Long-term effects of weight-reducing drugs in people with hypertension(review)

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1 Cochrane Database of Systematic Reviews Longterm effects of weightreducing drugs in people with hypertension(review) Siebenhofer A, Jeitler K, Horvath K, Berghold A, Posch N, Meschik J, Semlitsch T Siebenhofer A, Jeitler K, Horvath K, Berghold A, Posch N, Meschik J, Semlitsch T. Longterm effects of weightreducing drugs in people with hypertension. Cochrane Database of Systematic Reviews 2016, Issue 3. Art. No.: CD DOI: / CD pub4. Longterm effects of weightreducing drugs in people with hypertension(review) Copyright 2016 The Cochrane Collaboration. Published by John Wiley& Sons, Ltd.

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY SUMMARY OF FINDINGS FOR THE MAIN COMPARISON BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure Figure Figure Figure Figure Figure Figure ADDITIONAL SUMMARY OF FINDINGS DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES ADDITIONAL TABLES WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS Longterm effects of weightreducing drugs in people with hypertension (Review) i

3 [Intervention Review] Longterm effects of weightreducing drugs in people with hypertension Andrea Siebenhofer 1, Klaus Jeitler 2, Karl Horvath 3, Andrea Berghold 2, Nicole Posch 4, Jutta Meschik 4, Thomas Semlitsch 4 1 Institute of General Practice and EvidenceBased Health Services Research, Medical University of Graz, Graz, Austria / Institute of General Practice, Goethe University, Frankfurt am Main, Germany. 2 Institute of General Practice and EvidenceBased Health Services Research / Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria. 3 Institute of General Practice and EvidenceBased Health Services Research / Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria. 4 Institute of General Practice and EvidenceBased Health Services Research, Medical University of Graz, Graz, Austria Contact address: Andrea Siebenhofer, Institute of General Practice and EvidenceBased Health Services Research, Medical University of Graz, Graz, Austria / Institute of General Practice, Goethe University, Frankfurt am Main, Germany. andrea.siebenhofer@medunigraz.at, siebenhofer@allgemeinmedizin.unifrankfurt.de. Editorial group: Cochrane Hypertension Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 3, Citation: Siebenhofer A, Jeitler K, Horvath K, Berghold A, Posch N, Meschik J, Semlitsch T. Longterm effects of weightreducing drugs in people with hypertension. Cochrane Database of Systematic Reviews 2016, Issue 3. Art. No.: CD DOI: / CD pub4. Background A B S T R A C T All major guidelines on antihypertensive therapy recommend weight loss; antiobesity drugs may be able to help in this respect. Objectives Primary objectives: To assess the longterm effects of pharmacologically induced reduction in body weight in adults with essential hypertension on allcause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total nonserious adverse events). Secondary objectives: To assess the longterm effects of pharmacologically induced reduction in body weight in adults with essential hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction. Search methods We obtained studies using computerised searches of the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid EMBASE, the clinical trials registry ClinicalTrials.gov, and from handsearches in reference lists and systematic reviews (status as of 13 April 2015). Selection criteria Randomised controlled trials in hypertensive adults of at least 24 weeks duration that compared longterm pharmacologic interventions for weight loss with placebo. Longterm effects of weightreducing drugs in people with hypertension (Review) 1

