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Safety and efficacy of vorapaxar in secondary prevention of atherosclerotic disease: A meta-analysis of randomized control trials.
Sharma, A, Helft, G, Garg, A, Agrawal, S, Chatterjee, S, Lavie, CJ, Goel, S, Mukherjee, D, Marmur, JD
International journal of cardiology. 2017;:617-624
Abstract
OBJECTIVE To study the cumulative evidence for vorapaxar use in patients with atherosclerotic cardiovascular disease. METHODS A systematic review of randomized control trials in MEDLINE, EMBASE, EBSCO, CINAHL, Web of Science and Cochrane databases comparing vorapaxar with placebo was performed. Pre-specified efficacy endpoints were all-cause mortality, CV mortality, myocardial infarction (MI), ischemic stroke and repeat revascularization. The pre-specified safety endpoint was intracranial hemorrhage (ICH) and a composite of TIMI major and minor bleeding. Risk ratios were used as the metric of choice by applying random effects models. RESULTS Five randomized controlled trials with 40,630 patients were included in final analysis. Compared with placebo, vorapaxar led to a statistically non-significant reduction in risk of MI [RR 0.86; 95% CI 0.80-0.93, p=0.427] and ischemic stroke [RR 0.84; 95% CI 0.72-0.97, p=0.920]. No differences were observed between vorapaxar and placebo with respect to all-cause mortality [RR 0.99; 95% CI 0.90-1.08, p=0.620], cardiovascular mortality [RR 0.94; 95% CI 0.83-1.06, p=0.351], repeat revascularization [RR 0.97; 95% CI 0.82-1.15, p=0.236], and TIMI bleeding [RR 1.29; 95% CI 0.98-1.69, p=0.126]. Vorapaxar was associated with a statistically non-significant higher risk of ICH [RR 2.36; 95% CI 1.40-3.96, p=0.137] compared with placebo. CONCLUSION Addition of Vorapaxar to standard medical therapy in in patients with atherosclerotic disease led to a statistically non-significant reduction in the risk of MI and ischemic stroke at the cost of statistically non-significant increase in risk of ICH.
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Effect of orlistat on glycaemic control in overweight and obese patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.
Aldekhail, NM, Logue, J, McLoone, P, Morrison, DS
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2015;(12):1071-80
Abstract
Orlistat is an effective adjunctive treatment to lifestyle modifications in the treatment of obesity. While the majority of current evidence is on the effect of orlistat in obese patients without diabetes, some studies suggest that patients who are obese and have diabetes mellitus lose more weight and have greater improvements in diabetic outcomes when treated with orlistat plus a lifestyle intervention than when treated by lifestyle interventions alone. The aim of this study was to review the evidence of the effects of orlistat on glycaemic control in overweight and obese patients with type 2 diabetes. A systematic review of randomized controlled trials of orlistat in people with type 2 diabetes reporting diabetes outcomes in studies published between January 1990 and September 2013 was conducted. We searched for articles published in English in MEDLINE and EMBASE. Inclusion criteria included all randomized controlled trials of orlistat carried out on adult participants with a body mass index of 25 kg m(-2) or over diagnosed with type 2 diabetes, which reported weight change and at least one diabetic outcome. A total of 765 articles were identified out of which 12 fulfilled the inclusion criteria. The overall mean weight reduction (3, 6 and 12 months) in the orlistat group was -4.25 kg (95% CI: -4.5 to -3.9 kg). The mean weight difference between treatment and control groups was -2.10 kg (95% CI: -2.3 to -1.8 kg, P < 0.001), the mean HbA1c difference was -6.12 mmol mol(-1) (95% CI: -10.3 to -1.9 mmol mol(-1) , P < 0.004) and the mean fasting blood glucose difference was -1.16 mmol L(-1) (95% CI: -1.4 to -0.8 mmol L(-1) , P < 0.001). Treatment with orlistat plus lifestyle intervention resulted in significantly greater weight loss and improved glycaemic control in overweight and obese patients with type 2 diabetes compared with lifestyle intervention alone.
