Long-term effects of weight-reducing drugs in hypertensive patients

  • Review
  • Intervention

Authors


Abstract

Background

All major guidelines for antihypertensive therapy recommend weight loss; anti-obesity drugs might be a helpful option.

Objectives

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

even though sibutramine and rimonabant have been withdrawn from the market.

Search methods

Studies were obtained from computerised searches of Ovid MEDLINE, EMBASE, CENTRAL and from hand searches in reference lists and systematic reviews (status as of 17th August, 2012).

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

After the updated literature search, the number of studies remained the same, with eight studies comparing orlistat or sibutramine to placebo fulfilling 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 lacking. Rimonabant and sibutramine have been withdrawn from the market for the time being.

Résumé scientifique

Effets à long terme des médicaments amaigrissants chez les patients hypertendus

Contexte

Toutes les principales directives d'un traitement antihypertenseur recommandent la perte de poids ; les médicaments amaigrissants pourraient être une option efficace.

Objectifs

Objectifs principaux :

Évaluer les effets à long terme d'une perte de poids induite pharmacologiquement avec de l'orlistat, de la sibutramine ou du rimonabant sur :

- la mortalité toutes causes confondues
- la morbidité cardiovasculaire
- les événements indésirables

Objectifs secondaires :
- variations de la pression artérielle systolique et/ou diastolique
- perte de poids

même si la sibutramine et le rimonabant ont été retirés du marché.

Stratégie de recherche documentaire

Des études ont été obtenues suite à des recherches informatiques effectuées dans Ovid MEDLINE, EMBASE, CENTRAL et suite à des recherches manuelles effectuées dans les listes bibliographiques et les revues systématiques (statut au 17 août 2012).

Critères de sélection

Des essais contrôlés randomisés réalisés chez des patients adultes hypertendus et d'une durée d'au moins 24 semaines comparant des interventions pharmacologiques (orlistat, sibutramine, rimonabant) visant à perdre du poids à un placebo. 

Recueil et analyse des données

Deux auteurs ont indépendamment évalué les risques de biais et extrait des données. Les études ont été groupées à l'aide d'une méta-analyse à effets fixes en l'absence d'une hétérogénéité significative entre les études (p > 0,1). Sinon, nous avons utilisé une méthode à effets aléatoires et examiné la cause de l'hétérogénéité.

Résultats principaux

Après la recherche bibliographique mise à jour, le nombre d'études est resté identique, huit études comparant l'orlistat ou la sibutramine à un placebo remplissant nos critères d'inclusion. Aucune étude pertinente examinant le rimonabant n'a été identifiée pour la perte de poids. Aucune étude n'incluait la mortalité et la morbidité cardiovasculaire comme critères de jugement prédéfinis. L'incidence d'effets secondaires gastrointestinaux était sensiblement supérieure chez les patients traités par orlistat par rapport à ceux traités par placebo. Les effets secondaires les plus fréquents de la sibutramine étaient la sécheresse buccale, la constipation et les céphalées. Chez les patients affectés à des régimes amaigrissants, l'orlistat ou la sibutramine étaient plus efficaces pour la perte de poids par rapport aux patients affectés aux groupes de soins standard/placebo. La diminution de la pression artérielle chez les patients suivant un traitement par orlistat était pour la pression artérielle systolique (PAS) : différence moyenne pondérée (DMP) : - 2,5 mmHg ; IC à 95 %, - 4,0 à - 0,9 mmHg et pour la pression artérielle diastolique (PAD) : DMP - 1,9 mmHg ; IC à 95 %, - 3,0 à - 0,9 mmHg. La méta-analyse montrait une augmentation de la DMP dans un traitement par sibutramine : DMP + 3,2 mmHg ; IC à 95 % + 1,4 à + 4,9 mmHg.

Conclusions des auteurs

Chez les patients avec une pression artérielle élevée, l'orlistat et la sibutramine permettaient de perdre du poids dans des proportions similaires. Dans les mêmes essais, l'orlistat diminuait la pression artérielle alors que la sibutramine l'augmentait. Aucun essai examinant le rimonabant chez des personnes ayant une pression artérielle élevée n'a pu être inclus. Des essais à long terme évaluant les effets de l'orlistat, la sibutramine et le rimonabant sur la mortalité et la morbidité sont inexistants. Le rimonabant et la sibutramine ont pour l'instant été retirés du marché.

Plain language summary

Long-term effects of weight-reducing drugs in hypertensive patients

Doctors often recommend that overweight patients with elevated blood pressure doctors lose weight and sometimes advocate taking anti-obesity drugs to assist in weight and blood pressure reduction. However, sibutramine was withdrawn from the market in 2010 and rimonabant in 2009, making orlistat the only anti-obesity drug to remain available. Orlistat and sibutramine have been shown to modestly reduce weight. Orlistat also reduced blood pressure but sibutramine increased blood pressure. No study investigating rimonabant was found. No evidence is available for effects of any of these drugs on death or morbidity. The most frequent side effects were gastrointestinal for orlistat and dry mouth, constipation and headache for sibutramine.

Résumé simplifié

Effets à long terme des médicaments amaigrissants chez les patients hypertendus

Les médecins recommandent souvent aux patients en surpoids présentant une pression artérielle élevée de perdre du poids, et ils leur conseillent parfois de prendre des médicaments anti-obésité pour les aider à perdre du poids et à diminuer leur pression artérielle. Cependant, la sibutramine a été retirée du marché en 2010 et le rimonabant en 2009, l'orlistat restant de ce fait le seul médicament anti-obésité disponible. L'orlistat et la sibutramine ont montré qu'ils avaient des effets modestes sur la perte de poids. L'orlistat diminuait également la pression artérielle, contrairement à la sibutramine. Aucune étude examinant le rimonabant n'a été trouvée. Aucun effet de ces médicaments n'a été démontré sur la mortalité ou la morbidité. Les effets secondaires les plus fréquents étaient des effets gastrointestinaux pour l'orlistat et la sécheresse buccale, la constipation et des céphalées pour la sibutramine.

Notes de traduction

Traduit par: French Cochrane Centre 22nd March, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux pour la France: Minist�re en charge de la Sant�

எளியமொழிச் சுருக்கம்

உயர் இரத்த அழுத்தம் உள்ள நோயாளிகளில் உடல்-எடையை குறைக்கும் மருந்துகளின் நீண்ட-கால விளைவுகள்

மருத்துவர்கள், உயர் இரத்த அழுத்தம் கொண்ட அதிக எடையுடைய நோயாளிகளுக்கு உடல் எடையை குறைக்க அடிக்கடி பரிந்துரைத்து மற்றும் சில நேரங்களில் உடல் எடை மற்றும் இரத்த அழுத்த குறைவிற்கு உறுதுணையாக உடற் பருமன் -போக்கி மருந்தகளை எடுத்துக்கொள்வதை ஆதரிப்பர். எனினும், 2010-ல் சிபுட்ராமின் மற்றும் 2009-ல் ரிமொபன்ட், சந்தையிலிருந்து திரும்பப் பெற்றுக்கொள்ளப்பட்டு,ஒர்லிஸ்டாட் மட்டுமே ஒரே உடற்பருமன்-போக்கி மருந்தாக கிடைக்கப்பெற செய்து விட்டன. ஒர்லிஸ்டாட் மற்றும் சிபுட்ராமின், உடல் எடையை மிதமான அளவில் குறைத்தன என காட்டப்படுள்ளது. ஒர்லிஸ்டாட் இரத்த அழுத்தத்தையும் குறைத்தது ஆனால் சிபுட்ராமின் இரத்த அழுத்தத்தை உயர்த்தியது. ரிமொபன்ட்-ஐ ஆராய்ந்த எந்த ஆய்வும் காணப்படவில்லை. மரணம் அல்லது நோயுற்ற நிலை ஆகியவற்றின் மேல் இந்த மருந்துகளின் விளைவுகளுக்கு எந்த ஆதாரமும் கிடைக்கப் பெறவில்லை. அதிக முறை நிகழும் பக்க விளைவுகளில், ஒர்லிஸ்டாட்-ற்கு இரையக-குடலிய சார்ந்தது ஆகும் மற்றும் சிபுட்ராமின்-ற்கு காய்ந்த வாய், மலச்சிக்கல் மற்றும் தலைவலி ஆகியவை ஆகும்.

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பாளர்கள்: சிந்தியா ஸ்வர்ணலதா ஸ்ரீகேசவன், தங்கமணி ராமலிங்கம், ப்ளசிங்டா விஜய், ஸ்ரீகேசவன் சபாபதி.

Background

Description of the condition

Hypertension is a chronic condition associated with an increased risk of cardiovascular mortality and morbidity. High blood pressure is estimated to lead to over 7 million deaths each year, about 13% of the total deaths world wide (WHO 2011). Lowering blood pressure levels in hypertensive patients has been shown to be an effective means of reducing cardiovascular morbidity and mortality.

Consistently, epidemiological investigations have found an association between high blood pressure and different lifestyles, one of them being excess body weight. Weight reduction is recommended in major guidelines as a first step intervention in the therapy of hypertensive patients (ESH-ESC 2007, WHO 2005, JNC 2003, NICE 2011, CHEP 2012). Body weight may be reduced by lifestyle modifications, or pharmacological or invasive interventions. For selected patients in whom lifestyle interventions are unsuccessful, anti-obesity drugs could help to reduce body weight.

Description of the intervention

Orlistat, sibutramine and rimonabant are the main anti-obesity drugs, but only orlistat has market approval for the long-term treatment of obesity. Sibutramine was also approved by the Food and Drug Administration (FDA) in 1997 and by the European Medicines Agency (EMA) in 1999. However, as a post-marketing requirement the EMA stipulated that the Sibutramine Cardiovascular Outcomes Trial (SCOUT 2010), a large patient oriented outcome study, be initiated in 2002. Preliminary results presented in October 2009 showed an increased risk of serious cardiovascular events (such as heart attack or stroke) among patients with known cardiovascular disease who were taking sibutramine. This led the FDA and EMA to recommend the suspension of the marketing authorisations. (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 U.S.market (FDA 2010a). Rimonabant received regulatory approval in several European countries in 2006, but never received Food and Drug Administration (FDA) approval since preclinical and clinical data raised concerns about an association between rimonabant intake and an increased incidence of psychiatric adverse events, including suicidality, an ill-defined constellation of neurological signs and symptoms, and seizures (FDA 2007). In October 2008, the European Medical Agency (EMA) recommended the suspension of rimonabant from the market because of newly available post-marketing analyses demonstrating detrimental effects vs. 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).

How the intervention might work

Anti-obesity drugs aim to reduce body weight and maintain weight reduction over a longer period. Orlistat is a gastric and pancreatic lipase inhibitor, sibutramine is a centrally acting monoamine-reuptake inhibitor and rimonabant is an endocannabinoid receptor antagonist (Padwal 2007). Dietary intervention studies in hypertensive patients have shown a positive association between weight loss and blood pressure reduction (Horvath 2008). Therefore, one might hypothesize that medical weight reducing treatment might also result in a blood pressure reduction.

Why it is important to do this review

For overweight patients with established hypertension, blood pressure should first be managed via non-pharmacological interventions such as weight reduction (ESH-ESC 2007, WHO 2005, JNC 2003, NICE 2011, CHEP 2012). Since anti-obesity drugs might 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.

Recently published reviews and meta-analyses have shown that pharmacological weight-reducing interventions with orlistat (Horvath 2008, Rucker 2007) and rimonabant (Rucker 2007) reduce both blood pressure and weight. Sibutramine treatment reduced body weight but did not lower blood pressure (Horvath 2008, Rucker 2007, Kim 2003). None of these reviews provided data to answer the question of whether the risk of mortality or other patient-relevant endpoints can be lowered by pharmacological weight reduction. Studies examining clinical endpoints were underway when the first version of the review was published. Since then, both the CRESCENDO trial for rimonabant (CRESCENDO 2010) and the SCOUT trial for sibutramine (SCOUT 2010) have been completed and the results have led to the drugs’ withdrawal from the market. .

This systematic review will represent an update of the previously published Cochrane review (Siebenhofer 2009).

Objectives

Primary objectives:

To assess the long-term effects of pharmacologically induced reduction in body weight in hypertensive patients 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

Methods

Criteria for considering studies for this review

Types of studies

The study design must meet the following criteria: All randomized controlled trials comparing pharmacologic interventions (orlistat, sibutramine, rimonabant) for weight loss with placebo with a follow up of at least 24 weeks. The reason for including only studies with a follow up of at least 24 weeks was that studies with shorter duration cannot show long-term effects. Any additional active care (e.g. antihypertensive medication) must have been applied to the active treatment group and control group.