4 Data collection and analysis Two review authors independently selected studies, assessed risk of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using fixedeffect metaanalysis. When heterogeneity was present, we used the randomeffects method and investigated the cause of heterogeneity. Main results After updating the literature search, which was extended to include four new weightreducing drugs, we identified one additional study of phentermine/topiramate, bringing the total number of studies to nine that compare orlistat, sibutramine, or phentermine/ topiramate to placebo and thus fulfil our inclusion criteria. We identified no relevant studies investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion. No study included mortality and cardiovascular morbidity as predefined outcomes. Incidence of gastrointestinal side effects was consistently higher in those participants treated with orlistat versus those treated with placebo. The most frequent side effects were dry mouth, constipation, and headache with sibutramine, and dry mouth and paresthaesia with phentermine/ topiramate. In participants assigned to orlistat, sibutramine, or phentermine/topiramate body weight was reduced more effectively than in participants in the usualcare/placebo groups. Orlistat reduced systolic blood pressure as compared to placebo by 2.5 mm Hg (mean difference (MD); 95% confidence interval (CI): 4.0 to 0.9 mm Hg) and diastolic blood pressure by 1.9 mm Hg (MD; 95% CI: 3.0 to 0.9 mm Hg). Sibutramine increased diastolic blood pressure compared to placebo by +3.2 mm Hg (MD; 95% CI: +1.4 to +4.9 mm Hg). The one trial that investigated phentermine/topiramate suggested it lowered blood pressure. Authors conclusions In people with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree, while phentermine/topiramate reduced body weight to a greater extent. In the same trials, orlistat and phentermine/topiramate reduced blood pressure, while sibutramine increased it. We could include no trials investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion in people with elevated blood pressure. Longterm trials assessing the effect of orlistat, liraglutide, lorcaserin, phentermine/topiramate, or naltrexone/bupropion on mortality and morbidity are unavailable and needed. Rimonabant and sibutramine have been withdrawn from the market, after longterm trials on mortality and morbidity have confirmed concerns about the potential severe side effects of these two drugs. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while the application for European marketing authorisation for lorcaserin was withdrawn by the manufacturer after the Committee for Medicinal Products for Human Use judged the overall benefit/risk balance to be negative. P L A I N L A N G U A G E S U M M A R Y Longterm effects of weightreducing drugs in people with elevated blood pressure Doctors often recommend that people who are overweight or obese with elevated blood pressure lose weight, which may include taking antiobesity drugs to assist in weight and blood pressure reduction. Two active ingredients (rimonabant and sibutramine) were withdrawn from the market in 2009 and 2010, respectively. Current guidelines for the pharmacological management of obesity quote five medications (orlistat, lorcaserin, phentermine/topiramate, naltrexone/bupropion, and liraglutide) that have been approved for longterm weight reduction by the US Food and Drug Administration. However, two of these drugs (phentermine/topiramate and lorcaserin) did not obtain approval in Europe. We found evidence that orlistat, sibutramine, and phentermine/topiramate modestly reduce weight. Orlistat and phentermine/topiramate reduced blood pressure, while sibutramine increased it. We found no study investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion in people with elevated blood pressure. No evidence was available for the effects of any of these drugs on death or morbidity. The most common side effects were gastrointestinal for orlistat; dry mouth, constipation, and headache for sibutramine; and dry mouth and paresthaesia for phentermine/topiramate. Longterm effects of weightreducing drugs in people with hypertension (Review) 2

5 Longterm effects of weightreducing drugs in people with hypertension (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] Orlistat compared with placebo for weight reduction Patient or population: Men and nonpregnant women 18 years old with essential hypertension Intervention: Orlistat Comparison: Placebo Outcomes Change in systolic blood pressure as compared to placebo [mm Hg] from baseline to end of study Change in diastolic blood pressure as compared to placebo [mm Hg] from baseline to end of study Illustrative comparative risks(per 1000 patients) Effect estimate (95% CI) No of Participants (studies) Not applicable M D 2.46 [4.01,0.90] 2058 (4 studies) Not applicable M D 1.92 [2.99,0.85] 2058 (4 studies) Quality of the evidence (GRADE) low 1,2 low 1,2 Comments Changeinbodyweightas compared to placebo [kg] from baseline to end of study Not applicable M D 3.73 [4.65,2.80] 2080 (4 studies) moderate 1 CI: confidence interval; M D: mean difference GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. M oderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Lowquality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 High risk of bias in included studies. 2 Wide confidence intervals include nonclinically important effect. 3