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An integrated analysis of liver safety data from orlistat clinical trials.
Morris, M, Lane, P, Lee, K, Parks, D
Obesity facts. 2012;(4):485-94
Abstract
OBJECTIVE Orlistat is an oral gastrointestinal lipase inhibitor and is indicated for treatment of obesity in combination with a hypocaloric diet. Post-marketing reports of adverse reactions revealed hints for possible drug-induced liver injury which has prompted changes to the product information. Orlistat's development program, involving over 30,000 patients, did not indicate a hepatic safety issue. METHODS We analyzed liver function test data from randomized clinical trials of orlistat, using i) meta-analysis of published study safety data, ii) time-to-event analysis for individual patients, and iii) a novel and more sensitive method derived from the U.S. Food and Drug Administration's (FDA) evaluation of drug-induced serious hepatotoxicity (eDISH) technique. Over 10,000 subjects were included. RESULTS The combined odds ratio from a simple summary-level fixed-effects meta-analysis of treatment-emergent abnormalities in serum alanine aminotransferase (ALT) (defined as greater than the upper level of normal for 2 successive measurements) was 1.09 (95% CI 0.93-1.28), and in total bilirubin 1.24 (95% CI 1.03-1.49). Part of the small apparent effect was due to longer exposure to orlistat than to placebo, on average. A patient-level display, adjusting for regression towards the mean, and Kaplan-Meier analysis of changes in ALT and bilirubin, taking account of different exposure, showed no significant difference between orlistat and placebo. This shows that there is no signal for hepatic damage in clinical studies of orlistat. CONCLUSION While idiosyncratic liver injury following exposure to orlistat cannot be excluded, it is likely to be extremely rare.
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Long-term effects of weight-reducing drugs in hypertensive patients.
Siebenhofer, A, Horvath, K, Jeitler, K, Berghold, A, Stich, AK, Matyas, E, Pignitter, N, Siering, U
The Cochrane database of systematic reviews. 2009;(3):CD007654
Abstract
BACKGROUND All major guidelines for antihypertensive therapy recommend weight loss; anti-obesity drugs might be a helpful option. PRIMARY OBJECTIVES To assess the long-term effects of pharmacologically induced reduction in body weight with orlistat, sibutramine or rimonabant on:- all cause mortality - cardiovascular morbidity - adverse events SECONDARY OBJECTIVES - changes in systolic and/or diastolic blood pressure - body weight reduction SEARCH STRATEGY Studies were obtained from computerised searches of Ovid MEDLINE, EMBASE, CENTRAL and from hand searches in reference lists and systematic reviews. SELECTION CRITERIA Randomized controlled trials in adult hypertensive patients with a study duration of at least 24 weeks comparing pharmacologic interventions (orlistat, sibutramine, rimonabant) for weight loss with placebo. DATA COLLECTION AND ANALYSIS Two authors independently assessed risk of bias and extracted data. Studies were pooled using fixed-effect meta-analysis in the absence of significant heterogeneity between studies (p>0.1). Otherwise, we used the random effects method and investigated the cause of heterogeneity. MAIN RESULTS Eight studies comparing orlistat or sibutramine to placebo fulfilled our inclusion criteria. No relevant studies investigating rimonabant for weight loss were identified. No study included mortality and cardiovascular morbidity as a pre-defined outcome. Incidence of gastrointestinal side effects was consistently higher in orlistat treated vs. placebo treated patients. Most frequent side effects with sibutramine were dry mouth, constipation and headache. Patients assigned to weight loss diets, orlistat or sibutramine reduced their body weight more effectively than patients in the usual care/placebo groups. Blood pressure reduction in patients treated with orlistat was for systolic blood pressure (SBP): weighted mean difference (WMD): -2.5 mm Hg; 95% CI, -4.0 to -0.9 mm Hg and for diastolic blood pressure (DBP): WMD -1.9 mm Hg; 95% CI, -3.0 to -0.9 mm Hg. Meta-analysis showed DBP increase under therapy with sibutramine: WMD +3.2 mm Hg; 95%CI +1.4 to +4.9 mm Hg. AUTHORS' CONCLUSIONS In patients with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree. In the same trials, orlistat reduced blood pressure and sibutramine increased blood pressure. No trials investigating rimonabant in people with elevated blood pressure could be included. Long-term trials assessing the effect of orlistat, sibutramine and rimonabant on mortality and morbidity are needed.