Types of participants

Men and non-pregnant women >18 years old 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 patients on antihypertensive treatment), for whom at least 1 of the following outcomes was reported: mortality, cardiovascular outcomes, adverse events or blood pressure.

Types of interventions

Monotherapy with different doses of orlistat, sibutramine and rimonabant, either fixed or titrated as needed.

Types of outcome measures

Primary outcomes

The primary outcomes were total mortality, cardiovascular morbidity and adverse events (withdrawals due to adverse events, adverse events related to a certain anti-obesity drug).

Secondary outcomes

Secondary outcomes were the changes in systolic blood pressure, diastolic blood pressure and body weight.

Search methods for identification of studies

Electronic searches

The following electronic databases were searched to identify randomized, placebo-controlled trials of orlistat, sibutramine or rimonabant:

- Cochrane Central Register of Controlled Trials (CENTRAL) August 2012
- Ovid MEDLINE (1950 – August 2012)
- Ovid Embase (1988 – August 2012)

- ClinicalTrials.gov (searched on 29 January 2013)

The publication language was restricted to English, German, Dutch, French, Italian, Portuguese or Spanish. The protocol stated that only fully published papers were considered for inclusion in this review. In addition, relevant so far unpublished data from one RCT were considered for inclusion as a manufacturing company (Hoffmann-La Roche AG) provided relevant additional information for the IQWiG report (IQWiG 2006) on this topic.

The searches were based on a combination of subject headings and text words as documented in Appendix 1. The search strategy used in the original review is documented in Appendix 2.

Searching other resources

We also searched the reference lists of included trials and relevant systematic reviews and meta-analyses.

Data collection and analysis

Selection of studies

Two authors independently screened the title and abstract of each reference identified by the search and applied the inclusion criteria. When the two authors disagreed, the full article was obtained and inspected independently by both of them. Differences in opinion were resolved by a third party. If the disagreement could not be resolved, the article was classified as 'awaiting assessment' and the authors of the study were contacted for clarification.

Data extraction and management

Data from each included study were extracted by two independent authors using a data extraction form. Differences in data extraction were resolved by consensus, referring back to the original article. If necessary, information was sought from the authors of the primary studies. The following data were extracted, checked and recorded:

1. General Information

The general information included all publications on a single trial, the sponsor of the trial (specified, known or unknown) and the country of publication.

2. Methods Section

The information about the methods summarized the characteristics of the trial, the characteristics of participants, the characteristics of interventions and the outcome measures used and reported in the publication.

2.1. Characteristics of the trial

The reported items included the design and duration of the trial, randomization (and method), allocation concealment (and method), blinding (patients, persons administering treatment, outcome assessors) and the check of blinding.

2.2. Characteristics of participants

Information about the participants included the number of participants in each group, how the participants were selected (random, convenience), the exclusion criteria used and the general characteristics (e.g. age, gender, nationality, ethnicity). Disease-related information concerning duration of hypertension was extracted. The similarity of groups at baseline was checked as well as reports about withdrawals and losses to follow-up (reasons / description); these were described in the "Risk of bias" tables in the section Characteristics of included studies. If subgroups were analyzed, the reported reasons and the method were noted.

2.3. Characteristics of interventions

The relevant information to be extracted was the duration of intervention, the length of follow-up (in months), the type of anti-obesity drug (orlistat, sibutramine or rimonabant), the dose and route of administration.

2.4. Characteristics of outcome measures

The measures mentioned in the outcome section and any other outcomes measured in the study were reported.

Assessment of risk of bias in included studies

Trials fulfilling the review inclusion criteria were assessed independently by two authors to evaluate methodological quality. Any differences in opinion were resolved by discussion with a third author. All trials were assessed using the 'Risk of bias' assessment tool (COCHRANE 2011) under the categories adequate sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other biases.

Measures of treatment effect

Weighted mean differences (WMD) were calculated for the changes in blood pressure and body weight. Fixed and random effects models were considered for the meta-analyses. In case of between-study variability, the results of the random effects model were presented. Standard deviations were approximated on the basis of p-values and sample sizes if not available.

Dealing with missing data

Relevant missing data were obtained from authors and from the IQWiG report (IQWiG 2006). Important numerical data such as screened, eligible and randomized patients as well as intention-to-treat (ITT) and per-protocol (PP) population were evaluated carefully. Attrition rates, for example drop-outs, losses to follow-up and withdrawals were investigated. Issues of missing data, ITT and PP were critically appraised and compared to specification of primary outcome parameters and power calculation, if available.

Assessment of heterogeneity

Heterogeneity was assessed using Higgins I2. In case of substantial heterogeneity (I2>50%), we planned to perform sensitivity analyses and subgroup analyses for the following items: study quality, per-protocol vs. 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

Publication bias and small study effects in general were assessed using the funnel plot or other corrective analytical methods depending on the number of clinical trials included in the systematic review.

Data synthesis

Data were summarised statistically if they were available, sufficiently similar and of sufficient quality. Statistical analysis was performed according to the statistical guidelines referenced in the newest version of the Cochrane Handbook for Systematic Reviews of Interventions (COCHRANE 2011).

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

The search in the electronic databases yielded 1591 records, of which 1027 could be excluded as duplicates. Of the remaining 564 publications, 493 were excluded by consensus as not relevant to the question under study on the basis of their abstracts.
The Institute for Quality and Efficiency in Health Care report (IQWiG 2006) provided data of an unpublished subgroup analysis of hypertensive patients in the XENDOS study (XENDOS 2001-2006). The results section of this report and one corresponding citation were included as two additional publications of potential relevance. No further studies were identified from the reference lists of the included trials and of relevant systematic reviews and meta-analyses.
Seventy-three publications were identified for further examination.
After screening the full text of the selected publications, 11 publications on eight studies finally met the inclusion criteria (see Figure 1 for details of the PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses]statement (PRISMA 2009)).
All relevant studies were published after the year 2000 and written in English, except the report from the Institute for Quality and Efficiency in Health Care which is published in German.

Figure 1.

Study flow diagram

* IQWiG 2006

Included studies

Details of the characteristics of the included studies are given in the "Characteristics of included studies" table. The following gives a brief overview of the comparisons between orlistat vs. placebo and sibutramine vs. placebo. No relevant study investigating rimonabant was available for inclusion.

Orlistat vs. Placebo

All 4 included studies (Bakris 2002, Cocco 2005, Guy-Grand 2004, XENDOS 2001-2006) had a parallel, double-blind design. Only Cocco 2005 did not mention any industrial sponsoring. It was the only study that was performed as a single centre trial.

Participants and duration

The included 4 studies involved a total of 3132 hypertensive participants with a mean age of 46 to 55 years, a baseline systolic 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

In all studies patients received either 120 mg orlistat three times daily or placebo.

Outcomes
Primary outcomes

No study included mortality and cardiovascular morbidity as a pre-defined outcome. All studies reported adverse events.

Secondary outcomes

All studies described the mean change in systolic and diastolic blood pressure and the mean change in body weight.

Sibutramine vs. Placebo (marketing approval withdrawn)

All 4 included studies (Faria 2002, Fanghaenel 2003, McMahon 2000, McMahon 2002) had a parallel, double-blind design and all trials mentioned industrial sponsorship. Two studies were performed as single centre studies (Faria 2002, Fanghaenel 2003); there were two multicenter studies with numbers of study centres not provided (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 (Faria 2002, Fanghaenel 2003) compared 10 mg sibutramine vs. placebo once daily. In the two other studies (McMahon 2000, McMahon 2002), the initial dose of sibutramine 5 mg was titrated up to 20 mg once daily within the first eight weeks.

Outcomes
Primary outcomes

No study included mortality and cardiovascular morbidity as a pre-defined outcome. All studies reported on adverse events.

Secondary outcomes

All studies described the mean change in systolic and diastolic blood pressure and the mean change in body weight.

Excluded studies

The main reason for exclusion was a lack of (sufficient) results for the hypertensive subgroup in studies including normotensive as well as hypertensive patients. Only few studies were excluded because the study was not a randomized controlled trial, did not include patients with essential hypertension, had a duration of intervention less than 24 weeks, reported outcomes not relevant for this review or did not meet the prespecified criteria for publication language. Reasons for excluding each trial are listed in the "Characteristics of excluded studies" table.

Risk of bias in included studies

For details see "Risk of bias" tables in the section Characteristics of included studies . The following gives a brief overview.

Allocation

Orlistat vs. Placebo

In one study the method of randomization 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 (Fanghaenel 2003) adequately described the method of randomization and concealment.

Blinding

Orlistat vs. Placebo

While all included trials were described as double blind, in three trials information was insufficient, and blinding of participants and key study personnel was uncertain (Bakris 2002, Cocco 2005, Guy-Grand 2004). Only in one trial, based on the authors' information, can blinding throughout study duration be assumed (Cocco 2005).

Sibutramine vs. Placebo (marketing approval withdrawn)

While all included trials were described as double blind, in two trials information was insufficient and blinding of participants and key study personnel was uncertain (McMahon 2000, McMahon 2002). In the other studies, blinding can be assumed throughout study duration for patients and study personnel, but no information was available on blinding of the outcome assessors.

Incomplete outcome data

Orlistat vs. Placebo

In two studies, outcome data description was complete: Cocco 2005 had no losses to follow-up and Bakris 2002 described all reasons for withdrawals and losses to follow-up.

In Guy-Grand 2004, withdrawals were only reported for the whole study population and not for the hypertensive subgroup, and in XENDOS 2001-2006 documentation of reasons for withdrawals was incomplete.

Sibutramine vs. Placebo (marketing approval withdrawn)

In none of the studies were outcome data adequately assessed. In Fanghaenel 2003, 14% of randomized patients were not analysed and Faria 2002 presented only a completers analysis. In both McMahon studies (McMahon 2000, McMahon 2002), some reasons for patients’ withdrawal from the study were not reported.

Selective reporting

Orlistat vs. Placebo

As either no study protocol was provided (Bakris 2002, Cocco 2005, Guy-Grand 2004) or no full publication was obtainable (XENDOS 2001-2006) or more outcomes were reported than were pre-specified (Bakris 2002), the risk of bias for selective reporting is classified as being uncertain for all studies.

Sibutramine vs. Placebo (marketing approval withdrawn)

In none of the trials was a study protocol available. In addition, one study (Faria 2002) had inconsistencies between different publications and another study (Fanghaenel 2003) had an inconsistent patient flow. The risk of bias for selective reporting thus is classified as uncertain for all studies.

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 2001-2006, the combination of a high withdrawal rate and the unknown length of participation of subjects in the trial increases the risk of bias, even when the last observation carried forward analysis is used.

Sibutramine vs. Placebo (marketing approval withdrawn)

Two studies provided only completers analyses (Fanghaenel 2003, Faria 2002) with a high withdrawal rate. In the two other trials, the unknown length of participation of subjects in the trial increases risk of bias, even when the last observation carried forward analysis is used (McMahon 2000, McMahon 2002).

Effects of interventions

Orlistat vs. Placebo

Primary outcomes
Mortality

Three of four studies reported on mortality. Neither in Bakris 2002 nor in Cocco 2005 were there any deaths. In XENDOS 2001-2006, there were 2 deaths in the orlistat treated group in the first subgroup analysis (diastolic BP ≥ 90 mm Hg) and 1 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, 2 patients in the orlistat group suffered from a myocardial infarction, 2 had chest pain and 1 had an episode of atrial fibrillation. In the placebo group, 1 had a myocardial infarction, 1 had a worsening of atherosclerotic coronary artery disease and 2 had an episode of chest pain.

Cocco 2005 reported in patients with resting left ventricular ejection fraction (LVEF) below 50% at baseline that 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.

Table 1. Adverse events
  1. E: Events. nr: not reported. [O]: Orlistat. [OD]: Orlistat and diastolic blood pressure ≥ 90 mm Hg. [OS]: Orlistat and systolic blood pressure ≥140 mm Hg. P: Patients. [P]: Placebo. [PD]: Placebo and diastolic blood pressure ≥ 90 mm Hg. [PS]: Placebo and systolic blood pressure ≥ 140 mm Hg. [S]: Sibutramine.

    a: No data on adverse events were reported for the whole study duration. The data above refer to 4 and 3 weeks of treatment in the orlistat and placebo group, respectively. After 3 months the number of patients with events decreased to 5(11%)[O] with flatulence and mild abdominal cramps vs 6(13%)[P] with nausea and hunger feeling.

    b: Data are not available for the hypertensive subgroup, but only for the whole study population (withdrawal due to defecation troubles in 10 [O] vs. 2 [P] patients).

