Int J Clin Pract 2006 May; 60(5): 590-4 (Read article online)

Gruber A, Nasser K, Smith R, Sharma JC, Thomson GA

Over the past years, there has been an explosive increase in the prevalence of type 2 diabetes (T2DM) and this is expected to continue, entailing associated morbidity and mortality. An increasing number of studies explore the different ways T2DM could be prevented. On-going lifestyle modifications need to be addressed. High-risk patients should be given counselling on weight loss, possibly using a low glycaemic index diet, with a target of around 7-10% over 6-12 months, as well as instruction for increasing physical activity to around 150 min of physical exercise weekly (NNT = 4-8). Moderate alcohol consumption and coffee consumption may also be of benefit (NNT = 89 and 66, respectively). Metformin (NNT = 14), acarbose (NNT = 11) and troglitazone (NNT = 6) have been shown to prevent/delay T2DM and angiotensin-converting enzyme (ACE) inhibitors and statins appear to have an adjunctive role (NNT = 42 and 112, respectively). Trials with orlistat and bariatric surgery have also prevented T2DM (NNT = 36 and 6, respectively), and forthcoming treatment with GLP1 mimetics appears promising. Diabetes prevention studies should help create well-defined strategies for screening and treating high-risk populations in the real world, as prevention is our only chance to alleviate the ever growing burden of diabetes mellitus in the world.

Curr Med Res Opin 2006 May; 22(5): 873-883 (Read article online)

Athyros VG, Mikhailidis DP, Didangelos TP, Giouleme OI, Liberopoulos EN, Karagiannis A, Kakafika AI, Tziomalos K, Burroughs AK, Elisaf MS

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS). There is no established treatment for NAFLD.AIM: To evaluate a multifactorial intervention in the treatment of NAFLD.METHODS: A prospective, open-label, randomised study in non-diabetic patients (n = 186) with MetS (follow-up: 54 weeks). All patients had both biochemical and ultrasonographic evidence of NAFLD at baseline. Other causes of liver disease were excluded. Patients received lifestyle advice and treatment for hypertension (mainly inhibitors of the renin-angiotensin system), impaired fasting glucose (metformin), obesity (orlistat) and dyslipidaemia [randomly allocated to atorvastatin 20 mg/day (n = 63) or micronised fenofibrate 200 mg/day (n = 62) or both drugs (n = 61)]. Liver ultrasonography was assessed at baseline and at the end of the study.RESULTS: At the end of treatment, 67% of patients on atorvastatin, 42% on fenofibrate and 70% on combination treatment no longer had biochemical plus ultrasonographic evidence of NAFLD (p < 0.05 vs. baseline for all comparisons). The percentage of patients who no longer had evidence of NAFLD was significantly higher (p < 0.009) in the atorvastatin and combination groups compared with the fenofibrate group. This effect was independently related to drug treatment, as well as to reductions in high-sensitivity C-reactive protein, waist circumference, body weight, triglycerides, low-density lipoprotein-cholesterol, total cholesterol, systolic blood pressure and glucose. Four patients discontinued treatment because of adverse effects.CONCLUSIONS: Multifactorial intervention in MetS patients with both biochemical and ultrasonographic evidence of NAFLD offsets surrogate markers of NAFLD (i.e. elevated aminotransferase plus echogenic liver).

Ann Ital Chir 2005 Sep-Oct; 76(5): 407-11 (Read article online)