6 B A C K G R O U N D Description of the condition Hypertension is a chronic condition associated with an increased risk of cardiovascular mortality and morbidity. It is estimated that high blood pressure leads to over 9 million deaths each year (WHO 2013). Lowering blood pressure levels in hypertensive people has been shown to be an effective means of reducing cardiovascular morbidity and mortality. Epidemiological investigations have consistently found an association between high blood pressure and different lifestyles, one of them being excess body weight. Major guidelines recommend weight reduction as a firststep intervention in the therapy of hypertensive people (CHEP 2014; ESHESC 2013; JNC 2014; NICE 2011; WHO 2005). Body weight may be reduced by lifestyle modifications as well as pharmacological and invasive interventions. Description of the intervention For a select group of people for whom lifestyle interventions are unsuccessful, antiobesity drugs may be an option to help reduce body weight. Orlistat, sibutramine, and rimonabant were formerly the most commonly used antiobesity drugs, but only orlistat still has market approval for the longterm treatment of obesity. Sibutramine was approved by the US Food and Drug Administration (FDA) in 1997 and by the European Medicines Agency (EMA) in However, preliminary results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT 2010), presented in October 2009, showed an increased risk of serious cardiovascular events (such as heart attack or stroke) among people with known cardiovascular disease who were taking sibutramine. This led the FDA and EMA to recommend suspension of the marketing authorisation (EMA 2010; EMA 2010a; FDA 2010). In January 2010, Abbot Laboratories agreed to voluntarily withdraw sibutramine from the European market (Abbott 2010), and in October 2010 from the US market (FDA 2010a). Rimonabant received regulatory approval in several European countries in 2006, but failed to receive FDA approval after preclinical and clinical data raised concerns about an association between rimonabant intake and the increased incidence of psychiatric adverse events, including suicidality, an illdefined constellation of neurological signs and symptoms, and seizures (FDA 2007). In October 2008, the EMA recommended the suspension of rimonabant from the market because of newly available postmarketing analyses demonstrating detrimental effects versus placebo (EMA 2008; EMA 2008a). In January 2009, the European Commission decided to withdraw market authorisation for rimonabant in all countries of the European Union (EMA 2009). Since 2012, four new drugs (lorcaserin, liraglutide, phentermine/topiramate, and naltrexone/bupropion) have been approved by the FDA for obese (body mass index (BMI) 30 kg/ m 2 ) and overweight (BMI 27 kg/m 2 ) people with at least one obesityrelated comorbidity. These medications have recently been quoted in guidelines for the longterm pharmacological treatment of obesity (Apovian 2015). In Europe, liraglutide, which has also been approved for the treatment of diabetes mellitus type 2, and naltrexone/bupropion were approved for weight management in March 2015 by the EMA (EMA 2015; EMA 2015a). In 2013, the manufacturer of lorcaserin withdrew its application to the EMA after the Committee for Medicinal Products for Human Use raised safety concerns (EMA 2013), while the EMA refused marketing authorisation for phentermine/topiramate due to safety concerns (EMA 2013b). How the intervention might work Antiobesity drugs aim to reduce body weight and to maintain the weight reduction over a longer period. Orlistat is a gastric and pancreatic lipase inhibitor; sibutramine is a centrally acting monoaminereuptake inhibitor; and rimonabant is an endocannabinoid receptor antagonist (Padwal 2007). Liraglutide, a glucagonlike peptide 1 (GLP1) receptor agonist, appears to regulate appetite by increasing feelings of satiety (RussellJones 2009). The combination of phentermine, a neurostabiliser, and topiramate, an antiseizure medication, appears to have an additive effect on weight reduction (Aronne 2013). In combination with naltrexone, bupropion, a dopamine and norepinephrine reuptake inhibitor, reduces appetite and increases energy expenditure (Caixas 2014). The mechanisms by which these three medications cause weight loss are not yet fully understood. Lorcaserin is a selective serotonin receptor agonist and increases the sense of fullness (Taylor 2013). Dietaryintervention studies in hypertensive people have shown a positive association between weight loss and blood pressure reduction (Horvath 2008). It therefore seems reasonable to suppose that medical weightreducing treatment may also lead to a fall in blood pressure. Why it is important to do this review For overweight or obese people with established hypertension, blood pressure should first be managed via nonpharmacological interventions such as weight reduction (CHEP 2014; ESHESC 2013; JNC 2014; NICE 2011; WHO 2005). Since antiobesity drugs may support the efforts of patients to reduce body weight, it is important that the physician be informed about the efficacy and potential harms of these drugs before prescribing them. Systematic reviews and metaanalyses have shown that pharmacological weightreducing interventions with orlistat, Horvath 2008 and Rucker 2007, rimonabant, Rucker 2007, lorcaserin, Chan 2013, and liraglutide, Zhang 2015, reduce both blood pressure and body weight. Treatment with sibutramine, Horvath 2008, Longterm effects of weightreducing drugs in people with hypertension (Review) 4

7 Rucker 2007, and Kim 2003, and naltrexone/bupropion, Caixas 2014, reduced body weight but did not lower blood pressure. None of these reviews provided data that could answer the question of whether pharmacological weight reduction lowers the risk of mortality and other patientrelevant endpoints. Two studies examining clinical endpoints for rimonabant, CRESCENDO 2010, and sibutramine, SCOUT 2010, have resulted in the drugs being withdrawn from the market. This left only orlistat as approved for the longterm treatment of obesity in the last updated version of this review. Since then, the FDA has approved four new drugs (lorcaserin, phentermine/topiramate, naltrexone/bupropion, and liraglutide) for the longterm treatment of obesity. This systematic review is an update of the previously published Cochrane review (Siebenhofer 2013). Types of participants Men and nonpregnant women 18 years of age or older with essential hypertension (baseline blood pressure of at least 140 mm Hg systolic and/or a diastolic blood pressure of at least 90 mm Hg or people on antihypertensive treatment), for whom at least one of the following outcomes was reported: mortality, cardiovascular outcomes, adverse events, or blood pressure. Types of interventions Monotherapy with drugs for longterm weight management (orlistat, sibutramine, rimonabant, phentermine/topiramate, lorcaserin, naltrexone/bupropion, or liraglutide). Types of outcome measures O B J E C T I V E S Primary objectives: To assess the longterm effects of pharmacologically induced reduction in body weight in adults with essential hypertension on allcause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total nonserious adverse events). Primary outcomes The primary outcomes were total mortality, cardiovascular morbidity, and adverse events (withdrawals due to adverse events, adverse events related to a certain antiobesity drug). Secondary outcomes Secondary outcomes were changes in systolic blood pressure, diastolic blood pressure, and body weight. Secondary objectives: To assess the longterm effects of pharmacologically induced reduction in body weight in adults with essential hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction. M E T H O D S Criteria for considering studies for this review Types of studies The study design must meet the following criteria: all randomised controlled trials comparing pharmacologic interventions approved for longterm weight management with placebo with a followup of at least 24 weeks. The reason for including only studies with a followup of at least 24 weeks was that studies of shorter duration cannot show longterm effects. Any additional active care (for example antihypertensive medication) must have been applied to the active treatment group and control group. Search methods for identification of studies Electronic searches For the update of the review we searched the following electronic databases until 13 April 2015 to identify randomised, placebocontrolled trials of orlistat, sibutramine, rimonabant, lorcaserin, phentermine/topiramate, naltrexone/bupropion, or liraglutide: Cochrane Hypertension Specialised Register (up to April 2015) Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 4) via the Cochrane Register of Studies Online Ovid MEDLINE and MEDLINE InProcess (1946 to April 2015) Ovid EMBASE (1980 to April 2015) The protocol stated that we considered only published papers for inclusion in this review. We also considered relevant data from one randomised controlled trial that had not yet been published for inclusion, as a manufacturing company (HoffmannLa Roche AG) provided relevant additional information for the Institute for Quality and Efficiency in Health Care report (IQWiG 2006). The Cochrane Hypertension Specialised Register includes searches of Longterm effects of weightreducing drugs in people with hypertension (Review) 5