StudyAdverse eventsResults
Orlistat vs. Placebo

Bakris

2002

total

thereof leading to withdrawal

serious

gastrointestinal

thereof leading to withdrawal

musculoskeletal

89% of P [O] vs. 71% of P [P], p<0.001

7% [O] vs. 7% [P]

14 P (12%) [O] vs. 15 P (9%) [P]

200 P (73%) [O] vs. 120 P (44%) [P], p<0.001

15 P (8%) [O] vs. 6 P (5%) [P]

23% of P [O] vs. 16% [P], p<0.05

Cocco

2005

total

serious

gastrointestinal

nr

0 P [O] vs. 0 P [P]

16 P (36%) [O]a vs. 11 P (24%) [P]a

Guy-Grand

2004

total

serious

nrb

nrb

XENDOS

2001-2006

total

leading to withdrawal

serious

gastrointestinal

musculoskeletal

nervous system

dermatological

vascular

99% of P [OD] vs. 96% of P [PD]

99% of P [OS] vs. 97% of P [PS]

9% of P [OD] vs. 4% of P [PD]

9% of P [OS] vs. 4% of P [PS]

18% of P [OD] vs. 12% of P [PD]

18% of P [OS] vs. 12% of P [PS]

93% of P [OD] vs. 70% of P [PD]

93% of P [OS] vs. 71% of P [PS]

65% of P [OD] vs. 62% of P [PD]

65% of P [OS] vs. 63% of P [PS]

39% of P [OD] vs. 39% of P [PD]

40% of P [OS] vs. 37% of P [PS]

20% of P [OD] vs. 17% of P [PD]

22% of P [OS] vs. 17% of P [PS]

17% of P [OD] vs. 19% of P [PD]

17% of P [OS] vs. 19% of P [PS]

Sibutramine vs. Placebo

Fanghaenel

2003

total

constipation

dizziness

dry mouth

headache

insomnia

restlessness

14 P (21 E) [S] vs. 13 P (20 E) [P]

4 P [S] vs. 2 P [P]

1 P [S] vs. 1 P [P]

4 P [S] vs. 2 P [P]

5 P [S] vs. 2 P [P]

1 P [S] vs. 1 P [P]

1 P [S] vs. 0 P [P]

Faria

2002-2005

total

dry mouth

arthralgia

nr

37% of P [S] vs. 9% of P [P], p<0.005

16% of P[S] vs. 2% of P [P], p=0.03

McMahon

2002

total

serious

treatment related

leading to withdrawal

(mostly hypertension)

dry mouth

headache

141 P (97%) [S] vs. 65 P (88%) [P]

9 P (6%) [S] vs. 5 P (7%) [P]

2 E [S] vs. 0 E [P]

23 P (16%) [S] vs. 4 P (5%) [P]

30 P (21%) [S] vs. 0 P [P]

41 P (28%) [S] vs. 17 P (23%) [P]

McMahon

2000

total

leading to withdrawal

(mostly hypertension)

dry mouth

headache

constipation

rash

nr

30 P (20%) [S] vs. 8 P (11%) [P]

29 P (19%) [S] vs. 2 P (3%) [P], p<0.05

37 P (25%) [S] vs. 21 P (28%) [P]

25 P (17%) [S] vs. 2 P (3%) [P], p<0.05

16 P (11%) [S] vs. 2 P (3%) [P]

Bakris 2002:

At least one adverse event was reported by significantly more patients in the orlistat-treated group (89%) than in the placebo-treated group (71%) with a p-value of p<0.001. Of those, 7% patients in the orlistat vs. 7% patients in the placebo group withdrew. 12% in the orlistat-treated group vs. 9% in the placebo-treated group were classified as serious adverse events and none was classified as being related to study medication. Gastrointestinal side effects in the orlistat-treated group were significantly higher than in the placebo group (73% vs. 44%; p<0.001); of those, 8% in the orlistat and 5% in the placebo group stopped the medication for this reason. Musculoskeletal side effects were reported significantly more often in the orlistat vs. the placebo group as well (23% vs. 16%, p<0.05).

Cocco 2005:

As reported by the authors, side effects were mild. No results were presented on overall adverse events. Gastrointestinal side effects were the most common and were described in 24% in the placebo group within the first 3 weeks and in 36% in the orlistat group within the first 4 weeks.

Guy-Grand 2004:

Data were only presented for the whole study group, no information on the hypertensive subgroup was provided.

XENDOS 2001-2006:

First subgroup (diastolic BP ≥ 90 mm Hg): Side effects were reported in 99% of patients in the orlistat and 96% of patients in the placebo group. 18% of patients in the orlistat group and 12% of patients in the placebo group had severe adverse events. Gastrointestinal side effects were more common in the orlistat vs. the placebo group (93% vs. 70%). Musculoskeletal, nervous, dermatological and vascular events were comparable in both treatment groups. There were 9% withdrawals due to side effects in the orlistat vs. 4% in the placebo group, but it is not clear whether the reported side effects were study drug related.

Second subgroup (systolic BP ≥ 140 mm Hg): Side effects were reported in 99% of patients in the orlistat and 97% of patients in the placebo group. Eighteen percent of patients in the orlistat group and 12% of patients in the placebo group had severe adverse events. Gastrointestinal side effects were more common in the orlistat vs. the placebo group (93% vs. 71%). Musculoskeletal, nervous, dermatological and vascular events were comparable in both treatment groups. There were 9% withdrawals due to side effects in the orlistat vs. 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 between-study variability, results from random effects models are presented in the following analyses.

Table 2. Body weight
  1. Mo: Months. nr: not reported. [O]: Orlistat. [OD]: Orlistat and diastolic blood pressure ≥ 90 mm Hg. [OS]: Orlistat and systolic blood pressure ≥140 mm Hg. P: Patients. [P]: Placebo. [PD]: Placebo and diastolic blood pressure ≥ 90 mm Hg. [PS]: Placebo and systolic blood pressure ≥ 140 mm Hg. [S]: Sibutramine. SD: Standard deviation.

    a: Mean kg (SD), unless otherwise indicated.

    b: Data are reported for 267 of 278 [O] and 265 of 276 [P] patients only.

    c: Reported as being the standard deviation but probably the standard error due to its small number.

    d: Published values are different but data were corrected after personal communication with the author.

    e: 95% confidence interval.

StudyBaselinea6 Moa12 Moa48 Moa

Change

from baseline

to endpointa

Orlistat vs. Placebo

Bakris 2002b

Orlistat

Placebo

101 (1)c

102 (1)c

nr

nr

nr

nr

-

-

p<0.001

-5.4 (6.4)

-2.7 (6.4)

Cocco 2005

Orlistat

Placebo

107 (6)

106 (6)

102 (4)

104 (5)

-

-

-

-

p<0.001

-5.4d

-2.5d

Guy-Grand 2004

Orlistat

Placebo

94 (1)c

94 (1)c

nr

nr

-

-

-

-

p<0.0001

-5.8 (0.3)

-1.8 (0.2)

XENDOS 2001-2006

Orlistat [OD]

Placebo [PD]

Orlistat [OS]

Placebo [PS]

117 (18)

115 (18)

117 (17)

116 (18)

106 (17)

108 (18)

106 (17)

109 (18)

105 (18)

108 (19)

105 (17)

110 (19)

110 (19)

111 (20)

110 (18)

113 (19)

p<0.001

-6.6 (8.6)

-3.8 (7.8)

p<0.001

-6.8 (8.7)

-3.2 (7.4)

Sibutramine vs. Placebo

Fanghaenel 2003

Sibutramine

Placebo

75 (10)

78 (9)

70 (10)

75 (9)

-

-

-

-

significant

-5.5 (-3.8; -7.1)e

-3.4 (-1.9; -5.0)e

Faria 2002-2005

Sibutramine

Placebo

100 (19)

97 (14)

93 (18)

94 (15)

-

-

-

-

p<0.001

-6.8 (2.3) vs.

-2.4 (4.2);

McMahon 2002

Sibutramine

Placebo

97 (16)

99 (14)

nr

nr

nr

nr

-

-

p<0.05

-4.5

-0.4

McMahon 2000

Sibutramine

Placebo

97 (13)

96 (17)

nr

nr

nr

nr

-

-

p<0.05

-4.4

-0.5

Table 3. Systolic blood pressure
  1. Mo: Months. nr: not reported. [O]: Orlistat. [OD]: Orlistat and diastolic blood pressure ≥ 90 mm Hg. [OS]: Orlistat and systolic blood pressure ≥140 mm Hg. P: Patients. [P]: Placebo. [PD]: Placebo and diastolic blood pressure ≥ 90 mm Hg. [PS]: Placebo and systolic blood pressure ≥ 140 mm Hg. [S]: Sibutramine. SD: Standard deviation.

    a: Mean kg (SD), unless otherwise indicated.

    b: Data are reported for 267 of 278 [O] and 265 of 276 [P] patients only.

    c: Reported as being the standard deviation but probably the standard error due to its small number.

    d: Based on LOCF-data on 399 [OD], 423 [PD], 493 [OS] and 504 [PS] patients.

    e: Data at baseline were recorded after a 2-weeks washout-period of antihypertensiv drugs for diagnostic confirmation of hypertension.

    f: Calculated.

StudyBaselinea6 Moa12 Moa48 Moa

Change

from baseline

to endpointa

Orlistat vs. Placebo

Bakris 2002b

Orlistat

Placebo

154 (13)

151 (13)

nr

nr

nr

nr

-

-

ns

-13.3 (15.2)

-11.0 (15.0)

Cocco 2005

Orlistat

Placebo

146 (10)

142 (6)

142 (13)

141 (9)

-

-

-

-

p=0.025

-4.3

-0.9

Guy-Grand 2004

Orlistat

Placebo

150 (1)c

152 (1)c

nr

nr

-

-

-

-

ns

-9.8 (1)

-9.8 (1)

XENDOS 2001-2006

Orlistat [OD]d

Placebo [PD]d

Orlistat [OS]d

Placebo [PS]d

146 (13)

146 (12)

149 (10)

149 (8)

135 (14)

136 (15)

125 (14)

138 (14)

135 (14)

138 (16)

135 (14)

140 (14)

137 (15)

139 (16)

138 (15)

140 (15)

p<0.024

-8.8 (14.8)

-6.4 (15.1)

p<0.002

-11.5 (14.9)

-8.6 (14.3)

Sibutramine vs. Placebo

Fanghaenel 2003e

Sibutramine

Placebo

139 (9)

139 (13)

125 (9)

123 (10)

-

-

-

-

ns

-13.9f

-16.5f

Faria 2002-2005

Sibutramine

Placebo

150 (18)

150 (15)

146 (15)

149 (22)

-

-

-

-

ns

-4.6f

-0.6f

McMahon 2002

Sibutramine

Placebo

129 (11)

129 (11)

nr

nr

133

130

-

-

p=0.0497

3.8

1.1

McMahon 2000

Sibutramine

Placebo

134 (10)

134 (11)

nr

nr

nr

nr

-

-

ns

2.7

1.5

Table 4. Diastolic blood pressure
  1. Mo: Months. nr: not reported. [O]: Orlistat. [OD]: Orlistat and diastolic blood pressure ≥ 90 mm Hg. [OS]: Orlistat and systolic blood pressure ≥140 mm Hg. P: Patients. [P]: Placebo. [PD]: Placebo and diastolic blood pressure ≥ 90 mm Hg. [PS]: Placebo and systolic blood pressure ≥ 140 mm Hg. [S]: Sibutramine. SD: Standard deviation.

    a: Mean kg (SD), unless otherwise indicated.

    b: Data are reported for 267 of 278 [O] and 265 of 276 [P] patients only.

    c: The SD was published as being 35 but probably should be 3.5.

    d: Reported as being the standard deviation but probably the standard error due to its small number.

    e: Based on LOCF-data on 399 [OD], 423 [PD], 493 [OS] and 504 [PS] patients.

    f: Data at baseline were recorded after a 2-weeks washout-period of antihypertensiv drugs for diagnostic confirmation of hypertension.

    g: Calculated.