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Orlistat and sibutramine beyond weight loss.
Mannucci, E, Dicembrini, I, Rotella, F, Rotella, CM
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2008;(5):342-8
Abstract
BACKGROUND AND AIM To investigate, through a meta-analysis of clinical trials, the effect of two weight-reducing drugs, such as orlistat and sibutramine, on serum lipid profiles in overweight and obese subjects, independently of weight loss. METHODS A systematic search strategy, incorporating the terms orlistat, sibutramine, fat, cholesterol, lipid profile, cardiovascular risk, was developed to identify randomized trials in MEDLINE from inception to the end of May 2005. Trial selection was limited by language of publication (English) and duration (6-12 months). RESULTS Fifteen and ten randomized, double-blind, placebo-controlled trials on orlistat and sibutramine respectively, were eligible for inclusion. In the 15 trials with orlistat, mean weight loss showed a significant correlation with mean reduction of total cholesterol (r=0.48; p<0.05), which maintained statistical significance after adjustment for mean weight loss (B=-2.81+/-1.28; p<0.05). Conversely, in the ten trials with sibutramine, treatment was not associated with a significant decrease in cholesterol levels after adjustment for weight loss (B=3.25+/-4.13; p not significant). CONCLUSION Orlistat or sibutramine, when individually compared to placebo, are effective in promoting significant weight loss. In addition, orlistat determines a significant reduction of total cholesterol, independent of weight loss itself. These observations indicate that orlistat is a useful adjunctive tool for improving cardiovascular risk factor profiles in overweight and obese patients.
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Long term pharmacotherapy for obesity and overweight: updated meta-analysis.
Rucker, D, Padwal, R, Li, SK, Curioni, C, Lau, DC
BMJ (Clinical research ed.). 2007;(7631):1194-9
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Abstract
OBJECTIVE To summarise the long term efficacy of anti-obesity drugs in reducing weight and improving health status. DESIGN Updated meta-analysis of randomised trials. DATA SOURCES Medline, Embase, the Cochrane controlled trials register, the Current Science meta-register of controlled trials, and reference lists of identified articles. All data sources were searched from December 2002 (end date of last search) to December 2006. STUDIES REVIEWED Double blind randomised placebo controlled trials of approved anti-obesity drugs used in adults (age over 18) for one year or longer. RESULTS 30 trials of one to four years' duration met the inclusion criteria: 16 orlistat (n=10 631 participants), 10 sibutramine (n=2623), and four rimonabant (n=6365). Of these, 14 trials were new and 16 had previously been identified. Attrition rates averaged 30-40%. Compared with placebo, orlistat reduced weight by 2.9 kg (95% confidence interval 2.5 kg to 3.2 kg), sibutramine by 4.2 kg (3.6 kg to 4.7 kg), and rimonabant by 4.7 kg (4.1 kg to 5.3 kg). Patients receiving active drug treatment were significantly more likely to achieve 5% and 10% weight loss thresholds. Orlistat reduced the incidence of diabetes and improved concentrations of total cholesterol and low density lipoprotein cholesterol, blood pressure, and glycaemic control in patients with diabetes but increased rates of gastrointestinal side effects and slightly lowered concentrations of high density lipoprotein. Sibutramine improved [corrected] concentrations of high density lipoprotein cholesterol and triglycerides [corrected] Rimonabant improved concentrations of high density lipoprotein cholesterol and triglycerides, blood pressure, and glycaemic control in patients with diabetes but increased the risk of mood disorders. CONCLUSIONS Orlistat, sibutramine, and rimonabant modestly reduce weight, have differing effects on cardiovascular risk profiles, and have specific adverse effects.