Guagnano MT, Manigrasso MR, Capani F, Davì G

The prevalence of obesity has reached epidemic dimension in industrialized countries and it is known that obesity is associated with increased risk of cardiovascular morbidity and mortality. Commonly, obesity is defined by the Body Mass Index (BMI). However, BMI fails to consider body fat distribution. The relationship between the risk of metabolic-cardiovascular diseases and body fat distribution indices such as the waist-to-hip ratio (WHR) and the waist circumference, rather than measures of the degree of body fatness as expressed by BMI, has long been recognized. Recently, clinical and epidemiological research has found waist circumference to be the best anthropometric indicator of both total body fat and intra-abdominal fat mass. Android or visceral obesity is associated with metabolic syndrome and increased cardiovascular morbidity and mortality through a variety of molecular mechanisms possibly linking the metabolic syndrome to hemostatic and vascular abnormalities. Obesity guidelines suggest the need for weight reduction using behavioural change to reduce caloric intake and increasing physical activity. A realistic goal for weight reduction is to reduce body weight by 5% to 10% over a period of 6 to 12 months. Combined intervention of a low calories diet, increased physical activity, and behaviour therapy provides better outcomes for long-term weight reduction and weight maintenance than programs that use only one or two of these modalities. The drugs used to promote weight loss have been anorexiants or appetite suppressants. All classes of anorexiant drugs affect neurotransmitters in the brain. The new agent sibutramine has norepinephrine and serotonin effects. Another new agent, orlistat, has a different mechanism of action, the reduction of fat absorption. Weight loss drugs approved by the FDA for long-term use may be useful as an adjunct to diet, physical activity and behaviour therapy for patients with a BMI of > or =30 with no concomitant obesity-related risk factors or diseases, and for patients with a BMI of > or =27 with concomitant obesity-related risk factors or diseases.

J Clin Gastroenterol 2006 Mar; 40(3 Suppl 1): S39-43 (Read article online)

Clark JM

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that can progress to cirrhosis and hepatocellular carcinoma. NAFLD has been associated with obesity and other features of the metabolic syndrome, including insulin resistance, impaired glucose tolerance, and dyslipidemia. As a result, and with a lack of other effective treatments, weight loss achieved through lifestyle modifications (diet and exercise) has been promoted as the standard treatment. However, there is very little empiric evidence to support the effectiveness of weight loss for NAFLD. This article reviews the current literature on the effects of weight loss achieved through lifestyle modification or medications on NAFLD. To date, there have been no randomized controlled trials of weight loss interventions on hepatic pathology. Only three published trials (N = 89 subjects), which include a comparison group, have been published. These studies suggest improvement in liver enzymes and/or hepatic pathology; however, direct between group comparisons are lacking. Four small, nonrandomized studies (N = 59 subjects) have evaluated the effect of weight loss achieved with medications (4 of orlistat, 1 of sibutramine) on NAFLD. These suggest some improvement in liver enzymes and histopathology. Finally, a brief review of observational studies on the association between NAFLD pathology or liver enzymes and diet composition suggests a possible role for the manipulation of macronutrients and/or micronutrients in NAFLD treatment. In summary, there is little empiric evidence to support the role of weight loss achieved through lifestyle modification or medication in the treatment of NAFLD. Rigorously conducted, randomized controlled trials are needed in this area.

Heart Vessels 2006 Mar; 21(2): 84-8 (Read article online)

Dayi SU, Kasikcioglu H, Uslu N, Tartan Z, Uyarel H, Terzi S, Hobikoglu G, Okmen E, Cam N

Obese patients may have a phase of asymptomatic left ventricular dysfunction. A combined myocardial performance index (MPI) has been demonstrated to be a useful index to estimate left ventricular function and to predict the prognosis of patients with heart failure. The objective of the study was to determine the influence of weight loss on MPI. A total of 18 obese patients (3 men, 15 women, mean age 49.6 +/- 5.5 years, body mass index [BMI] >30 kg/m(2)) were investigated in the study. All patients were treated with a multidisciplinary approach consisting of a hypocaloric diet and orlistat therapy (120 mg three times daily), and all of them underwent two-dimensional and Doppler echocardiographic examination two times before starting the study and after a period of weight loss. Using echo-Doppler methods, ejection fraction, peak velocities of early (E) and late (A) diastolic filling, the E/A ratio, deceleration time (DT), isovolumic contraction time (IVCT), isovolumic relaxation time, ejection time, and MPI were measured. The MPI was obtained by subtraction ejection time from the interval between cessation and onset of the mitral flow. All patients lost at least 10% of their initial body weight, with a mean decrease of 10.8 +/- 3.7 kg. This was associated with significant reductions in BMI with a mean decrease 4.5 +/- 1.4 kg/m(2). Compared with baseline, after weight loss the E/A ratio of 1.01 +/- 0.22 before treatment increased to 1.17 +/- 0.26 (P = 0.012), left ventricular mass index decreased from 88 +/- 23 to 82 +/- 19 g/m(2) (P = 0.028), IVCT from 71 +/- 20 to 53 +/- 30 ms (P = 0.004), DT from 233.65 +/- 38.14 to 196.72 +/- 47.73 s (P = 0.004), and MPI from 0.63 +/- 0.13 to 0.50 +/- 0.13 (P = 0.0001). Weight loss ameliorates MPI and seems to be a clinically relevant measurement of left ventricular global function, and may prove to be a valuable tool in assessing the risk of developing heart failure.