StudyBaselinea6 Moa12 Moa48 Moa

Change

from baseline

to endpointa

Orlistat vs. Placebo

Bakris 2002b

Orlistat

Placebo

98 (4)

98 (4)c

nr

nr

nr

nr

-

-

p=0.002

-11.4 (8.3)

-9.2 (8.4)

Cocco 2005

Orlistat

Placebo

88 (7)

85 (6)

84 (9)

85 (7)

-

-

-

-

p=0.012

-3.6

-0.8

Guy-Grand 2004

Orlistat

Placebo

97 (0)d

97 (0)d

nr

nr

-

-

-

-

ns

-7.5 (0.6)

-7.3 (0.6)

XENDOS 2001-2006

Orlistat [OD]e

Placebo [PD]e

Orlistat [OS]e

Placebo [PS]e

95 (6)

95 (5)

91 (9)

91 (8)

86 (8)

88 (9)

84 (9)

87 (9)

86 (8)

88 (10)

85 (9)

88 (10)

87 (9)

89 (10)

86 (9)

88 (10)

p<0.006

-8.1 (9.3)

-6.2 (9.9)

p<0.001

-5.0 (9.9)

-3.0 (10.4)

Sibutramine vs. Placebo

Fanghaenel 2003f

Sibutramine

Placebo

93 (7)

92 (8)

82 (5)

80 (5)

-

-

-

-

ns

-11.4g

-11.7g

Faria 2002-2005

Sibutramine

Placebo

91 (12)

94 (12)

92 (13)

92 (14)

-

-

-

-

ns

1.0g

-2.06g

McMahon 2002

Sibutramine

Placebo

82 (6)

83 (6)

nr

nr

86

83

-

-

p=0.004

3.0

-0.1

McMahon 2000

Sibutramine

Placebo

84 (5)

84 (6)

nr

nr

nr

nr

-

-

p<0.05

2.0

-1.3

Changes in systolic blood pressure

All four studies investigating the effects of orlistat on systolic blood pressure could be included in the meta-analysis. For the XENDOS study (XENDOS 2001-2006), the results after 12 months’ study duration for the subgroup of patients with diastolic blood pressure ≥ 90 mm Hg at baseline were used for the analysis. There was a significant reduction of SBP with a WMD of -2.5 mm Hg (95% CI: -4.0 to -0.9) in favour of orlistat. The test of heterogeneity gave a p-value of 0.2 ( I2 = 36%) (see Analysis 1.1, Figure 2). Differences in study quality could not explain heterogeneity. No plausible explanation for heterogeneity could be deduced from differences in study design, study duration, sample sizes, interventions or characteristics of included patients.

Figure 2.

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

All four studies investigating the effects of orlistat on diastolic blood pressure could be included in the meta-analysis. For the XENDOS study (XENDOS 2001-2006), the results for the subgroup of patients with diastolic blood pressure ≥ 90 mm Hg at baseline (subgroup 1) after 12 months of study duration were used for the analysis. DBP was also significantly reduced in patients treated with orlistat with a WMD of -1.9 mm Hg (95% CI: -3.0 to -0.9) The test of heterogeneity gave a p-value of 0.1 ( I2 = 47%) (see Analysis 1.2, Figure 3). Differences in study quality could not explain heterogeneity. No plausible explanation for heterogeneity could be deduced from differences in study design, study duration, sample sizes, interventions or characteristics of included patients.

Figure 3.

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 meta-analysis of orlistat studies obtained a WMD of -3.7 kg (95% CI: -4.7 to -2. 8). The test of heterogeneity gave a p-value of 0.03 ( I2 = 66%) (see Analysis 1.3, Figure 4). Differences in study quality could not explain heterogeneity. No plausible explanation for heterogeneity could be deduced from differences in study design, study duration, sample sizes, interventions or characteristics of included patients.

Figure 4.

Forest plot of comparison: 1 Orlistat versus Placebo, outcome: 1.3 Change in body weight from baseline to endpoint [kg].

Heterogeneity

See appropriate statements in the outcomes section.

Subgroup analyses

Not performed due to lack of data.

Sensitivity analyses

Not performed due to lack of data.

Publication an small study bias

A clear interpretation of the funnel plot was not possible, which we mainly attributed to the relatively small number of included studies

Sibutramine vs. Placebo (marketing approval withdrawn)

Primary outcomes
Mortality

Only one study reported on mortality (McMahon 2002) and there was no death in either treatment group.

Cardiovascular morbidity

None of the four studies presented data on cardiovascular morbidity.

Adverse events

For details on adverse events see Table 1.

Fanghaenel 2003:

In the sibutramine group, 14 patients reported 21 adverse events. In the placebo group, 13 patients experienced 20 adverse events. None of the adverse events were associated with withdrawals from treatment. Most common were constipation, headache and dry mouth in the sibutramine group.

Faria 2002:

Overall numbers of adverse events were not reported. Dry mouth in 37% in the sibutramine group occurred significantly more often vs. 9% in the placebo group (p<0.005). Patients also suffered significantly more often from arthralgia in the sibutramine group (16%) vs. in the placebo group (2%), with a p-value of 0.03.

McMahon 2002:

Side effects were reported in 97% of patients in the sibutramine group vs. 88% of patients in the placebo group, which was not statistically significantly different. 16% of patients in the sibutramine group vs. 5 % in the placebo group discontinued because of adverse events. Main reasons for discontinuation were a protocol-defined exceeding of blood pressure. The rates of withdrawal due to hypertension did not differ between the groups (p>0.05). As absolute numbers were missing, not even a trend in favour of either sibutramine or placebo could be discerned. Headache and dry mouth were the most frequent side effects in the sibutramine group. Rate of serious adverse events with 6% in the sibutramine vs. 7% in the placebo group were comparable. Two events in the sibutramine vs. none in the placebo group were possibly related to study drug.

McMahon 2000:

Overall numbers of adverse events and serious adverse events were not reported. 20% of patients in the sibutramine group vs. 11% in the placebo group discontinued because of adverse events. Main reasons for discontinuation were high blood pressure reported for 5% in the sibutramine vs. 1 % in the placebo group. Dry mouth (19% vs. 3%) and constipation (17% vs. 3%) were the most frequent side effects in the sibutramine group with p<0.05 for both comparisons.

Secondary outcomes

For details on secondary outcome data see Table 2, Table 3, Table 4 .

Changes in systolic blood pressure

A meta-analysis was not possible as variability measurements were not available. In two studies in both treatment arms the blood pressure decreased until study end (Fanghaenel 2003, Faria 2002). In one of these, the decrease in the placebo group was higher than in the sibutramine group, without reaching statistical difference (Fanghaenel 2003). In the other study, systolic blood pressure decreased more in the sibutramine group without reaching any statistical significance (Faria 2002). The other two studies found an increase in systolic blood pressure between baseline and follow up. In one study, the mean increase in systolic blood pressure between the treatment groups was statistically higher in the sibutramine group with a p-value of 0.05 (McMahon 2002). The last study did also show a more pronounced increase in systolic blood pressure in the sibutramine group vs. the placebo group without being statistically significant (McMahon 2000).

Changes in diastolic blood pressure

Two studies investigating the effects of sibutramine on diastolic blood pressure could be included in a meta-analysis. For McMahon 2000 and McMahon 2002, standard deviations could be calculated from p-values presented. For the other studies, no variability measurements were available (Fanghaenel 2003, Faria 2002).

A combined analysis for DBP of the remaining two studies by McMahon (McMahon 2000, McMahon 2002) showed a statistically significant difference between sibutramine and placebo, with a detrimental effect in patients treated with sibutramine with a WMD +3.2 mm Hg (95% CI: +1.4 to +4.9). The test of heterogeneity gave a p-value of 0.9 ( I2=0%) (see Analysis 2.1, Figure 5).

Figure 5.

Forest plot of comparison: 2 Sibutramine versus Placebo, outcome: 2.1 Change in diastolic blood pressure from baseline to endpoint [mm Hg].

The other 2 studies showed the following results: A decrease in diastolic blood pressure in both treatment groups in one trial (Fanghaenel 2003), without any statistically significant difference between the groups. In the other study (Faria 2002), diastolic blood pressure decreased in the placebo group only, whereas an increase in diastolic blood pressure in the sibutramine group was observed. This difference was not statistically significantly different.

Body weight

Sibutramine was found to lower body weight significantly more effectively than placebo in all four studies. The meta-analysis of sibutramine studies obtained a WMD of -3.7 kg (95% CI: -4.8 to -2.6). The test of heterogeneity gave a p-value of 0.4 ( I2 = 3%) (see Analysis 2.2, Figure 6).

Figure 6.

Forest plot of comparison: 2 Sibutramine versus Placebo, outcome: 2.2 Change in body weight from baseline to endpoint [kg].

Heterogeneity

The meta-analysis performed provided homogeneous results.

Subgroup analyses

Not performed due to lack of data.

Sensitivity analyses

Not performed due to lack of data.

Publication and small study bias

A clear interpretation of the funnel plot was not possible, which we attributed to the small number of included studies.

Discussion

Summary of main results

This updated systematic review attempted to determine the long-term effects of weight loss through pharmacological intervention on patient relevant endpoints, namely death and cardiovascular complications, in the antihypertensive therapy of patients with essential hypertension, but found that currently, no randomized controlled trials designed to answer this question are available. Our search revealed only short-term studies mainly evaluating the effects on body weight, blood pressure and adverse events. We identified no new study as a result of the update and only four relevant orlistat and four relevant sibutramine trials remained. No study examining rimonabant could be included in this review as the only potentially relevant trial failed to present analyses of hypertensive patients.

We found that of the four studies on the effects of orlistat included in our analyses, only one was judged as having major deficiencies of study quality. The meta-analyses showed that patients under therapy with orlistat could reduce their weight and blood pressure levels statistically significantly more than patients in the placebo groups. While these results show that orlistat may be a helpful option in the antihypertensive therapy of obese hypertensive patients, some questions still remain. First, patients with orlistat therapy experienced side effects to a high degree, foremost of a gastrointestinal nature. This might limit the effectiveness of the medication in settings outside of scientific studies. Furthermore, it remains unclear whether blood pressure levels will remain low over a longer period of time or once the medication is discontinued, since some investigations found body weight to increase again after one year, whether or not orlistat was continued (Davidson 1999, Sjostrom 1998).

Even though sibutramine reduced body weight to about the same extent as orlistat, it did not show the same beneficial effects on blood pressure. In two studies using a dosage of 20 mg per day, which is higher than the currently approved dosage (in Germany) of 10 to 15 mg per day, blood pressure even rose in patients treated with sibutramine. This finding is further underlined by the result of a head–to-head comparison of orlistat vs. sibutramine (Derosa 2005). It was found that while in patients in the orlistat group (120 mg three times a day) a reduction of -8.4 kg body weight resulted in a reduction of SBP and DBP of -4.0 and -3.0 mm Hg respectively, the same loss of body weight of -8.3 kg in the sibutramine group did not cause a change in blood pressure in patients treated with sibutramine 10 mg per day (0.0 and 0.0 mm Hg respectively). In a meta-analysis by Kim et al. (Kim 2003) comparing sibutramine with placebo in patients with or without hypertension at baseline, a significant increase of SBP (+1.6 ) and DBP (+1.8 mm Hg) was also found in the sibutramine treatment group despite a large effect on weight loss in this group. As there are safety concerns in hypertensive patients, the European Medical Agency (EMA) demanded a long-term trial in patients with high cardiovascular risks and the Sibutramine Cardiovascular Outcome trial (SCOUT) was initiated. This double-blind, randomized, placebo-controlled outcome trial in approximately 10,000 overweight/obese cardiovascular high –risk patients started recruitment in December 2002 and has been designed to determine the impact of weight loss in 10742 patients (SCOUT 2010). After a mean duration of 3.5 years 11.4% of patients in the sibutramine and 10.0% in the placebo group had a primary outcome event. These were either a non-fatal myocardial infarction, a non-fatal stroke, resuscitation after cardiac arrest, or cardiovascular death [Hazard Ratio (HR): 1.16; 95% CI, 1.03-1.31; p=0.02; NNH: 71]. As any observed loss in body weight was only modest, the FDA and EMA concluded that the risk of an adverse cardiovascular event outweighed any benefit resulting from taking sibutramine. Even though about one third of the study population was hypertensive, the SCOUT study was not included in our review as no hypertensive subgroup analyses were presented. In addition, as marketing approval for sibutramine has been withdrawn, we abstained from contacting the authors to obtain the necessary data for this subgroup.