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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.
Hutton, B, Fergusson, D
The American journal of clinical nutrition. 2004;(6):1461-8
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BACKGROUND Obesity is a growing health concern in Canada and the United States, and pharmacologic therapies such as orlistat are being more commonly prescribed to assist with weight loss. OBJECTIVE Our goal was to assess the efficacy and safety of orlistat compared with either placebo or an active control with regard to weight loss and serum lipid changes in overweight patients. DESIGN We performed a systematic literature search of MEDLINE (1966 through December 2003) and the Cochrane Central Register of Controlled Trials. Relevant trials and reviews were searched by hand. Randomized trials comparing orlistat and a control and reporting changes in weight loss, serum lipids (total cholesterol, LDL cholesterol, HDL cholesterol, LDL:HDL, and triacylglycerols), or both in overweight and obese patients [body mass index (in kg/m2) > or =25] were included. RESULTS Twenty-eight randomized trials met our inclusion criteria. Seventeen studies including 10,041 patients compared 3 x 120 mg orlistat/d with placebo or an inactive control along with a hypocaloric diet over a 1-y period. Relative risks (RRs) associated with clinically significant weight losses of 5% and 10% were 1.74 (95% CI: 1.57, 1.91) and 1.96 (1.74, 2.21), both favoring orlistat. Improvement in total cholesterol, LDL cholesterol, HDL cholesterol, and LDL:HDL were also greater with orlistat. Gastrointestinal events were more common with orlistat than with placebo [RR: 1.46 (1.37, 1.55)]. CONCLUSION Our findings suggest that 3 x 120 mg orlistat/d is effective for improving both weight loss and serum lipid profiles in obese patients at low and high cardiovascular disease risk and in obese patients with type 2 diabetes.
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Effect of orlistat-induced weight loss on blood pressure and heart rate in obese patients with hypertension.
Sharma, AM, Golay, A
Journal of hypertension. 2002;(9):1873-8
Abstract
OBJECTIVE To investigate the effects of long-term weight management with orlistat on blood pressure in obese hypertensive patients. DESIGN A meta-analysis of data from five multicenter, randomized, placebo-controlled studies, conducted in Europe and the USA, was performed. PATIENTS Obese adults [body mass index (BMI) 28-43 kg/m(2) ] with uncontrolled diastolic hypertension or isolated systolic hypertension (ISH) were eligible for inclusion. INTERVENTIONS Following a 4-week placebo lead-in period, patients were randomized to orlistat 120 mg or placebo three times daily, in conjunction with a mildly reduced calorie diet for 1 year. MAIN OUTCOME MEASURES Change in body weight was the primary efficacy parameter. Blood pressure, heart rate and systolic workload were assessed as secondary efficacy parameters. RESULTS A total of 628 patients were included in the intent-to-treat (ITT) analysis. After 56 weeks, orlistat-treated patients had lost significantly more body weight than placebo recipients (8.0 versus 4.0%; P<0.001). Among patients with ISH, mean systolic pressure was reduced to a significantly greater degree after 1 year with orlistat compared to placebo (-9.4 versus -4.6 mmHg; P= 0.022). Similarly, reductions in mean diastolic pressure in patients with diastolic hypertension were greater with orlistat than with placebo (-7.7 versus -5.6 mmHg; P= 0.017). Weight loss of >or= 10% was associated with significant reductions in blood pressure, heart rate and systolic workload. CONCLUSIONS Orlistat promotes clinically meaningful weight loss that is associated with significant reductions in blood pressure and heart rate, and may therefore have a role in the management of hypertension in overweight and obese patients.