J Chromatogr A 2006 Apr 5; (Read article online)

Mohammadi A, Haririan I, Rezanour N, Ghiasi L, Walker RB

A stability-indicating HPLC method was developed and validated for the quantitative determination of orlistat in capsule dosage forms. An isocratic separation was achieved using a Perfectsil((R)) target ODS-3, 250mmx4.6mm i.d., 5mum particle size column with a flow rate of 0.7ml/min and using a UV detector to monitor the eluate at 210nm. The mobile phase consisted of methanol:acetonitrile:trifluoroacetic acid (82.5:17.5:0.01, v/v/v). The drug was subjected oxidation, hydrolysis, photolysis and heat to apply stress conditions. Complete separation was achieved for the parent compound and all degradation products in an overall analytical run time of approximately 15min with the parent compound orlistat eluting at approximately 9min. The method was linear over the concentration range of 0.02-0.75mg/ml (r=0.9998) with a limit of detection and quantitation 0.006 and 0.02mg/ml, respectively. The method has the requisite accuracy, selectivity, sensitivity and precision to assay orlistat in capsules. Degradation products resulting from the stress studies did not interfere with the detection of orlistat and the assay is thus stability-indicating.

Endocr Pract 2006 Jan-Feb; 12 Suppl 1: 31-3 (Read article online)

Sjöström L

OBJECTIVE: To present an overview and analysis of the previously published XENDOS (Xenical in the Prevention of Diabetes in Obese Subjects) study. METHODS: The design, methods, and results of the XENDOS study are reviewed. On the basis of the findings, conclusions are discussed. RESULTS: The XENDOS study was a double-blind, prospective investigation with 3,305 participants, who had either normal or impaired glucose tolerance. The patients were randomly assigned to lifestyle plus placebo intervention or lifestyle changes plus orlistat (Xenical) (120 mg 3 times daily). After 4 years of treatment, the cumulative incidence of type 2 diabetes was 9.0% in the placebo group and 6.2% in the orlistat group (P = 0.0032). The incidence of diabetes was low and not significantly different in the two treatment arms of the study in those patients with normal glucose tolerance at baseline. In patients with impaired glucose tolerance, however, the conversion to type 2 diabetes was significantly greater in the placebo group than in the orlistat-treated group (P = 0.0024). Division of the baseline fasting plasma glucose levels into an upper and a lower subclassification revealed a significant difference (P < 0.05) in incidence of diabetes between the placebo (17.8%) and orlistat (9.4%) groups in the upper stratification but no significant difference in the lower subclassification (3.2% versus 2.5%, respectively). The weight loss was significantly greater in the orlistat group than in the placebo group for the entire study period (P < 0.001). CONCLUSION: In the XENDOS study, orlistat therapy reduced the incidence of diabetes beyond the result achieved with lifestyle changes only, an effect that was especially evident in patients with baseline impairment of glucose tolerance.