Four studies (the RIO studies) (Despres 2005, Pi-Sunyer 2006, Scheen 2006, Van Gaal 2005) investigated the effects of therapy with rimonabant 20 mg and 5 mg per day in comparison to placebo in study populations including normo- and hypertensive (30% to 60%) patients. We contacted the study author, Luc F Van Gaal, to request results on the hypertensive subgroup. As we received no reply, the study was excluded from analysis and is only discussed here in detail. None of the RIO studies were designed to assess the effects on patient relevant endpoints. Patients under therapy with rimonabant, regardless of the dosage, reduced their body weight statistically significantly more than placebo treated patients. Contrary to these findings, the studies yielded heterogeneous results concerning blood pressure changes. Especially therapy with 5 mg rimonabant showed inconsistent results, with a higher reduction of blood pressure compared to placebo in some studies but less of a reduction in others. Treatment with 20 mg rimonabant daily showed more uniform findings with a higher reduction of SBP in all four studies (the difference was statistically significant in two). Also, the reduction of DBP was more pronounced in patients with rimonabant 20 mg therapy than in placebo treated patients in three studies (the difference was statistically significant in one), but slightly less in one study. Only the publication of the RIO Lipid study (Despres 2005) reported information on a hypertensive subgroup. In hypertensive patients treated with 20 mg rimonabant, blood pressure was reduced statistically significantly more than in patients in the placebo group (SBP: -5.9 mm Hg and DBP: -3.9 mm Hg). Since no other information on the hypertensive subgroup is given (the paper does not even report the percentage of patients with hypertension at baseline), the relevance of these findings remains unclear. In addition, it has to be noted that rimonabant was never approved by the FDA because serious safety concerns arose (FDA 2007). Original data analysis performed by the FDA showed that the incidence of suicidality was doubled by rimonabant vs. placebo. Similarly, the incidences of psychiatric adverse events, neurological adverse events and seizures were consistently higher for 20 mg rimonabant compared to placebo. In Europe, rimonabant received marketing approval from the EMEA on June 19, 2006. However, new data from post-marketing experience and ongoing clinical trials lead EMEA on October 23, 2008, to recommend suspension of the marketing authorisation for rimonabant in Europe as well (EMA 2008, EMA 2008a). In January 2009, the European Commission issued a decision to withdraw market authorisation for rimonabant in all countries of the European Union (EMA 2009). For rimonabant, many more results from long-term data will have to be published before a decision on its usefulness can be made. The results of the CRESCENDO trial published in 2010 (CRESCENDO 2010) did not change the recommendation made by EMA in 2009. This study was closed early in November 2008 due to high suicide rates and other psychiatric side-effects related to rimonabant. It was a multicenter double-blind placebo controlled trial with a mean follow up of 13.8 months, aimed at determining whether long-term treatment with rimonabant 20mg had the potential to reduce the risk of cardiovascular events in 9314 patients with previously manifest or increased risk of vascular disease. The primary endpoint measure consisted of cardiovascular death, myocardial infarction, or stroke which occurred in 3.9% of patients assigned to rimonabant, compared with  4.0% of patients assigned to placebo [HR: 0.97, 95% CI 0.84 -1.12, p=0.68]. Among patients taking rimonabant, the incidence of gastrointestinal (33% vs. 22%), neuropsychiatric (32% vs 21%) and serious psychiatric side-effects (2.5% vs 1.3%) was significantly increased compared with placebo. Four patients in the rimonabant group and one in the placebo group committed suicide. Even though about 88% of patients were hypertensive the CRESCENDO study was not included in our review as no hypertensive subgroup analyses were presented. In addition, as marketing approval has been withdrawn, we abstained from contacting the authors to obtain the required data for this subgroup.

Overall completeness and applicability of evidence

We searched in three electronic databases until the August 17, 2012, and searched the reference lists of included trials and relevant systematic reviews and meta-analyses. Each study's quality was assessed and the results were summarized. The results of this review can therefore be taken to be complete and applicable. For full information please see details in the relevant sections.

Quality of the evidence

We found that of the four orlistat studies included in our analyses, only one was judged as having major deficiencies of study quality. In terms of the sibutramine studies all were assessed as having major deficiencies of study quality. Full details are provided in the "Risk of bias" tables in the section Characteristics of included studies .

Potential biases in the review process

A major limitation of this review is that because of the lack of information in the included studies, no conclusions on the effects of the different pharmaceutical weight-loss interventions on patient relevant long-term outcomes can be drawn.

Agreements and disagreements with other studies or reviews

Systematic reviews on long-term effects of weight-reducing drugs on patients with hypertension are rare. There was one systematic review published by Aucott 2005 that reached the same conclusion, i.e. that only short-term trials were available. The authors also warned, "that extrapolation of short-term blood pressure changes with weight loss to the longer term is potentially misleading. The weight/hypertension relationship is complex and needs well-conducted studies with long-term follow-up to examine the effects of weight loss on hypertension outcomes."
In addition, as we were also involved in the preparation of the scientific report on the evaluation of the benefits and harms of non-drug treatment strategies in patients with essential hypertension (IQWiG 2006) and published a paper on this topic in 2008 (Horvath 2008), we are aware of all major and relevant systematic reviews and studies and can say with confidence that our findings are in good agreement with recently published reviews and studies.

Authors' conclusions

Implications for practice

Of the three initially included anti-obesity drugs only orlistat is still on the market. Trials on orlistat in patients with elevated blood pressure have demonstrated statistically significant decreases in weight and a decline in blood pressure. However, no long-term mortality and morbidity RCT evidence is available for any of the drugs. For sibutramine and rimonabant, approval was withdrawn due to potential cardiovascular risks (sibutramine) and psychiatric side-effects (rimonabant).

Implications for research

Long-term trials assessing the effect of orlistat, sibutramine and rimonabant on mortality and morbidity have confirmed concerns about the potential severe side effects that led to marketing withdrawal throughout the world. However, long-term trials assessing the effects of orlistat in patients with elevated blood pressure are lacking, although evidence is needed for this drug as well.

Acknowledgements

We should like to thank Phillip Elliott for final editing of the manuscript.

Data and analyses

Download statistical data

Comparison 1. Orlistat versus Placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Change in systolic blood pressure from baseline to endpoint42058Mean Difference (IV, Random, 95% CI)-2.46 [-4.01, -0.90]
2 Change in diastolic blood pressure from baseline to endpoint42058Mean Difference (IV, Random, 95% CI)-1.92 [-2.99, -0.85]
3 Change in body weight from baseline to endpoint42080Mean Difference (IV, Random, 95% CI)-3.73 [-4.65, -2.80]
Analysis 1.1.

Comparison 1 Orlistat versus Placebo, Outcome 1 Change in systolic blood pressure from baseline to endpoint.

Analysis 1.2.

Comparison 1 Orlistat versus Placebo, Outcome 2 Change in diastolic blood pressure from baseline to endpoint.

Analysis 1.3.

Comparison 1 Orlistat versus Placebo, Outcome 3 Change in body weight from baseline to endpoint.

Comparison 2. Sibutramine versus Placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Change in diastolic blood pressure from baseline to endpoint2428Mean Difference (IV, Fixed, 95% CI)3.16 [1.40, 4.92]
2 Change in body weight from baseline to endpoint4574Mean Difference (IV, Fixed, 95% CI)-3.74 [-4.84, -2.64]
Analysis 2.1.

Comparison 2 Sibutramine versus Placebo, Outcome 1 Change in diastolic blood pressure from baseline to endpoint.

Analysis 2.2.

Comparison 2 Sibutramine versus Placebo, Outcome 2 Change in body weight from baseline to endpoint.

Appendices

Appendix 1. Search Strategies

Ovid MEDLINE(R) <1946 to August Week 2 2012>

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations <August 16, 2012>

Embase <1988 to 2012 Week 32>

EBM Reviews - Cochrane Central Register of Controlled Trials <August 2012>

Search Date: 17 August 2012

1. exp hypertension/ or exp blood pressure/
2. (hypertens$ or antihypertens$ or anti hypertens$).ti,ab,ot.
3. ((systolic or diastolic or arterial) adj pressur$).ti,ab,ot.
4. (blood pressur$ or bloodpressur$).ti,ab,ot.
5. or/1-4
6. (orlistat$ or tetrahydrolipstatin or thlp).ti,ab,ot,tn,sh.
7. (orlistat or 96829-58-2).rn.
8. (ro180647 or "ro 180647" or "ro 18-0647").ti,ab,ot,tn.
9. (xenical or alli).ti,ab,ot,tn.
10. or/6-9
11. sibutramin$.ti,ab,ot,tn,sh.
12. (sibutramine or 106650-56-0).rn.
13. (BTS-54524 or BTS-54-524 or BTS54-524).ti,ab,ot,tn.
14. (reductil or medaria or meridia or arcalion).ti,ab,ot,tn.
15. or/11-14
16. rimonabant$.ti,ab,ot,tn,sh.
17. (rimonabant or "168273-06-1" or "158681-13-1").rn.
18. (sr141716 or sr141716a or (sr adj ("141716" or 141716a))).ti,ab,ot,tn.
19. (acomplia or accomplia or zimulti).ti,ab,ot,tn.
20. or/16-19
21. or/10,15,20
22. randomized controlled trial.pt.
23. controlled clinical trial.pt.
24. randomized.ab.
25. placebo.ab.
26. clinical trials as topic.sh.
27. randomly.ab.
28. trial.ti.
29. or/22-28
30. exp animals/ not humans.sh.
31. 29 not 30
32. crossover procedure/
33. Double Blind Procedure/
34. Randomized Controlled Trial/
35. Single Blind Procedure/
36. random$.ti,ab.
37. factorial$.ti,ab.
38. (crossover$ or cross-over$).ti,ab.
39. placebo$.ti,ab.
40. (doubl$ adj blind$).ti,ab.
41. (singl$ adj blind$).ti,ab.
42. assign$.ti,ab.
43. allocat$.ti,ab.
44. volunteer$.ti,ab.
45. or/32-44
46. 5 and 21 and 31 use prem
47. 5 and 21 and 31 use mesz
48. 5 and 21 and 45 use emed
49. 5 and 21 use cctr
50. or/46-49

Appendix 2. Search strategy used in original review

1. exp hypertension/ or exp blood pressure/
2. (hypertens$ or antihypertens$ or anti hypertens$).ti,ab,ot.
3. ((systolic or diastolic or arterial) adj pressur$).ti,ab,ot.
4. (blood pressur$ or bloodpressur$).ti,ab,ot.
5. or/1-4
6. (orlistat$ or tetrahydrolipstatin or thlp).ti,ab,ot,tn,sh.
7. (xenical or alli).ti,ab,ot,tn.
8. or/6,7
9. sibutramin$.ti,ab,ot,tn,sh.
10. (reductil or medaria or meridia or arcalion).ti,ab,ot,tn.
11. or/9,10
12. rimonabant$.ti,ab,ot,tn,sh.
13. (acomplia or zimulti).ti,ab,ot,tn.
14. or/12,13
15. or/8,11,14
16. controlled clinical trial.pt.
17. controlled clinical trials/
18. randomized controlled trial.pt.
19. randomized controlled trials/
20. random allocation/
21. cross-over studies/
22. double-blind method/
23. single-blind method/
24. or/16-23
25. ((singl$ or doubl$ or trebl$ or tripl$) adj6 (blind$ or mask$)).ti,ab,ot.
26. ((random$ or cross-over or crossover) adj25 (trial$ or study or studies or intervention$ or investigat$ or experiment$ or design$ or method$ or group$ or evaluation$ or evidenc$ or data or test$ or condition$)).ti,ab,ot.
27. (random$ adj25 (cross over or crossover)).ti,ab,ot.
28. (RCT or placebo$).ti,ab,ot.
29. or/25-28
30. 24 or 29
31. 5 and 15
32. 31 use prem
33. 31 use mesz
34. 31 use emed
35. or/32-34
36. 35 and 30
37. 31 use cctr
38. 36 or 37

What's new

Last assessed as up-to-date: 15 January 2013.

DateEventDescription
25 February 2013New citation required but conclusions have not changedupdate published with changed authors and additional background information
15 January 2013New search has been performedThe electronic search for new studies was updated to August 2012. No new studies were identified that met the inclusion criteria of this review.

