy of measurement, but imaging techniques (eg, MRI and CT) should be considered in future studies of orlistat to quantify the effects on visceral fat and/or other related ectopic fat depositions.

Furthermore, in a study on 71 female subjects randomly assigned to diet and orlistat, or diet alone during a 6-month period, orlistat treatment reduced several pro-inflammatory factors, and this effect was independent of weight change [30]. Apart from the effects on these various markers, a 6-month randomized controlled study examined the effects of orlistat on oxidative stress measured by serum human paraoxonase enzyme 1 (PON1) activity in 139 subjects treated with diet plus orlistat or placebo. Orlistat treatment was shown to increase serum PON1 activity, suggesting decreased atherogenesis [31].

When evaluating cardiovascular risk in obese patients, it is necessary to have a multi-risk assessment strategy and to consider pharmacological options such as orlistat in addition to lifestyle modifications. Although orlistat provides significant benefits, the observed effects are generally small. It is reasonable, therefore, to suggest that future evaluations of lipase inhibition in the treatment of obese patients with increased CVD risk consider the use of orlistat in pharmacological combinations with additive or synergistic effects.

The mechanism by which orlistat affects the production of adipose tissue-derived pro-inflammatory factors is still unknown. It has been demonstrated, however, that lipopolysaccharides (LPS) derived from gut bacteria are potent triggers for adipose tissue to produce some of the inflammatory factors that are elevated in patients with increased cardiovascular risk. In a recently published report examining 31 subjects with IGT, who were treated with diet plus orlistat or diet alone for one year, Dixon et al showed that orlistat significantly reduced serum LPS levels [32]. This decrease in LPS levels was associated with an increase in adiponectin levels.

Even though a systematic review of the available data from clinical trials found that the use of orlistat to treat obesity is cost-effective [36], compliance with orlistat treatment is frequently reported to be an issue. Lipase inhibition is associated with an increased risk of gastro-intestinal side effects such as loose stools and oily spotting. In large longterm studies, such as the Xendos study with its high overall attrition rate, however, 18% more patients completed the 4-year treatment protocol in the orlistat group compared to the placebo group [16]. The observed compliance issue is thus likely related to obesity treatment in general rather than to the use of orlistat in particular. It has been suggested that if the use of orlistat were redirected from weight loss to the

Food intake Orlistat acts as a gastrointestinal tract lipase inhibitor that blocks the intestinal absorption of ingested fat. In addition, it may, at least initially, improve adherence to a low fat JCMD 2010; 000:(000). Month 2010

4

www.slm-jcmd.com

Orlistat in the treatment of abdominal obesity and cardiometabolic risk factors

treatment of cardiometabolic risk, adherence would potentially improve [25, 37].

13.

In conclusion, this review summarizes the current knowledge of the effects of the lipase inhibitor orlistat on abdominal obesity. It is also clear from this report that orlistat treatment not only reduces abdominal fat but also is associated with significant improvements in various metabolic variables such as hyperglycemia, dyslipidemia, and hypertension. Orlistat has also shown promising effects on atherosclerotic pro-inflammatory markers and lipid oxidation. Taken together, these data suggest that lipase inhibition is a valuable treatment option in reducing overall cardiovascular risk in subjects with abdominal obesity, and outcome studies should be considered.

14.

15.

16.

17.

Disclosure: The author is an employee at the Sahlgrenska University Hospital, Gothenburg, Sweden and does not have any competing interests.

18.

Funding: The author has also received funding for clinical trials from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co, Janssen-Cilag, and Sanofi-Aventis.

19.

Acknowledgements: This research was funded in part by strategic regional research funding from the Va¨ straGo¨taland region.

20.

21.

REFERENCES 1. Haomiao J, Erica IL. Trends in Quality-Adjusted Life-Years Lost Contributed by Smoking and Obesity. Am J Prev Med. 2010;38(2): 138144. 2. Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet. 2005;366(9497):16401649. 3. Pischon T, Boeing H, Hoffmann K, et al. General and abdominal adiposity and risk of death in Europe. N Engl J Med. 2008;359(20): 21052120. 4. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome*a new worldwide definition. Lancet. 2005;366(9491):10591062. 5. Despres JP, Lemieux I, Bergeron J, et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol. 2008;28(6):10391049. 6. Aydin N, Topsever P, Kaya A, Karasakal M, Duman C, Dagar A. Orlistat, sibutramine, or combination therapy: which performs better on waist circumference in relation with body mass index in obese patients? Tohoku J Exp Med. 2004;202(3):173180. 7. Kopelman P, de HGG, Rissanen A, et al. Weight loss, HbA(1c) reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (Xenical). Obesity (Silver Spring) 2010;18(1):108115. 8. Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev. 2003(4):CD004094. 9. Jacob S, Rabbia M, Meier MK, Hauptman J. Orlistat 120 mg improves glycaemic control in type 2 diabetic patients with or without concurrent weight loss. Diabet Obes Metab. 2009;11(4):361371. 10. Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J. Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial. Jama. 2005;293(23):28732883. 11. Rossner S, Sjostrom L, Noack R, Meinders AE, Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes Res. 2000;8(1):4961. 12. Richelsen B, Tonstad S, Rossner S, et al. Effect of orlistat on weight regain and cardiovascular risk factors following a very-low-energy diet in

www.slm-jcmd.com

22.

23.

24.

25.

26.

27.

28.

29. 30.