Obes Rev 2006 May; 7(2): 163-82 (Read article online)

Huda MS, Wilding JP, Pinkney JH

There is a growing worldwide epidemic of obesity. Obese people have a higher incidence of type 2 diabetes and cardiovascular disease, and hence present increasing social, financial and health burdens. Weight loss is always difficult to achieve through lifestyle changes alone, and currently licensed anti-obesity drug treatments, such as orlistat and sibutramine, if tolerated, only achieve modest weight loss. Therefore, there is a need to identify more potent pharmacological targets. In the last 10 years, discoveries of new hormones such as leptin and ghrelin, together with greater understanding of previously described hormones such as cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), have led to a rapid increase in our knowledge of the regulation of energy balance. Among the most important factors, controlling appetite and satiety are peptide hormones released from the gut. In this paper, we provide a full up-to-date overview of the current state of knowledge of this field, together with the potential of these peptides as drugs, or as other therapeutic targets, in the treatment of obesity. Finally, we propose an integrated model to describe the complex interplay of these hormones in the broader physiology of energy balance.

Pediatr Res 2006 Apr; 59(4 Pt 1): 506-12 (Read article online)

Hafkamp AM, Havinga R, Ostrow JD, Tiribelli C, Pascolo L, Sinaasappel M, Verkade HJ

Treatment with phototherapy or with the lipase inhibitor orlistat decreases plasma unconjugated bilirubin (UCB) concentrations in hyperbilirubinemic Gunn rats. We investigated the mechanism(s) underlying the effects of orlistat, phototherapy, and combined treatment, using steady-state 3H-UCB kinetics. After three weeks of treatment with orlistat (200 mg/kg chow), phototherapy (19 microW/cm2/nm) or combined treatment, tracer 3H-UCB was administered IV to treated and untreated (control) Gunn rats. Plasma samples and feces were collected every 12h for 60h, and bile for 30 min at 60h. The following results were obtained: 1) each treatment decreased plasma bilirubin levels compared with controls: orlistat- 19%, phototherapy-32%, combined treatment-53%; 2) plasma bilirubin concentrations were strongly, negatively correlated with fractional bilirubin turnover; 3) orlistat treatment induced net transmucosal excretion of UCB into the intestinal lumen, whereas phototherapy increased biliary UCB excretion rate; 4) all treatments profoundly increased the enterohepatic circulation of UCB derivatives, indicating enhanced metabolism by intestinal bacteria. In conclusion, orlistat and phototherapy lower plasma bilirubin concentrations in Gunn rats by increasing (net) intestinal influx of UCB, either by transmucosal excretion (orlistat), or increased biliary secretion (phototherapy). The mechanism of phototherapy and orlistat treatment involves increasing the availability of UCB in the intestinal lumen for fecal excretion and for metabolism by intestinal bacteria.

J Indian Med Assoc 2005 Nov; 103(11): 603-5, 608 (Read article online)

Mukhopadhyay P, Chowdhury S

Patients with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) have been designated by American Diabetes Association (ADA, 2004) as having 'prediabetes', which indicates the higher risk of developing the disease in these patients. Prediabetes is important to recognise because of at least 2 major implications: increased risk for future diabetes and for atherosclerotic cardiovascular diseases. Pharmacotherapy in prediabetes should therefore be directed at preventing or, at least, delaying the onset of the disease as well as reducing the morbidity and mortality from atherosclerotic complications. Several drugs having different mechanisms of action, such as metformin, glitazones, acarbose, orlistat, nateglinide, glicazide, angiotensin-converting enzymes, angiotensin receptor blockers have been found to be effective in prediabetes to improve the glycaemic status, though they are still not recommended by any professional organisation.