Contributions of authors

Andrea Siebenhofer: protocol development, quality assessment of trials, data extraction, development of final review and review update, corresponding author

Klaus Jeitler: protocol development, searching for trials, quality assessment of trials, data extraction, development of review update

Karl Horvath: protocol development, quality assessment of trials, data extraction, development of final review and review update

Andrea Berghold: statistical analysis, development of final review and review update

Ulrich Siering: protocol development, development of final review, quality assessment of trials, data extraction

Thomas Semlitsch: searching for trials, quality assessment, development of review update

Declarations of interest

Andrea Siebenhofer, Klaus Jeitler and Karl Horvath were involved in the preparation of a report on the evaluation of the benefits and harms of non-drug treatment strategies in patients with essential hypertension: weight reduction for IQWiG, the German Institute for Quality and Efficiency in Health Care (http://iqwig.de/). Ulrich Siering is an employee of IQWiG. The other authors have no potential conflicts of interest.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Medical University of Graz, Austria.

Characteristics of studies

Characteristics of included studies [author-defined order]

Bakris 2002

Methods

DESIGN: parallel, randomized, double-blind

DURATION: 12 months

NUMBER OF STUDY CENTRES: 41

COUNTRY OF PUBLICATION: USA

Participants

WHO PARTICIPATED: obese patients with insufficiently controlled hypertension

SETTING: outpatient clinic

MAIN INCLUSION CRITERIA: age ≥ 40 years, BMI 28-43 kg/m2, at least one antihypertensive medication, sitting diastolic blood pressure 96-109 mm Hg

MAIN EXCLUSION CRITERIA: recent initiation or change in diuretic therapy, previous gastrointestinal surgery for weight reduction, active gastrointestinal disorders, use of nicotine replacement therapy, appetite suppressants, fish-oil supplements, chronic systemic steroids, acute antidepressant or anxiolytic therapy

GENERAL BASELINE CHARACTERISTICS (Orlistat vs. Placebo)

NUMBER: 278 vs. 276 were randomized, 267 vs. 265 were analysed

MEAN AGE [YEARS]: 53 vs. 53

GENDER [% MALE]: 37% vs. 41%

NATIONALITY: USA

ETHNICITY: 85-86% white; 11-12% blacks, 1-4% hispanics, 0-1% other

WEIGHT [kg]: 101 vs. 102 

BODY MASS INDEX [kg/m2]: 36 vs. 35 

SITTING SYSTOLIC BLOOD PRESSURE [mm Hg]: 154 vs. 151 

SITTING DIASTOLIC BLOOD PRESSURE [mm Hg]: 98 vs. 98 

CO-MORBID CONDITIONS: 8% diabetes in both groups

ANTIHYPERTENSIVE TREATMENT. 95% vs. 94%

DURATION OF HYPERTENSION: -

 

SUBGROUP: diabetic patients (no information on reasons and method are noted)

Interventions

INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Orlistat 120 mg three times a day with meals

CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Placebo three times a day with meals

ADDITIONAL TREATMENT:

hypocaloric diet, lifestyle intervention, moderate physical activity

Outcomes

LENGTH OF FOLLOW-UP: 12 months

PRIMARY OUTCOMES:

1. MORTALITY: -

2. CARDIOVASCULAR MORBIDITY: -

3. ADVERSE EVENTS:

Definition: reported were serious adverse events as necessitating or prolonging hospitalization; withdrawals due to adverse events; gastrointestinal and musculoskeletal symptoms

SECONDARY OUTCOMES:

1. CHANGES IN SYSTOLIC BLOOD PRESSURE [mm Hg]

Definition: sitting systolic blood pressure change from baseline to endpoint visit

2. CHANGES IN DIASTOLIC BLOOD PRESSURE [mm Hg]

Definition: sitting diastolic blood pressure change from baseline to endpoint visit

3. BODY WEIGHT [kg]

Definition: body weight change from baseline to endpoint visit

ADDITIONAL OUTCOMES MEASURED IN THE STUDY:

  1. BMI [kg/m2]

  2. Antihypertensive medication

  3. Number of patients who reach goal blood pressure

  4. Change in waist circumference

  5. Change in insulin concentration

  6. Changes in lipid parameters

  7. >30% reduction in cardiovascular composite risk

NotesSPONSOR: Roche Laboratories, New Jersey; USA
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details on generation sequence are provided.
Allocation concealment (selection bias)Unclear riskMethod of concealment is not described.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

Quote: "... randomized, double-blind, placebo-controlled study..."

No details provided to assure that blinding of participants and key study personnel has not been broken.

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "... statistical analyses were performed on an ITT basis ..."

Last observation was carried forward and reasons and description for withdrawals are provided.

 ----------------------------------------------------------------------

WITHDRAWALS: 116 vs. 168 (Orlistat vs. Placebo)

REASONS / DESCRIPTIONS (Orlistat vs. Placebo):

   - adverse events: 18 vs. 20 

   - refused treatment: 40 vs. 91 

   - lost to follow-up: 48 vs. 47 

   - other: 8 vs. 9 

   - excluded: 2 vs. 1

Selective reporting (reporting bias)High riskNo study protocol, outcomes are reported that were not pre-specified (e.g. systolic blood pressure).
Other biasHigh risk

1. The combination of a high withdrawal rate and the unknown duration of participation in the trial increases risk of bias even using the LOCF analysis.

2. There are inconsistencies in reporting between text and flowchart on the numbers of patients who finished the study.

Cocco 2005

Methods

DESIGN: parallel, randomized, double-blind

DURATION OF INTERVENTION: 6 months

NUMBER OF STUDY CENTRES: 1

COUNTRY OF PUBLICATION: Switzerland

Participants

WHO PARTICIPATED: obese patients with metabolic syndrome, diabetes type 2, hypertension, mostly with coronary heart disease and concomitant cardiac dysfunction

SETTING: outpatient clinic

MAIN INCLUSION CRITERIA: age ≥ 35 years, BMI 31-40 kg/m2, left ventricular function 42-50%

MAIN EXCLUSION CRITERIA: inability of subjects to monitor their own glucose and blood pressure, active participation in a dietary program, use of weight-losing medication

GENERAL BASELINE CHARACTERISTICS (Orlistat vs. Placebo)

NUMBER: 45 vs. 45

MEAN AGE [YEARS]: 55 vs. 55

GENDER [% MALE]: 49% vs. 49%

NATIONALITY: probably Swiss

ETHNICITY: 100% white

WEIGHT [kg]: 107 vs. 106

HbA1c: 7.3% vs. 6.9%

BODY MASS INDEX [kg/m2]: 37 vs. 36

SYSTOLIC BLOOD PRESSURE [mm Hg]: 146 vs. 142

DIASTOLIC BLOOD PRESSURE [mm Hg]: 88 vs. 85

CO-MORBID CONDITIONS: 100% metabolic syndrome and diabetes, 77% coronary heart disease, 47% myocardial infarction

ANTIHYPERTENSIVE TREATMENT: 100%

DURATION OF HYPERTENSION: -

SUBGROUP: -

Interventions

INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Orlistat 120 mg three times a day

CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Placebo three times a day

ADDITIONAL TREATMENT:

hypocaloric diet, teaching sessions for lifestyle intervention, moderate physical activity

Outcomes

LENGTH OF FOLLOW-UP: 6 months

PRIMARY OUTCOMES:

1. MORTALITY: -

2. CARDIOVASCULAR MORBIDITY: -

3. ADVERSE EVENTS:

Definition: gastrointestinal side effects were reported (no severe effects)

SECONDARY OUTCOMES:

1. CHANGES IN SYSTOLIC BLOOD PRESSURE [mm Hg]

Definition: systolic blood pressure change from baseline to endpoint visit

2. CHANGES IN DIASTOLIC BLOOD PRESSURE [mm Hg]

Definition: diastolic blood pressure change from baseline to endpoint visit

3. BODY WEIGHT [kg]

Definition: body weight change from baseline to endpoint visit

ADDITIONAL OUTCOMES MEASURED IN THE STUDY:

  1. BMI [kg/m2]

  2. Caloric consumption

  3. Changes in lipid- and glucose parameters

  4. Change in insulin concentration

  5. Change in heart rate and left ventricular ejection fraction

  6. Changes in uric acid concentrations

NotesSPONSOR: -
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "To ensure that each group would contain approximately equal numbers of risk factors, stratified randomization was used with an algorithm generated from a random set of numbers."
Allocation concealment (selection bias)Unclear riskMethod of concealment is not described.
Blinding (performance bias and detection bias)
All outcomes
Low riskAuthors' reply gave further detailed information that patients, study personnel and outcome assessment were blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data.
Selective reporting (reporting bias)High riskNo study protocol or reporting on pre-specified endpoint, no primary endpoint reported.
Other biasLow risk

-similar baselines

- only small inconsistencies between changes in body weight in the table and text in comparison with calculated numbers in the table

Guy-Grand 2004

Methods

DESIGN: parallel, randomized, double-blind

DURATION OF INTERVENTION: 6 months

NUMBER OF STUDY CENTRES: 253

COUNTRY OF PUBLICATION: France

Participants

WHO PARTICIPATED: obese patients with diabetes type 2, hypertension, or hypercholesterolaemia; only the predefined subgroup of hypertensive patients is reported here

SETTING: private endocrinologists

MAIN INCLUSION CRITERIA: age 18-65 years, BMI 28-40 kg/m2, diastolic blood pressure 90-110 mm Hg or untreated hypertensives or treatment stopped for more than 3 months or insufficiently controlled by the last 6 months of treatment

MAIN EXCLUSION CRITERIA: secondary hypertension, history or presence of drug and alcohol abuse, significant cardiac, renal, hepatic gastrointestinal, endocrine and psychiatric disorders

GENERAL BASELINE CHARACTERISTICS (Orlistat vs. Placebo)

NUMBER: 304 vs. 310

MEAN AGE [YEARS]: 49 vs. 50

GENDER [% MALE]: 31% vs. 35%

NATIONALITY: probably French

ETHNICITY: -

WEIGHT [kg]: 94 vs. 94

BODY MASS INDEX [kg/m2]: 34 vs. 34

SITTING SYSTOLIC BLOOD PRESSURE [mm Hg]: 150 vs. 152

DIASTOLIC BLOOD PRESSURE [mm Hg]: 97 vs. 97

CO-MORBID CONDITIONS: -

ANTIHYPERTENSIVE TREATMENT: 70%

DURATION OF HYPERTENSION: -

SUBGROUP: -

Interventions

INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Orlistat 120 mg three times a day with meals

CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Placebo three times a day with meals

ADDITIONAL TREATMENT:

hypocaloric diet

Outcomes

LENGTH OF FOLLOW-UP: 6 months

PRIMARY OUTCOMES:

1. MORTALITY: -

2. CARDIOVASCULAR MORBIDITY: -

3. ADVERSE EVENTS:

Definition: Gastrointestinal events are only reported for the whole study population having diabetes type 2, hypertension, or hypercholesterolaemia.

SECONDARY OUTCOMES:

1. CHANGES IN SYSTOLIC BLOOD PRESSURE [mm Hg]

Definition: systolic blood pressure change from baseline to endpoint visit

2. CHANGES IN DIASTOLIC BLOOD PRESSURE [mm Hg]

Definition: diastolic blood pressure change from baseline to endpoint visit

3. BODY WEIGHT [kg]

Definition: body weight change from baseline to endpoint visit

ADDITIONAL OUTCOMES MEASURED IN THE STUDY:

  1. BMI [kg/m2]

  2. Changes in lipid- and glucose parameters

  3. Dosage of concomitant treatment

  4. Change in waist circumference

  5. Change in insulin concentration

  6. Change in pulse pressure

NotesSPONSOR: Roche Pharma, Paris, France
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Randomization was performed by a centralized procedure in which patients were stratified by both centre and comorbidity. According to minimization procedure, patients were randomized to ensure that treatment groups were well balanced by both centre and by concomitant disease."
Allocation concealment (selection bias)Low riskCentral allocation
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

Quote: "... randomized, double-blind, placebo controlled, parallel-group study ..."

No details provided to ensure that blinding of participants and key study personnel was not broken.

Incomplete outcome data (attrition bias)
All outcomes
High risk

Quote: "Efficacy was assessed on an intent-to-treat (ITT) basis. The ITT population included all randomized patients and the safety population consisted of all randomized patients who had received at least one dose of study treatment. Principal criteria missing at six months were replaced by the last-measured value (last observation carried forward, LOCF)."

 ----------------------------------------------------------------------

WITHDRAWALS and LOST TO FOLLOW UP:

REASONS / DESCRIPTIONS: only reported for the whole study population having diabetes type 2, hypertension, or hypercholesterolaemia.