8 the WHO International Clinical Trials Registry Platform. We also searched the clinical trials registry ClinicalTrials.gov and reference lists of included trials and relevant systematic reviews and metaanalyses. The updated searches were based on a combination of subject headings and text words as documented in Appendix 1. The search strategy used in the previous review versions is documented in Appendix 2 and Appendix 3. Searching other resources We searched the reference lists of all relevant studies and systematic reviews for additional studies. We contacted authors of included studies to request information about any other relevant unpublished or ongoing studies. Data collection and analysis 2.1. Characteristics of the trial The reported items included the design and duration of the trial, randomisation (and method), allocation concealment (and method), blinding (participants, people administering treatment, outcome assessors), and the check of blinding Characteristics of participants This information included the number of participants in each group, how the participants were selected (random, convenience), the exclusion criteria used, and the general characteristics (for example age, gender, nationality, ethnicity). We extracted diseaserelated information concerning duration of hypertension. We checked the similarity of groups at baseline as well as reports about withdrawals and losses to followup (reasons/description), describing these in the Risk of bias tables in Characteristics of included studies. If subgroups were analysed, the reported reasons and the method were noted. Selection of studies Two review authors independently screened the title and abstract of each reference identified by the search and applied the inclusion criteria. Potentially relevant studies were retrieved in full and again two review authors independently decided, whether these studies met the inclusion criteria. In case of disagreement, we also obtained the full article and the two review authors inspected it independently. Differences in opinion were resolved by a third party. If a resolution of the disagreement was not possible, we classified the article as awaiting assessment and contacted the authors of the study for clarification Characteristics of interventions The relevant information to be extracted was the duration of the intervention, length of followup (in months), the type of antiobesity drug (orlistat, sibutramine, rimonabant, lorcaserin, phentermine/topiramate, naltrexone/bupropion, or liraglutide), the dose, and the administration route Characteristics of outcome measures We reported the measures mentioned in the outcome section and any other outcomes measured in the study. Data extraction and management Two review authors independently extracted data using a data extraction form. Differences in data extraction were resolved by consensus, referring back to the original article. We sought information from the authors of the primary studies if necessary. We extracted, checked, and recorded the following data. 1. General information The general information included all publications of a single trial, the sponsor of the trial (specified, known or unknown), and the country of publication. 2. Methods section The information on the methods summarised the characteristics of the trial, participants, and interventions and the outcome measures used and reported in the publication. Assessment of risk of bias in included studies Two review authors independently assessed trials fulfilling the inclusion criteria in order to evaluate methodological quality. Any differences in opinion were resolved by discussion with a third review author. We assessed all trials using the Risk of bias assessment tool under the categories adequate sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other biases (Higgins 2011). Measures of treatment effect We calculated mean differences for changes in blood pressure and body weight. We considered fixedeffect and randomeffects models for the metaanalyses. In case of betweenstudy variability, we presented the results of the randomeffects model. If standard deviations were unavailable, we approximated them on the basis of P values and sample sizes. Longterm effects of weightreducing drugs in people with hypertension (Review) 6