Chin J Physiol 2005 Dec 31; 48(4): 217-22 (Read article online)

Caner M, Dogruman H, TaÅŸkin E, Kandil A, Demirci C

Nitric oxide (NO) is known to be a messenger molecule that plays an important role in physiological and pathological conditions. It is synthesized by an enzyme called nitric oxide synthase (NOS). Inducible NOS (iNOS), one of the three isomers of NOS, has both protective and toxic properties. In this study, the role of NO has been evaluated by gastrointestinal symptoms induced by orlistat which is used in obesity treatment. Orlistat was given to Wistar rats with and without iNOS inhibition. The effects of orlistat and inhibition of NOS were studied. Glucose, urea, alanine transaminase (ALT), and gamma glutamil transpeptidase (GGT) were descreased after short- and long- term orlistat applications. Dexamethasone increased level of these enzymes. Cholesterol and triglyceride were increased in all experimental groups than the controls. This increment was more severe in animals received orlistat and dexamethasone together. Small intestinal tissue also were researched histologically and NADPH-diaphorase (NADPH-d) histochemistrically. Orlistat caused histological damages in brush border membranes, connective tissues of villi, and lymphocyte migration also increased. Dexamethasone treatment prevented these damages partially while orlistat increased the NOS distribution in the tissue sections. Dexamethasone, which is an iNOS inhibitor, decreased NADPH-d histochemistry. There was a similiar NOS distribution both in the control and orlistat+dexamethasone group. Hence, we concluded that long- term trials with orlistat and similar drugs are needed.

Minerva Gastroenterol Dietol 2001 Dec; 47(4): 223-8 (Read article online)

Magnani L

Prevention of obesity is the first step in management of diabetes mellitus type 2, but prevention programmes have had poor long-term efficacy. The cornerstones of treatment in obese type 2 diabetic patients are diet, physical activity and behavioural modifications. A small weight loss results in improvement of type 2 diabetic patients. The obese type 2 diabetic patient shows extra impediments to weight loss, such as the adverse effects of diabetic medications. New drugs, as orlistat and sibutramine, can offer some additional help, by providing the benefit associated with weight loss. Bariatric surgery can produce major long-term weight loss in severely obese patients.

Clin Gastroenterol Hepatol 2006 Apr 17; (Read article online)

Zelber-Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, Leshno M, Blendis L, Halpern Z, Oren R

BACKGROUND & AIMS: Few controlled studies have addressed the issue of effective medical treatment for nonalcoholic fatty liver disease (NAFLD). We herein assessed the effect of orlistat in patients with NAFLD. METHODS: We performed a randomized, double-blind, placebo-controlled study on 52 patients with NAFLD diagnosed by ultrasound (US) and confirmed by liver biopsy (40 patients). The patients were randomized to receive either orlistat (120 mg 3 times daily for 6 months) or placebo. All patients participated in an identical behavioral weight loss program. All patients underwent monthly evaluation by abdominal US; liver enzyme levels, lipid profiles, insulin levels, and anthropometric parameters were monitored, and all patients underwent nutritional follow-up evaluation. Twenty-two patients underwent a second liver biopsy examination at the end of the study. RESULTS: Fifty-two patients were recruited and 44 (mean age, 47.7 y; mean body mass index, 33) completed the study. Serum glucose and insulin levels (P < .03) were significantly higher in the orlistat group, which also presented a higher degree of fibrosis. Body mass index was reduced significantly in each group, with a nonsignificant difference between the groups. Serum alanine transaminase (ALT) levels decreased significantly in both groups, with an almost 2-fold reduction in the orlistat group (48% vs 26.4%). There was a statistically significant reversal of fatty liver by US only in the orlistat group (P < .05). CONCLUSIONS: Orlistat improves serum ALT levels and steatosis on US in NAFLD patients, beyond its effect on weight reduction.