Selective reporting (reporting bias)High riskNo study protocol
Other biasLow risk

- Similar baselines

- Power calculation is provided

XENDOS 2001-2006

Methods

DESIGN: parallel, randomized, double-blind

DURATION OF INTERVENTION: 48 months

NUMBER OF STUDY CENTRES: 22

COUNTRY OF PUBLICATION: Sweden

Participants

WHO PARTICIPATED: obese patients with normal or impaired glucose tolerance. Only the predefined subgroup of hypertensive patients is reported here. Data were obtained from the publicly available scientific report of the Institute for Quality and Efficiency in Health Care (IQWiG 2006)

SETTING: medical centres

MAIN INCLUSION CRITERIA: age 30-60 years, BMI ≥ 30 kg/m2, normal or impaired glucose tolerance, either diastolic blood pressure ≥90 mm Hg (first pre-defined subgroup) or systolic blood pressure ≥140 mm Hg (second pre-defined subgroup)

MAIN EXCLUSION CRITERIA: systolic blood pressure >165 mm Hg or diastolic blood pressure > 105 mm Hg, diabetes mellitus, ongoing and active cardiovascular and gastrointestinal disease

BASELINE CHARACTERISTICS OF THE FIRST SUBGROUP: (Orlistat vs. Placebo)

NUMBER: 408 vs. 441 were randomized and 407 vs. 437 were analysed

MEAN AGE [YEARS]: 46 vs. 46

GENDER [% MALE]: 62% vs. 56%

NATIONALITY: Swedish

ETHNICITY: -

WEIGHT [kg]: 116 vs. 114

BODY MASS INDEX [kg/m2]: -

SYSTOLIC BLOOD PRESSURE [mm Hg]: 146 vs. 146

DIASTOLIC BLOOD PRESSURE [mm Hg]: 95 vs. 95

CO-MORBID CONDITIONS: -

ANTIHYPERTENSIVE TREATMENT: -

DURATION OF HYPERTENSION: -

BASELINE CHARACTERISTICS OF THE SECOND SUBGROUP: (Orlistat vs. Placebo)

NUMBER: 516 vs. 509 were randomized and 513 vs. 508 were analysed

MEAN AGE [YEARS]: 47 vs. 47

GENDER [% MALE]: 58% vs. 58%

NATIONALITY: Swedish

ETHNICITY: -

WEIGHT [kg]: 116 vs.115

BODY MASS INDEX [kg/m2]: -

SYSTOLIC BLOOD PRESSURE [mm Hg]: 149 vs.149

DIASTOLIC BLOOD PRESSURE [mm Hg]: 91 vs.91

CO-MORBIDID CONDITIONS: -

ANTIHYPERTENSIVE TREATMENT: -

DURATION OF HYPERTENSION: -

Interventions

INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Orlistat 120 mg three times a day with meals

CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Placebo three times a day with meals

ADDITIONAL TREATMENT:

hypocaloric diet, teaching sessions for lifestyle intervention, moderate physical activity

Outcomes

LENGTH OF FOLLOW-UP: 48 months

PRIMARY OUTCOMES:

1. MORTALITY: -

2. CARDIOVASCULAR MORBIDITY: -

3. ADVERSE EVENTS:

Definition: severe, overall and withdrawals were reported, further reported were gastrointestinal, musculoskeletal, dermatological, vascular and nervous side effects.

SECONDARY OUTCOMES:

1. CHANGES IN SYSTOLIC BLOOD PRESSURE [mm Hg]

Definition: systolic blood pressure change from baseline to endpoint visit

2. CHANGES IN DIASTOLIC BLOOD PRESSURE [mm Hg]

Definition: diastolic blood pressure change from baseline to endpoint visit

3. BODY WEIGHT [kg]

Definition: body weight change from baseline to endpoint visit

ADDITIONAL OUTCOMES MEASURED IN THE STUDY:

  1. Time to onset of type 2 diabetes

  2. Time to onset of hypertension

  3. Changes in anthropometric measurements, metabolic profile and glucose parameters

  4. Time to onset of IGT

NotesSPONSOR: Hoffmann-La Roche, Nutley, (NJ) USA
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskInformation obtained from the scientific report (IQWiG 2006)
Allocation concealment (selection bias)Low riskInformation obtained from the scientific report (IQWiG 2006)
Blinding (performance bias and detection bias)
All outcomes
Unclear riskInformation obtained from the scientific report (IQWiG 2006)
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Information obtained from the scientific report (IQWiG 2006)

Quote: "Efficacy was assessed on an intention-to treat (ITT) basis with a last observation carried forward principle (LOCF). The ITT population included all randomized patients who had received at least one dose of study treatment and one follow up examination." 

 ---------------------------------------------------------------------- 

First subgroup

WITHDRAWALS: 183 (45%) vs. 268 (61%) (Orlistat vs. Placebo)

 REASONS / DESCRIPTIONS (Orlistat vs. Placebo)

   - study withdrawals 22 (5%) vs. 20 (5%)

   - adverse events: 9% vs. 4% 

   - no further reasons mentioned

 

Second subgroup

WITHDRAWALS: 215 (42%) vs. 307 (60%) (Orlistat vs. Placebo)

 REASONS/DESCRIPTIONS (Orlistat vs. Placebo)

   - study withdrawals 25 (4%) vs. 22 (5%)

   - adverse events: 9% vs. 4% 

   - no further reasons mentioned

Selective reporting (reporting bias)Unclear riskInformation was only obtained from the scientific report (IQWiG 2006) and no publication in full was available to allow judgement of either yes or no.
Other biasHigh risk

- combination of a high withdrawal rate and the unknown length of stay of participants in the trial increases risk of bias even using the LOCF analysis

-similar baselines

- power calculation is only provided for the whole group

Fanghaenel 2003

Methods

DESIGN: parallel, randomized, double-blind

DURATION OF INTERVENTION: 6 months

NUMBER OF STUDY CENTRES: 1

COUNTRY OF PUBLICATION: Mexico

Participants

WHO PARTICIPATED: obese patients with hypertension

SETTING: Endocrinology Service of the General Hospital of Mexico

MAIN INCLUSION CRITERIA: BMI > 27 kg/m2, after 2 weeks of antihypertensive washout diastolic blood pressure  90 - 109 mm Hg or systolic blood pressure ≥140 mm Hg, then start with antihypertensive treatment unless blood pressure was <140/90 mm Hg.

MAIN EXCLUSION CRITERIA: uncontrolled hypertension, thyroid-replacement drugs, endocrine (other than type 2 diabetes mellitus) disease,  autoimmune or ischemic heart diseases, arrhythmia, or diuretic treatment

GENERAL BASELINE CHARACTERISTICS (Sibutramine vs. Placebo)

NUMBER: 66 were randomized (no details to which treatment group), 29 vs. 28 were analysed

MEAN AGE [YEARS]: 49 vs. 46

GENDER [% MALE]: 17% vs. 25%

NATIONALITY: Mexican

ETHNICITY: Hispanic (Latin-Americans)

WEIGHT [kg]: 75 vs. 78

BODY MASS INDEX [kg/m2]: 31 vs. 31

SYSTOLIC BLOOD PRESSURE [mm Hg]: 139 vs. 139

DIASTOLIC BLOOD PRESSURE [mm Hg]: 93 vs. 92

CO-MORBID CONDITIONS: hypertension

ANTIHYPERTENSIVE TREATMENT: 100%

DURATION OF HYPERTENSION: -

 

SUBGROUP: -

Interventions

INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Sibutramine 10 mg once a day

CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Placebo once a day

ADDITIONAL TREATMENT:

hypocaloric diet

Outcomes

LENGTH OF FOLLOW-UP: 6 months

PRIMARY OUTCOMES:

1. MORTALITY: -

2. CARDIOVASCULAR MORBIDITY: -

3. ADVERSE EVENTS:

Definition: reported adverse events such as headache, gastrointestinal events, insomnia

SECONDARY OUTCOMES:

1. CHANGES IN SYSTOLIC BLOOD PRESSURE [mm Hg]:

Definition: baseline and follow up measurements are provided and change can be calculated.

2. CHANGES IN DIASTOLIC BLOOD PRESSURE [mm Hg]:

Definition: baseline and follow up measurements are provided and change can be calculated.

3. BODY WEIGHT [kg]

Definition: body weight change from baseline to endpoint visit

ADDITIONAL OUTCOMES MEASURED IN THE STUDY:

  1. Change in antihypertensive treatment

  2. BMI [kg/m2]

  3. Change in waist circumference

  4. Change in waist-to-hip ratio (WHR)

  5. Changes in heart rate and electrocardiograms

  6. Changes in laboratory parameters

NotesSPONSOR: Química Knoll de México, Mexico
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "... prepared a computer list of 70 random numbers in seven blocks of 10 ..."
Allocation concealment (selection bias)Low riskQuote: "... opaque sealed envelope with drug  code ..."
Blinding (performance bias and detection bias)
All outcomes
Low riskAccording to text in the publication blinding of participants and key study personnel can be ensured. It was unclear if outcome assessment was blinded. 
Incomplete outcome data (attrition bias)
All outcomes
High risk

66 patients were randomized and 9 patients withdrew during run-in period without knowing to which group the patients had been randomized.

 ----------------------------------------------------------------------  

WITHDRAWALS and LOST TO FOLLOW UP (Sibutramine vs. Placebo): only reported for the patients who were included in the completers analysis

REASONS / DESCRIPTIONS (Sibutramine vs. Placebo):

- lost to follow up: 1 vs. 2

- protocol violation: 2 vs. 1

- withdrew consent: 3 vs. 1

Selective reporting (reporting bias)High risk

No study protocol and

patient flow is inconsistent.

Other biasHigh riskAs 14% of randomized patients (unclear of which treatment group) were not included in the analysis it can be judged that the handling with dropouts is inadequate.

Faria 2002

Methods

DESIGN: parallel, randomized, double-blind

DURATION OF INTERVENTION: 6 months

NUMBER OF STUDY CENTRES: 1

COUNTRY OF PUBLICATION: Brazil

Participants

WHO PARTICIPATED: obese hypertensive patients

SETTING: hypertension outpatient clinic of Hospital do Rim e da Hipertensão

MAIN INCLUSION CRITERIA: BMI ≥ 30 to < 50kg/m2, office systolic blood pressure ≥ 140 mm Hg and diastolic blood pressure >90 and < 110 mm Hg or < 95 mm Hg if on antihypertensive therapy, waist/hip ratio (WHR) ≥ 0.85 for women and ≥ 0.95 for men

MAIN EXCLUSION CRITERIA: diabetes (fasting glucose of over 7.05 mmol/l), severe dyslipidaemia (cholesterol levels of ≥ 7.74 mmol/l and triglyceride levels of ≥ 4.51 mmol/l), congestive heart failure, coronary heart disease, renal or hepatic insufficiency

GENERAL BASELINE CHARACTERISTICS for the analysed patients (Sibutramine vs. Placebo)

NUMBER: 56 vs. 53 were randomized, 43 vs. 43 were analysed

MEAN AGE [YEARS]: 46 vs. 51

GENDER [% MALE]: 17% vs. 12%

NATIONALITY: Brazil

ETHNICITY: -

WEIGHT [kg]: 100 vs. 97 

BODY MASS INDEX [kg/m2]: 40 vs. 39

24-h SYSTOLIC BLOOD PRESSURE [mm Hg]: 150 vs. 150 

24-h DIASTOLIC BLOOD PRESSURE [mm Hg]: 91 vs. 94

CO-MORBID CONDITIONS: -

ANTIHYPERTENSIVE TREATMENT. 81% vs. 81%

DURATION OF HYPERTENSION: -

 

SUBGROUP: -

Interventions

INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Sibutramine 10 mg once a day in the morning

CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Placebo once a day in the morning

ADDITIONAL TREATMENT:

hypocaloric diet, increased physical activity

Outcomes

LENGTH OF FOLLOW-UP: 6 months

PRIMARY OUTCOMES:

1. MORTALITY: -

2. CARDIOVASCULAR MORBIDITY: -

3. ADVERSE EVENTS: -

Definition: reported as symptoms such as dry mouth, and joint pain

SECONDARY OUTCOMES:

1. CHANGES IN SYSTOLIC BLOOD PRESSURE [mm Hg]

Definition: systolic blood pressure at baseline and at endpoint visit

2. CHANGES IN DIASTOLIC BLOOD PRESSURE [mm Hg]

Definition: diastolic blood pressure at baseline and at endpoint visit

3. BODY WEIGHT [kg]

Definition: body weight at baseline and at endpoint visit

ADDITIONAL OUTCOMES MEASURED IN THE STUDY:

  1. Body fat mass

  2. Change in heart rate

  3. Change in antihypertensive medication

  4. Change in ventricular hypertrophy

  5. Change in waist circumference

  6. Change in insulin concentration

  7. Changes in laboratory parameters

  8. Change in waist/hip ratio

  9. Change in BMI

NotesSPONSOR: Abbott Laboratories of Brazil
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details on generation sequence are provided.
Allocation concealment (selection bias)Low riskQuote: "... administration of sequential numbers ..."
Blinding (performance bias and detection bias)
All outcomes
Low riskAccording to personal communication with one of the authors of this Cochrane review (U.S.) it can be assured that blinding of patients, study personal and outcome assessors can be guaranteed. 
Incomplete outcome data (attrition bias)
All outcomes
High risk

No missing data but no ITT analysis, only a completers analysis was performed.