31.

5

abdominally obese patients: a 3-year randomized, placebo-controlled study. Diabetes Care. 2007;30(1):2732. Tong PC, Lee ZS, Sea MM, et al. The effect of orlistat-induced weight loss, without concomitant hypocaloric diet, on cardiovascular risk factors and insulin sensitivity in young obese Chinese subjects with or without type 2 diabetes. Arch Intern Med. 2002;162(21):24282435. Tiikkainen M, Bergholm R, Rissanen A, et al. Effects of equal weight loss with orlistat and placebo on body fat and serum fatty acid composition and insulin resistance in obese women. Am J Clin Nutr. 2004;79(1):2230. Heymsfield SB, Segal KR, Hauptman J, et al. Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch Intern Med. 2000;160(9):13211326. 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. Diabet Care. 2004;27(1):155161. Siebenhofer A, Horvath K, Jeitler K, et al. Long-term effects of weightreducing drugs in hypertensive patients. Cochrane Database Syst Rev. 2009(3):CD007654. Tan KC, Tso AW, Tam SC, Pang RW, Lam KS. Acute effect of orlistat on post-prandial lipaemia and free fatty acids in overweight patients with Type 2 diabetes mellitus. Diabet Med. 2002;19(11):944948. Kelley DE, Kuller LH, McKolanis TM, Harper P, Mancino J, Kalhan S. Effects of moderate weight loss and orlistat on insulin resistance, regional adiposity, and fatty acids in type 2 diabetes. Diabet Care. 2004;27(1):3340. Norris SL, Zhang X, Avenell A, Gregg E, Schmid CH, Lau J. Pharmacotherapy for weight loss in adults with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005(1):CD004096. 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. 2004; 80(6):14611468. Mannucci E, Dicembrini I, Rotella F, Rotella CM. Orlistat and sibutramine beyond weight loss. Nutr Metab Cardiovasc Dis. 2008;18(5): 342348. Filippatos TD, Liberopoulos EN, Kostapanos M, et al. The effects of orlistat and fenofibrate, alone or in combination, on high-density lipoprotein subfractions and pre-beta1-HDL levels in obese patients with metabolic syndrome. Diabet Obes Metab. 2008;10(6):476483. Filippatos TD, Gazi IF, Liberopoulos EN, et al. The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis. 2007;193(2):428437. Florentin M, Kostapanos MS, Nakou ES, Elisaf M, Liberopoulos EN. Efficacy and safety of ezetimibe plus orlistat or rimonabant in statinintolerant nondiabetic overweight/obese patients with dyslipidemia. J Cardiovasc Pharmacol Ther. 2009;14(4):274282. Filippatos TD, Kiortsis DN, Liberopoulos EN, Georgoula M, Mikhailidis DP, Elisaf MS. Effect of orlistat, micronised fenofibrate and their combination on metabolic parameters in overweight and obese patients with the metabolic syndrome: the FenOrli study. Curr Med Res Opin. 2005;21(12):19972006. Valsamakis G, McTernan PG, Chetty R, et al. Modest weight loss and reduction in waist circumference after medical treatment are associated with favorable changes in serum adipocytokines. Metabolism. 2004;53(4):430434. Yesilbursa D, Serdar A, Heper Y, et al. The effect of orlistat-induced weight loss on interleukin-6 and C-reactive protein levels in obese subjects. Acta Cardiol. 2005;60(3):265269. Hsieh CJ, Wang PW, Liu RT, et al. Orlistat for obesity: benefits beyond weight loss. Diabet Res Clin Pract. 2005;67(1):7883. Bougoulia M, Triantos A, Koliakos G. Effect of weight loss with or without orlistat treatment on adipocytokines, inflammation, and oxidative markers in obese women. Hormones (Athens) 2006;5(4):259269. Audikovszky M, Pados G, Seres I, et al. Orlistat increases serum paraoxonase activity in obese patients. Nutr Metab Cardiovasc Dis. 2007;17(4):268273.

JCMD 2010; 000:(000). Month 2010

Journal of Clinical Metabolism & Diabetes

35. Panoulas VF, Ahmad N, Fazal AA, et al. The inter-operator variability in measuring waist circumference and its potential impact on the diagnosis of the metabolic syndrome. Postgrad Med J. 2008;84(993):344347. 36. Neovius M, Narbro K. Cost-effectiveness of pharmacological anti-obesity treatments: a systematic review. Int J Obes. (Lond) 2008;32(12):17521763. 37. Fabricatore AN, Wadden TA, Moore RH, et al. Attrition from randomized controlled trials of pharmacological weight loss agents: a systematic review and analysis. Obes Rev. 2009;10(3):333341.

32. Dixon AN, Valsamakis G, Hanif MW, et al. Effect of the orlistat on serum endotoxin lipopolysaccharide and adipocytokines in South Asian individuals with impaired glucose tolerance. Int J Clin Pract. 2008;62(7): 11241129. 33. Svendsen M, Helgeland M, Tonstad S. The long-term influence of orlistat on dietary intake in obese subjects with components of metabolic syndrome. J Hum Nutr Diet. 2009;22(1):5563. 34. Ellrichmann M, Ritter PR, Otte JM, et al. Orlistat reduces gallbladder emptying by inhibition of CCK release in response to a test meal. Regul Pept. 2007;139(13):136140.

JCMD 2010; 000:(000). Month 2010

6

www.slm-jcmd.com