Nutr Metab Cardiovasc Dis 2006 Mar; 16 Suppl 1: S11-6 (Read article online)

Winzell MS, Ström K, Holm C, Ahrén B

BACKGROUND AND AIMS: Lipids are needed for optimal glucose-stimulated insulin secretion (GSIS), and long-chain acyl-CoA (LC-CoA) has been suggested as one candidate molecule active as a lipidic coupling factor. LC-CoAs may be available to the beta-cell via uptake of circulating free fatty acids or from hydrolysis of intracellularly stored triglycerides. Inhibition of lipolysis in rat islets using a non-specific lipase inhibitor (orlistat) resulted in blunted GSIS. The aim of this study was to investigate the relationship between GSIS and lipolysis in clonal beta-cells and in mouse islets. METHODS AND RESULTS: INS-1 cells, cultured overnight at 3.3 mM or 11.1 mM glucose, or freshly isolated islets were incubated with 3.3 mM or 16.7 mM glucose for 1 h. Medium samples were collected and analyzed for insulin and glycerol. Triglycerides were measured in both INS-1 cells and islets. There was a dose-dependent glucose-stimulated lipolysis in INS-1 cells, which strongly correlated with insulin secretion (r=0.85, P<0.0001). The same phenomenon was observed in mouse islets (r=0.9, P=0.013). Low levels of triglycerides, which were observed in INS-1 cells pre-cultured at 3.3 mM glucose, were associated with reduced GSIS. CONCLUSIONS: This study suggests that lipids obtained from lipolysis of intracellular triglycerides are involved in GSIS.

Drug Saf 2006; 29(4): 277-302 (Read article online)

Ioannides-Demos LL, Proietto J, Tonkin AM, McNeil JJ

Some of the medications used for weight loss in the management of obesity have been associated with unacceptable morbidity and mortality. Safety concerns have led to the withdrawal of aminorex, followed by the fenfluramines in 1997, and phenylpropanolamine (norephedrine) in 2000. Aminorex was associated with an increased prevalence of primary pulmonary hypertension (PPH), fenfluramines with an increased prevalence of PPH and valvulopathy, and phenylpropanolamine with an increased risk of haemorrhagic stroke.Several studies have investigated the safety of the fenfluramines, yet the benefit-risk profile has not been conclusively quantified. This is due to several deficiencies in the published studies, including a lack of data on the baseline prevalences of comorbid conditions in obese subjects, and potential confounders and biases in the study designs. Although several studies and systematic reviews support an increased risk of PPH and valvulopathy in patients who have taken fenfluramines, without knowledge of the background prevalence it is not possible to determine if the exposure preceded the outcome. The population at higher risk of these adverse effects includes those taking higher doses or with a longer duration of exposure to fenfluramines and those with pre-existing cardiac disease or a genetic predisposition. Patients exposed to fenfluramines continue to be monitored, with some follow-up studies indicating no overall worsening in valvulopathy over time.There are limited efficacy and safety data for amfepramone (diethylpropion) and phentermine and their approval for the management of obesity is limited to short-term use. Orlistat and sibutramine are the only currently approved medications for long-term management of obesity. Although the benefit-risk profiles of sibutramine and orlistat appear positive, sibutramine continues to be monitored because of long-term safety concerns.The safety and efficacy of currently approved drug therapies have not been evaluated in children and elderly patient populations and there is limited information in adolescents, whilst the long-term safety of current and potential new drug therapies in adults will require several years of postmarketing surveillance to fully elucidate their adverse effect profiles.

Orv Hetil 2006 Apr 2; 147(13): 579-90 (Read article online)

Juhász A, Katona E, Csongrádi E, Paragh G

Overweight and obesity are worldwide problems, its health and psychosocial burden on the individual and on society are tremendous. Diagnosing obesity is rather easy, and is based on simple anthropometric measurements, such as body weight, height and waist circumference. The different classes of obesity are determined by body mass index, which, together with waist circumference and comorbid conditions and other risk factors determine the individual risk for mortality and morbidity. Obesity is due to genetic and environmental factors, mainly is the consequence of excess calorie intake and sedentary lifestyle. The fat mass of the body is under neuroendocrine control, the central controller is the hypothalamus. Leptin, produced by adipocytes in proportion to fat mass, is the afferent signal to the hypothalamus. Decreasing or increasing levels of leptin result in orexigen and anorexigen neurotransmission, which mediate efferent activation towards food consumption and energy storage, or towards food restriction and energy expenditure, respectively. The balance of these events and/or the ,set point" of the controller--if leptin resistance is present--is shifted towards higher body/fat mass in obesity. Management of obesity is complex, however, in all stages of obesity lifestyle changes are mandatory--including diet, exersize and behavior modification. Pharmacotherapy might be needed if lifestyle changes alone do not result an acceptable weight loss. For the long-term treatment of obesity sibutramin and orlistat are the available approved drugs. In case of morbid obesity (body mass index > 40 kg/m2, or > 35 kg/m2 plus comorbid conditions and other risk factors) surgery might be the treatment of choice. There are different surgical methods, among those a widely used method nowadays is the laparoscopic adjustable gastric banding procedure.