 ----------------------------------------------------------------------   

WITHDRAWALS: 13 vs. 10 (Sibutramine vs. Placebo)

REASONS / DESCRIPTIONS (Sibutramine vs. Placebo)

-  loss of compliance: 7 vs. 8

- biochemical abnormalities: 1 vs. 1

- increases of BP: 1 vs. 1

- introduction of corticoid therapy: 1 vs. 2

- urinary infection: 0 vs. 1

Selective reporting (reporting bias)High riskNo study protocol, small differences in reporting between the two publications in 2002 and 2005.
Other biasHigh riskThere was inadequate handling of dropouts in the analyses, it is unclear whether patients were comparable for prognosis-relevant factors at baseline.

McMahon 2000

Methods

DESIGN: parallel, randomized, double-blind

DURATION OF INTERVENTION: 12 months

NUMBER OF STUDY CENTRES: multicenter (numbers unclear)

COUNTRY OF PUBLICATION: USA

Participants

WHO PARTICIPATED: obese hypertensive patients

SETTING: clinic visits

MAIN INCLUSION CRITERIA: age > 18 years, BMI between 27 and 40 kg/m2, diagnosis of hypertension for at least 12 month before screening with adequate medical control (a constant dose of a calcium channel blocker for at least 60 days and stable dose of a single thiazide diuretic in addition was allowed): mean diastolic blood pressure ≤ 95 mm Hg during run-in period and variations in mean DBP measured at 3 consecutive run-in visits had to be within 10 mm Hg

MAIN EXCLUSION CRITERIA: secondary elevated blood pressure, pulse rate > 95/min at baseline, diastolic blood pressure > 95 mm Hg during run-in period, significant cardiac disease, endocrine abnormalities, severe cerebral trauma, stroke, substance abuse within 2 years before screening

GENERAL BASELINE CHARACTERISTICS (Sibutramine vs. Placebo)

NUMBER: 150 vs. 74 were randomized, 142 vs. 69 were analysed

MEAN AGE [YEARS]: 52 vs. 53

GENDER [% MALE]: 39% vs. 40%

NATIONALITY: Americans

ETHNICITY: 55% vs. 64% White, 39% vs. 30% African American, 7% vs. 6% others

WEIGHT [kg]: 97 vs. 96

BODY MASS INDEX [kg/m2]: 35 vs. 34 

MEAN SYSTOLIC BLOOD PRESSURE [mm Hg]: 134 vs. 134 

MEAN DIASTOLIC BLOOD PRESSURE [mm Hg]: 84 vs. 84

CO-MORBID CONDITIONS: -

ANTIHYPERTENSIVE TREATMENT. 100% (calcium channel blocker), 37% vs. 38% (diuretics), 3% vs. 4% (β-adrenergic receptor antagonists)

DURATION OF HYPERTENSION: for at least 12 months

 

SUBGROUP: African Americans

Interventions

INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Sibutramine initial dosage of  5mg once daily titrated up to 20mg per day in 5-mg increments every 2 weeks, maintained at 20mg per day between weeks 8 and 52

CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Placebo once a day

ADDITIONAL TREATMENT:

general dietary advice

Outcomes

LENGTH OF FOLLOW-UP: 12 months

PRIMARY OUTCOMES:

1. MORTALITY: -

2. CARDIOVASCULAR MORBIDITY: -

3. ADVERSE EVENTS:

Definition: study related withdrawals and adverse events such as dry mouth and headache are reported.

 SECONDARY OUTCOMES:

1. CHANGES IN SYSTOLIC BLOOD PRESSURE [mm Hg]

Definition: mean change in systolic blood pressure

2. CHANGES IN DIASTOLIC BLOOD PRESSURE [mm Hg]

Definition: mean change in diastolic blood pressure

3. BODY WEIGHT [kg]

Definition: mean change in body weight

ADDITIONAL OUTCOMES MEASURED IN THE STUDY:

  1. Mean change in BMI (kg/m2)

  2. Quality of life parameters

  3. Changes in heart rate

  4. Mean change in waist / hip circumference

  5. Mean changes in lipid parameters, glucose and uric acid levels

NotesSPONSOR: Knoll Pharmaceutical Co, Mount Olive, (NJ) USA
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskOnly information was a 2:1 randomization ratio.
Allocation concealment (selection bias)Unclear riskMethod of concealment is not described.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskInsufficient information to permit any judgement.
Incomplete outcome data (attrition bias)
All outcomes
High risk

Quote: "... statistical analyses were performed on an ITT basis ...last observation was carried forward (LOCF) ..."

The ITT population included all randomized patients who had at least one measurement after baseline.

 ----------------------------------------------------------------------    

WITHDRAWALS: 71 vs. 33 (Sibutramine vs. Placebo)

REASONS / DESCRIPTIONS (Sibutramine vs. Placebo)

- adverse events: 30 vs. 8

- no effects: 1 vs. 4

- withdrew consent: 3 vs. 4

- no follow up data: 10 vs. 1

- protocol violation: 10 vs. 5

- no further reasons mentioned: 17 vs. 11

Selective reporting (reporting bias)Unclear riskNo study protocol provided.
Other biasHigh risk

1. The combination of a high withdrawal rate and the unknown length of stay of participants in the trial increases risk of bias even using the LOCF analysis.

2. It is unclear whether patients were comparable for prognostic factors at baseline.

McMahon 2002

Methods

DESIGN: parallel, randomized, double-blind

DURATION OF INTERVENTION: 12 months

NUMBER OF STUDY CENTRES: multicenter (numbers unclear)

COUNTRY OF PUBLICATION: USA

Participants

WHO PARTICIPATED: obese hypertensive patients treated with ACE-inhibitors

SETTING: outpatient clinic

MAIN INCLUSION CRITERIA: age ≥ 18 years, BMI ≥ 27 and ≤ 40 kg/m2, history of well-controlled hypertension for ≥ 60 days preceding the screening visit with a constant dose of an ACE inhibitor, with or without a thiazide diuretic (dose and nature unchanged for ≥ 60 days preceding the screening visit)

Well-controlled hypertension was protocol-defined as a mean supine diastolic blood pressure ≤ 95 mm Hg at each "qualifying" visit, with an overall difference of 10 mm Hg or less between visits, without changes to the dose of the ACE inhibitor or thiazide diuretic;

MAIN EXCLUSION CRITERIA: secondary elevated blood pressure, mean supine pulse rate > 95/min at baseline, mean supine diastolic blood pressure > 95 mm Hg at any run-in visit, significant cardiac disease, gastric surgery to reduce obesity, previous treatment with sibutramine

 

GENERAL BASELINE CHARACTERISTICS (Sibutramine vs. Placebo)

NUMBER: 146 vs. 74 were randomized, 84 vs. 36 were analysed

MEAN AGE [YEARS]: 52 vs. 51

GENDER [% MALE]: 42% vs. 43%

NATIONALITY: Americans

ETHNICITY: 80% vs. 87% Caucasians, 18% vs. 11% Blacks, 2% vs. 3% Mexican Americans, 1% vs. 0% Others

WEIGHT [kg]: 97 vs. 99

BODY MASS INDEX [kg/m2]: 34 vs. 34 

SUPINE SYSTOLIC BLOOD PRESSURE [mm Hg]: 129 vs. 129 

SUPINE DIASTOLIC BLOOD PRESSURE [mm Hg]: 82 vs. 83

CO-MORBID CONDITIONS: -

ANTIHYPERTENSIVE TREATMENT. 100% (ACE inhibitors), 49% vs. 55% (diuretics)

DURATION OF HYPERTENSION: controlled for ≥ 60 days

 

SUBGROUP: -

Interventions

INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Sibutramine initial dosage of  5mg once daily in the morning titrated up to 20mg per day in 5-mg increments every 2 weeks, maintained at 20mg per day between weeks 8 and 52

CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):

Placebo once daily in the morning

ADDITIONAL TREATMENT:

general dietary advice

Outcomes

LENGTH OF FOLLOW-UP: 12 months

PRIMARY OUTCOMES:

1. MORTALITY: -

2. CARDIOVASCULAR MORBIDITY: -

3. ADVERSE EVENTS:

Definition: study related withdrawals and severe adverse events and symptoms such as dry mouth and headache are reported.

SECONDARY OUTCOMES:

1. CHANGES IN SYSTOLIC BLOOD PRESSURE [mm Hg]

Definition: change in systolic blood pressure from baseline

2. CHANGES IN DIASTOLIC BLOOD PRESSURE [mm Hg]

Definition: change in diastolic blood pressure from baseline

3. BODY WEIGHT [kg]

Definition: mean change in body weight

ADDITIONAL OTUCOMES MEASURED IN THE STUDY:

  1. Mean change in BMI (kg/m2)

  2. Change in heart rate

  3. Change in visceral fat mass

  4. Mean change in waist / hip circumference (cm)

  5. Mean changes in lipid parameters, glucose and uric acid levels

  6. Change in waist/hip ratio

NotesSPONSOR: Abbott Laboratories, Abbott Park, Illinois, USA
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskOnly information was a 2:1 randomisation ratio.
Allocation concealment (selection bias)Unclear riskMethod of concealment is not described.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskInsufficient information to permit any judgement.
Incomplete outcome data (attrition bias)
All outcomes
High risk

Quote: "... statistical analyses were performed on an ITT basis ...last observation was carried forward (LOCF) ..."

The ITT population included all randomized patients who had efficacy measurements after baseline.

 ----------------------------------------------------------------------  

WITHDRAWALS: 62 vs. 38 (Sibutramine vs. Placebo)

REASONS / DESCRIPTIONS (Sibutramine vs. Placebo)

- adverse events: 23 vs. 4

- no effects: 1 vs. 6

- no follow up data: 1 vs. 2

- protocol violation: 6 vs. 5

 no further reasons mentioned: 31 vs. 21

Selective reporting (reporting bias)Unclear riskNo study protocol provided.
Other biasHigh risk

1. The combination of a high withdrawal rate and the unknown length of participation in the trial increases risk of bias even using the LOCF analysis.

2. It is unclear whether patients were comparable for prognostic factors at baseline.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Bach 1999The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Bray 1999The study does not include participants with essential hypertension.
Broom 2002The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Davidson 1999The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
de Castro 2009 
Derosa 2003The study does not include participants with essential hypertension.
Derosa 2008The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Derosa 2010 
Despres 2005The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Despres 2009 
Dujovne 2001The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Erdmann 2004The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Fanghaenel 2000The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Fanhaenel 2001The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Finer 2000The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Fujioka 2000The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Gentile 2005The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Ginsberg 2004The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Halpern 2002The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Halpern 2003The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Hauner 2004The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Hauptman 2000The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Heinonen 2009 
Hollander 2007The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Hung 2005The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Jain 2011 
James 1997The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
James 2000The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Kaukua 2004The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Kelley 2002The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Lindgarde 2000The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Lindgarde 2001The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Lindgarde 2001AThe study is not a randomized controlled trial.
Madsen 2009 
McNulty 2003The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Miles 2002The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Nissen 2008 
O'Leary 2011 
Pathan 2004The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Patschan 2007The duration of the intervention is less than 24 weeks.
Pi-Sunyer 2006The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Reaven 2001The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Rossner 2000The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Rossner 2001The study is published in Swedish which is not among the languages prespecified for this report.
Samuelsson 2003The reported outcomes in this study are not relevant for this review.
Scheen 2002The study is not a randomized controlled trial.
SCOUT 2010 
Sjostrom 1998The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Suyog 2011 
Svendsen 2008 
Swinburn 2005The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Tambascia 2003The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Tiikkainen 2004The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Triay 2012 
Van Gaal 2005The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Van Gaal 2008The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Wirth 2001The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Zannad 2002The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.
Zavoral 1998The study includes normotensive and hypertensive patients but does not report any or sufficient results for the hypertensive subgroup.

Ancillary