9 Dealing with missing data We obtained relevant missing data from authors and from the Institute for Quality and Efficiency in Health Care report (IQWiG 2006). We evaluated important numerical data such as screened, eligible, and randomised patients as well as intentiontotreat (ITT) and perprotocol (PP) population. We investigated attrition rates, for example dropouts, losses to followup, and withdrawals. Issues of missing data, ITT, and PP were critically appraised and, if available, compared to the specification of primary outcome parameters and power calculations. R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies Assessment of heterogeneity We assessed heterogeneity using Higgins I 2. In case of substantial heterogeneity (I 2 greater than 50%), we planned to perform sensitivity analyses and subgroup analyses for the following items: study quality, PP versus ITT analyses, sex, age, body mass index, concomitant diseases, ethnicity, blood pressure at baseline, blood pressure goals, concomitant antihypertensive therapy, and socioeconomic status. Assessment of reporting biases We assessed publication bias and smallstudy effects in general using the funnel plot or other corrective analytical methods depending on the number of trials included in the systematic review. Data synthesis We summarised data statistically when they were available, sufficiently similar, and of sufficient quality. We performed analyses separately for each drug. We performed statistical analysis according to the statistical guidelines referenced in the newest version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Results of the search Our search of the electronic databases yielded 1047 records after correcting for duplication. The consensus was that on the basis of their abstracts, 903 of these were not relevant to the question under study and should be excluded. The Institute for Quality and Efficiency in Health Care report provided data of an unpublished subgroup analysis of hypertensive people in the Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) study (IQWiG 2006; XENDOS ). We included the results section of this report and one corresponding citation as two additional publications of potential relevance. We identified no further studies from the reference lists of the included trials and relevant systematic reviews and metaanalyses. We therefore identified 146 publications for further examination. Thirty publications describing nine studies finally met the inclusion criteria after screening the full text of the selected publications (see Figure 1 for details of the PRISMA (Preferred Reporting Items for Systematic Reviews and MetaAnalyses) statement ) (PRISMA 2009). Five publications on a potentially relevant ongoing trial were also among the excluded items because they only described the rationale for conducting the trial and its design (LEADER 2013). For details see Characteristics of ongoing studies. Longterm effects of weightreducing drugs in people with hypertension (Review) 7

10 Figure 1. Study flow diagram Longterm effects of weightreducing drugs in people with hypertension (Review) 8

11 All relevant studies were published after the year 2000 and were written in English, except the report from the Institute for Quality and Efficiency in Health Care, which was published in German. Included studies We have provided details of the characteristics of the included studies in the Characteristics of included studies table. The following gives a brief overview of the comparisons between orlistat and placebo, sibutramine and placebo, and phentermine/topiramate and placebo. No relevant study investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion was available for inclusion. Orlistat vs placebo All four included studies had a parallel, doubleblind design (Bakris 2002; Cocco 2005; GuyGrand 2004; XENDOS ). Only Cocco 2005 did not mention any industry sponsoring, and it was the only study that was performed as a singlecentre trial. Participants and duration The four included studies involved a total of 3132 hypertensive participants with a mean age of 46 to 55 years, a baseline systolic blood pressure (BP) of 142 to 154 mm Hg and a baseline diastolic BP of 85 to 98 mm Hg. Mean treatment duration was 6 to 48 months. Interventions Participants received either 120 mg orlistat three times daily or placebo in all studies. Outcomes Sibutramine vs placebo (marketing approval withdrawn) All four included studies had a parallel, doubleblind design and mentioned industry sponsorship (Fanghänel 2003; Faria 2002; McMahon 2000; McMahon 2002). Two studies were performed as singlecentre studies (Fanghänel 2003; Faria 2002); the two multicentre studies did not provide information on the numbers of study centres (McMahon 2000; McMahon 2002). Participants and duration The four included studies involved a total of 619 hypertensive participants with a mean age of 46 to 53 years, a baseline systolic BP of 129 to 150 mm Hg and a baseline diastolic BP of 82 to 94 mm Hg. Mean treatment duration was 6 to 12 months. Interventions Two studies compared 10 mg sibutramine versus placebo once daily (Fanghänel 2003; Faria 2002). In the two other studies ( McMahon 2000; McMahon 2002), the initial dose of 5 mg of sibutramine was titrated up to 20 mg once daily within the first eight weeks. Outcomes Primary outcomes No study included mortality and cardiovascular morbidity as predefined outcomes. All studies reported on adverse events. Secondary outcomes All studies described the mean change in systolic and diastolic BP and the mean change in body weight. Primary outcomes No study included mortality and cardiovascular morbidity as predefined outcomes. All studies reported adverse events. Secondary outcomes All studies described the mean change in systolic and diastolic BP and the mean change in body weight. Phentermine/topiramate vs placebo The new included study was a multicentre study with 93 study sites in the US (CONQUER 2013). The study had a parallel, doubleblind design and the industry sponsor was mentioned. Participants and duration The included study involved a total of 1305 participants in the hypertensive subgroup with a mean age of 53 years, a mean baseline systolic BP of 134 mm Hg and a mean baseline diastolic BP of 84 mm Hg. Among the hypertensive subgroup, 216 participants had Longterm effects of weightreducing drugs in people with hypertension (Review) 9