Metabolism 2006 Apr; 55(4): 494-500 (Read article online)

Diamanti-Kandarakis E, Piperi C, Alexandraki K, Katsilambros N, Kouroupi E, Papailiou J, Lazaridis S, Koulouri E, Kandarakis HA, Douzinas EE, Creatsas G, Kalofoutis A

Exogenous advanced glycation endproducts (AGEs, known atherogenic molecules) abundant in everyday precooked, rich in fat, overheated meals can possibly contribute to the increased risk for diabetes and cardiovascular disease in women with polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the effect of a lipase inhibitor on absorbed food glycotoxins in healthy women and those with PCOS. A 2-day protocol was followed. In the first day, a meal rich in AGE was provided, which on the second day was followed by two 120-mg capsules of lipase inhibitor, orlistat. Serum AGE levels were evaluated at baseline (0 hours), and at 3 and 5 hours postmeal during the study. Thirty-six women were studied, 15 controls (mean age, 28.80 +/- 5.47 years; body mass index, 25.85 +/- 6.73 kg/m(2)) and 21 with PCOS (mean age, 25.29 +/- 5.06 years; body mass index, 30.40 +/- 7.51 kg/m(2)) (University Hospital, Athens, Greece, institutional practice). Serum AGE levels, on day 1, were significantly increased both in the control group and in the PCOS group as compared with basal values (control group, 14.1%; PCOS group, 6.0%; P < .001). The corresponding rise was significantly lower on day 2 when the same meal was combined with orlistat (control group, 4.1%; PCOS group, 2.0%; P < .01). A limitation of the study is that it is a nonplacebo, nonrandomized therapeutic trial where each subject is considered as its own control. In conclusion, this study demonstrated the beneficial effect of orlistat on the absorption of food glycotoxins.

Int J Obes (Lond) 2006 Mar 21; (Read article online)

Acharya NV, Wilton LV, Shakir SA

Introduction:Orlistat, the first of a new class of drugs for the treatment of obesity, was launched in the UK in December 1998. The prescribing information recommends that treatment with orlistat should be discontinued after 12 weeks if the patient has not achieved a specified loss of weight.Objective:To monitor the safety of orlistat prescribed in the primary care setting in England using prescription-event monitoring (PEM).Methods:A postmarketing surveillance study using the observational cohort technique of PEM. Patients were identified from dispensed prescriptions issued by primary care physicians for orlistat between December 1998 and November 1999. The outcome data were event reports obtained by sending questionnaires (green forms) to the prescribing doctor at least 6 months after the first prescription for an individual patient. Incidence densities, expressed as number of first reports of an event/1000 patient-months of exposure, were calculated. Significant differences between incidence densities (IDs) for events reported in the 1st month (ID(1)) and months 2 and 3 (ID(2-3)) of exposure were regarded as potential signals. Reasons for stopping orlistat were analysed. Follow-up information was requested for selected events and used to assess the causal association with orlistat.Results:Green forms containing clinically useful information on 16 021 patients (median age 45 years (interquartile range 35-54); 80.1% females) were received. The events reported most frequently during the 1st month of treatment were 'not effective' (639; 4.0% of cohort), diarrhoea (371; 2.3%) and weight loss (230; 1.4%). Twelve clinical adverse events were identified for which ID(1) was significantly greater than ID(2-3). These included non-specific events (e.g. intolerance, malaise/lassitude, unspecified side effects), weight loss and vaginitis/vulvitis. The remaining events were gastrointestinal in nature and included diarrhoea, pain abdomen, flatulence, nausea/vomiting, rectal discharge, faecal incontinence and 'gastrointestinal unspecified' events. A similar pattern of predominately gastrointestinal events was seen for reasons for stopping and suspected adverse drug reactions. Review of selected events for causality revealed 45 events which were assessed as possibly or probably related to orlistat.Conclusions:This study shows that orlistat is fairly well tolerated. The safety profile of orlistat was similar to the prescribing information and experience reported in the literature.International Journal of Obesity advance online publication, 21 March 2006; doi:10.1038/sj.ijo.0803323.