12 uncontrolled hypertension at baseline. The treatment duration was 56 weeks. Interventions The study compared two different dose regimens of phentermine/ topiramate once daily versus placebo. All participants in the active groups received an initial dose of 7.5 mg phentermine and 23 mg topiramate. During an initial fourweek titration period, doses were increased weekly (3.75 mg phentermine and 23 mg topiramate) until the assigned dosages of 7.5 mg phentermine/46.0 mg topiramate (group low dose) or 15 mg phentermine/92.0 mg topiramate (group high dose) were achieved. The assigned dosages were maintained for 52 weeks. Outcomes Primary outcomes The study did not include mortality and cardiovascular morbidity as predefined outcomes. Adverse events were reported. Secondary outcomes The study described the mean change in systolic and diastolic BP and the mean percentage change in body weight. Excluded studies The main reason for exclusion was a lack of data for the hypertensive subgroup in studies including normotensive as well as hypertensive participants. Other reasons for exclusion were not describing a randomised controlled trial, not including participants with essential hypertension, having a duration of intervention less than 24 weeks, reporting outcomes that were not relevant for this review, or including different accompanying antihypertensive therapies in the study groups. Reasons for excluding each trial are provided in the Characteristics of excluded studies table. Risk of bias in included studies The judgements of the risk of bias for all included studies are shown in the Risk of bias summary figures (Figure 2; Figure 3). For details see the Risk of bias tables in Characteristics of included studies. The following provides a brief overview. Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as percentages across all included studies. Longterm effects of weightreducing drugs in people with hypertension (Review) 10

13 Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included study. Longterm effects of weightreducing drugs in people with hypertension (Review) 11

14 Allocation Incomplete outcome data Orlistat vs placebo In one study the method of randomisation was not reported ( Bakris 2002), and in two studies the method of concealment was not described (Bakris 2002; Cocco 2005). Sibutramine vs placebo (marketing approval withdrawn) Only one study adequately described the method of randomisation and concealment (Fanghänel 2003). Phentermine/topiramate vs placebo The included study adequately described the method of randomisation and concealment (CONQUER 2013). Blinding Orlistat vs placebo In two studies, the outcome data description was complete: Cocco 2005 had no losses to followup, and Bakris 2002 described all reasons for withdrawals and losses to followup. In GuyGrand 2004, withdrawals were only reported for the whole study population and not for the hypertensive subgroup, and in XENDOS , the documentation of reasons for withdrawals was incomplete. Sibutramine vs placebo (marketing approval withdrawn) In none of the studies were outcome data adequately assessed. In Fanghänel 2003, 14% of randomised participants were not analysed, and Faria 2002 presented only a completers analysis. In both McMahon studies (McMahon 2000; McMahon 2002), some reasons for participants withdrawal from the study were not reported. Orlistat vs placebo While all included trials were described as double blind, three trials provided too little information, and the blinding of participants and key study personnel was uncertain (Bakris 2002; Cocco 2005; GuyGrand 2004). Based on the authors information, we can only assume that blinding took place throughout the duration of one study (Cocco 2005). Sibutramine vs placebo (marketing approval withdrawn) While all included trials were described as double blind, two trials provided too little information, and the blinding of participants and key study personnel was uncertain (McMahon 2000; McMahon 2002). In the other studies, we can assume that blinding occurred throughout the study duration for participants and study personnel, but no information was available on the blinding of outcome assessors. Phentermine/topiramate vs placebo The total number of withdrawals was only reported for the whole study population and not for the hypertensive subgroup of the study (CONQUER 2013). For the hypertensive subgroup, only the number of withdrawals due to adverse events was reported, therefore the documentation of reasons for withdrawals was incomplete. Selective reporting Orlistat vs placebo As either no study protocol was provided (Bakris 2002; Cocco 2005; GuyGrand 2004), or no full publication was obtainable (XENDOS ), or more outcomes were reported than were prespecified (Bakris 2002), we classified the risk of bias for selective reporting as uncertain for all studies. Phentermine/topiramate vs placebo The included study was described as double blind. The investigators, participants, and study sponsors were masked to treatment assignment, and all study drugs were administered as capsules that were identical in size and appearance (CONQUER 2013). Sibutramine vs placebo (marketing approval withdrawn) In none of the trials was a study protocol available. In addition, one study showed inconsistencies between different publications (Faria 2002), and another study had an inconsistent participant flow (Fanghänel 2003). We thus classified the risk of bias for selective reporting as uncertain for all studies. Longterm effects of weightreducing drugs in people with hypertension (Review) 12

15 Phentermine/topiramate vs placebo No study protocol was available for the study (CONQUER 2013). We thus classified the risk of bias for selective reporting as uncertain. Other potential sources of bias Orlistat vs placebo No trial included in the review reported any significant differences between groups in the main characteristics of participants at baseline. However, in Bakris 2002 and XENDOS , the combination of a high withdrawal rate and the unknown length of involvement of participants in the trial increases the risk of bias, even when last observation carried forward (LOCF) analysis is used. Sibutramine vs placebo (marketing approval withdrawn) Two studies provided only completers analyses with a high withdrawal rate (Fanghänel 2003; Faria 2002). In the two other trials, the unknown length of involvement of participants in the trial increases risk of bias, even when LOCF analysis is used (McMahon 2000; McMahon 2002). Phentermine/topiramate vs placebo We could identify no other potential source of bias in the included study (CONQUER 2013). Effects of interventions See: Summary of findings for the main comparison Summary of findings for orlistat versus placebo; Summary of findings 2 Summary of findings for sibutramine versus placebo Orlistat vs placebo See: Summary of findings for the main comparison Primary outcomes Mortality Three of four studies reported on mortality. No deaths were reported in either Bakris 2002 or Cocco In XENDOS , there were two deaths in the orlistattreated group in the first subgroup analysis (diastolic BP 90 mm Hg) and one death in the orlistat group in the second subgroup analysis (systolic BP 140 mm Hg). Cardiovascular morbidity Two studies presented data on cardiovascular morbidity. In Bakris 2002, two participants in the orlistat group suffered a myocardial infarction, two had chest pain, and one had an episode of atrial fibrillation. In the placebo group, one participant had a myocardial infarction, one had worsening atherosclerotic coronary artery disease, and two had an episode of chest pain. Cocco 2005 reported that in participants with resting left ventricular ejection fraction (LVEF) below 50% at baseline, LVEF did not change with placebo (0.6%), but was increased by 4.3% in the orlistat group (P < 0.001). Adverse events For details on adverse events see Table 1. Bakris 2002: At least one adverse event was reported by significantly more participants in the orlistattreated group (89%) than in the placebotreated group (71%) with a P value of < Of those, 7% of participants in the orlistat group versus 7% of participants in the placebo group withdrew. Twelve per cent of all adverse events in the orlistattreated group versus 9% in the placebotreated group were classified as serious adverse events, and none was classified as being related to study medication. Gastrointestinal side effects were significantly higher in the orlistattreated group than in the placebo group (73% versus 44%; P < 0.001); 8% of those participants in the orlistat group and 5% in the placebo group stopped taking the medication for this reason. Musculoskeletal side effects were also reported significantly more often in the orlistat versus the placebo group (23% versus 16%, P < 0.05). Cocco 2005: As reported by the authors, side effects were mild. No overall adverse events were reported. Gastrointestinal side effects were the most common adverse events and were described for 24% of the placebo group within the first three weeks and for 36% of the orlistat group within the first four weeks. GuyGrand 2004: Data were only presented for the whole study group, no information on the hypertensive subgroup was provided. XENDOS : First subgroup (diastolic BP 90 mm Hg): Side effects were reported in 99% of participants in the orlistat and 96% of participants in the placebo group. Eighteen per cent of participants in the orlistat group and 12% of participants in the placebo group experienced severe adverse events. Gastrointestinal side effects were more common in the orlistat versus the placebo group (93% versus 70%). Musculoskeletal, nervous, dermatological, and vascular events were comparable in both treatment groups. Nine per cent withdrew due to side effects in the orlistat versus 4% in the placebo group, but it is not clear whether the reported side effects were study drug related. Longterm effects of weightreducing drugs in people with hypertension (Review) 13

16 Second subgroup (systolic BP 140 mm Hg): Side effects were reported in 99% of participants in the orlistat and 97% of participants in the placebo group. Eighteen per cent of participants in the orlistat group and 12% of participants in the placebo group experienced severe adverse events. Gastrointestinal side effects were more common in the orlistat versus the placebo group (93% versus 71%). Musculoskeletal, nervous, dermatological, and vascular events were comparable in both treatment groups. Nine per cent withdrew due to side effects in the orlistat versus 4% in the placebo group. It is not clear whether the reported side effects were study drug related. Secondary outcomes For details on secondary outcome data see Table 2, Table 3, Table 4. Due to betweenstudy variability, we have presented results from randomeffects models in the following analyses. Changes in systolic blood pressure We could include all four studies investigating the effects of orlistat on systolic BP in the metaanalysis. For the XENDOS study ( XENDOS ), we used the results after 12 months study duration for the subgroup of participants with diastolic BP 90 mm Hg at baseline for the analysis. There was a significant reduction in systolic BP with a mean difference (MD) of 2.5 mm Hg (95% confidence interval (CI) 4.0 to 0.9) in favour of orlistat. The test of heterogeneity gave a P value of 0.2 (I 2 = 36%) (see Analysis 1.1, Figure 4). Differences in study quality could not explain heterogeneity. We could deduce no plausible explanation for heterogeneity from differences in study design, study duration, sample sizes, interventions, or characteristics of included participants. Figure 4. Forest plot of comparison: 1 Orlistat versus placebo, outcome: 1.1 Change in systolic blood pressure from baseline to endpoint [mm Hg]. Changes in diastolic blood pressure We could include all four studies investigating the effects of orlistat on diastolic BP in the metaanalysis. For the XENDOS study (XENDOS ), we used the results for the subgroup of participants with diastolic BP 90 mm Hg at baseline (subgroup 1) after 12 months study duration for the analysis. Diastolic BP was also significantly reduced in participants treated with orlistat with a MD of 1.9 mm Hg (95% CI 3.0 to 0.9). The test of heterogeneity gave a P value of 0.1 (I 2 = 47%) (see Analysis 1.2, Figure 5). Differences in study quality could not explain heterogeneity. We could deduce no plausible explanation for heterogeneity from differences in study design, study duration, sample sizes, interventions, or characteristics of included participants. Longterm effects of weightreducing drugs in people with hypertension (Review) 14