Endocr Pract 2006 Jan-Feb; 12(1): 18-28 (Read article online)

Maahs D, de Serna DG, Kolotkin RL, Ralston S, Sandate J, Qualls C, Schade DS

OBJECTIVE: To evaluate the efficacy of orlistat to enhance weight loss in obese adolescents. METHODS: The study was a 6-month randomized, double-blind, placebo-controlled trial to compare the effects of orlistat (120 mg orally 3 times a day) and placebo on reduction of body mass index (BMI). Forty adolescents between 14 and 18 years of age with a mean BMI of 40 kg/m2 entered the protocol between December 2002 and February 2003. Study subjects stayed overnight in the General Clinical Research Center, during which dietary records were reviewed and lifestyle recommendations were given. The study participants received either orlistat (120 mg orally 3 times a day) or placebo and were assessed monthly for 6 months. At 0, 3, and 6 months, fasting laboratory tests were performed. The primary end point was the change in BMI from baseline to 6 months. Secondary outcomes included changes in weight, lean body mass, and results of blood chemistry studies. RESULTS: No statistically significant difference was noted between the 2 study groups for decrease in BMI from baseline to 6 months (P = 0.39). The decrease in BMI within the orlistat group (-1.3 +/- 1.6 kg/m2; P = 0.04) and within the placebo group (-0.8 +/- 3.0 kg/m2; P = 0.02), however, was statistically significant. Laboratory measurements did not differ between the 2 groups. In comparison with the placebo group, the orlistat group had increased adverse events, primarily gastrointestinal symptoms and findings. CONCLUSION: In this study of obese adolescents, orlistat did not significantly reduce BMI in comparison with placebo at 6 months.

J Lipid Res 2006 Apr 25; (Read article online)

Saraswathi V, Hasty AH

Hypertriglyceridemia is an important risk factor for atherosclerosis, especially in obesity. Macrophages are one of the primary cell types involved in atherogenesis and are thought to contribute to lesion formation through both lipid accumulation and pro-inflammatory gene expression. In this study, we sought to determine the direct impact of triglyceride-rich very low density lipoprotein (VLDL)-induced lipid accumulation on macrophage pro-inflammatory processes. Incubation of mouse peritoneal macrophages with 100 {micro}g/ml of VLDL for 6 h led to 2.8- and 3.7-fold increases in intracellular triglycerides (TGs) and free fatty acids (FFAs), respectively (P<0.05). The inflammatory proteins TNF-alpha, IL-1beta, MCP-1, ICAM-1, MMP3, and MIP-1alpha were all upregulated by at least 2-fold (P<0.05) in a dose-dependent manner in VLDL-treated macrophages. The increase in inflammatory gene expression coincided with phosphorylation of MAPK pathway members ERK1/2, SAPK/JNK, and p38 MAPK, and was ameliorated by U0126, an inhibitor of ERK1/2. Inhibition of extracellular triglyceride hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by amelioration of ERK1/2 phosphorylation and MIP-1alpha gene expression. These data indicate that VLDL hydrolysis, and the subsequent accumulation of intracellular FFA and TG, plays a substantive role in mediating the pro-inflammatory effects of VLDL. These data have important implication for direct pro-atherogenic effects of VLDL on macrophage-driven atherosclerosis.