17 Figure 5. Forest plot of comparison: 1 Orlistat versus placebo, outcome: 1.2 Change in diastolic blood pressure from baseline to endpoint [mm Hg]. Body weight Orlistat was found to lower body weight significantly more effectively than placebo in all studies. The metaanalysis of orlistat studies obtained a MD of 3.7 kg (95% CI 4.7 to 2.8). The test of heterogeneity gave a P value of 0.03 (I 2 = 66%) (see Analysis 1.3, Figure 6). Differences in study quality could not explain heterogeneity. We could deduce no plausible explanation for heterogeneity from differences in study design, study duration, sample sizes, interventions, or characteristics of included participants. Figure 6. Forest plot of comparison: 1 Orlistat versus placebo, outcome: 1.3 Change in body weight from baseline to endpoint [kg]. Subgroup analyses Not performed due to lack of data. Sibutramine vs placebo (marketing approval withdrawn) See: Summary of findings 2 Primary outcomes Sensitivity analyses Not performed due to lack of data. Publication and smallstudy bias A clear interpretation of the funnel plot was not possible, which we mainly attributed to the relatively small number of included studies. Mortality Only one study reported on mortality (McMahon 2002), and there were no deaths in either treatment group. Cardiovascular morbidity Longterm effects of weightreducing drugs in people with hypertension (Review) 15

18 None of the four studies presented data on cardiovascular morbidity. constipation (17% versus 3%) were the most frequent side effects in the sibutramine group, with P < 0.05 for both comparisons. Adverse events For details on adverse events see Table 1. Fanghänel 2003: In the sibutramine group, 14 participants reported 21 adverse events. In the placebo group, 13 participants reported 20 adverse events. None of the adverse events were associated with withdrawals from treatment. The most common adverse events in the sibutramine group were constipation, headache, and dry mouth. Faria 2002: Overall numbers of adverse events were not reported. Dry mouth occurred significantly more often in the sibutramine group (37%) versus in the placebo group (9%) (P < 0.005). Participants also suffered significantly more often from arthralgia in the sibutramine group (16%) versus in the placebo group (2%) (P value = 0.03). McMahon 2002: Side effects were reported in 97% of participants in the sibutramine group versus 88% of participants in the placebo group, which was not statistically significantly different. Sixteen per cent of participants in the sibutramine group versus 5% in the placebo group discontinued because of adverse events. The main reason for discontinuation was a protocoldefined increase in blood pressure. The rates of withdrawal due to hypertension did not differ between the groups (P > 0.05). As absolute numbers were missing, we could not discern a trend in favour of either sibutramine or placebo. Headache and dry mouth were the most frequent side effects in the sibutramine group. The rates of serious adverse events of 6% in the sibutramine group versus 7% in the placebo group were comparable. Two events in the sibutramine group versus no events in the placebo group were possibly related to study drug. McMahon 2000: Overall numbers of adverse events and serious adverse events were not reported. Twenty per cent of participants in the sibutramine group versus 11% in the placebo group discontinued because of adverse events. The main reason for discontinuation was high blood pressure, reported in 5% of participants in the sibutramine group versus 1% in the placebo group. Dry mouth (19% versus 3%) and Secondary outcomes For details on secondary outcome data see Table 2, Table 3, Table 4. Changes in systolic blood pressure As variability measurements were not available, a metaanalysis was not possible. In two studies blood pressure decreased until study end in both treatment arms (Fanghänel 2003; Faria 2002). In one of these studies, the decrease in the placebo group was greater than in the sibutramine group, without reaching statistical significance (Fanghänel 2003). In the other study, systolic BP decreased more in the sibutramine group without reaching statistical significance (Faria 2002). The other two studies found an increase in systolic BP between baseline and followup. In one study, the mean increase in systolic BP between the treatment groups was statistically higher in the sibutramine group with a P value of 0.05 (McMahon 2002). The last study also showed a more pronounced increase in systolic BP in the sibutramine group versus the placebo group, but it was not statistically significant (McMahon 2000). Changes in diastolic blood pressure We could include two studies investigating the effects of sibutramine on diastolic BP in a metaanalysis. For McMahon 2000 and McMahon 2002, we could calculate standard deviations from provided P values. No variability measurements were available for the other studies (Fanghänel 2003; Faria 2002). A combined analysis for the diastolic BP of the remaining two studies by McMahon showed a statistically significant difference between sibutramine and placebo, with a detrimental effect in participants treated with sibutramine with a MD +3.2 mm Hg (95% CI +1.4 to +4.9) (McMahon 2000; McMahon 2002). The test of heterogeneity gave a P value of 0.9 (I 2 = 0%) (see Analysis 2.1, Figure 7). Figure 7. Forest plot of comparison: 2 Sibutramine versus placebo, outcome: 2.1 Change in diastolic blood pressure from baseline to endpoint [mm Hg]. Longterm effects of weightreducing drugs in people with hypertension (Review) 16