Key messages
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The effects of three weight-reducing medicines (orlistat, phentermine/topiramate and naltrexone/bupropion) on death rates and cases of heart disease are unclear for people with hypertension (high blood pressure) due to a lack of reliable evidence. There is no information about these measures for the medicines semaglutide and tirzepatide.
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Taking phentermine/topiramate or naltrexone/bupropion probably causes more unwanted events in people with hypertension than taking a placebo (inactive 'dummy' medicine). Taking orlistat probably causes an increase in the number of serious unwanted effects compared to taking a placebo. We did not find any information about side effects for people with hypertension taking semaglutide or tirzepatide.
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Long-term studies are needed to assess the effects of medicines used for weight management on death rates and heart and blood vessel problems in people with hypertension. It is also important that results for people with hypertension be provided by authors of any completed study that included people with and without hypertension.
What is high blood pressure (hypertension)?
Blood pressure is a measure of the force that your heart uses to pump blood around your body. It is usually given as two numbers: the pressure when your heart pushes blood out (systolic pressure), and the pressure when your heart rests between beats (diastolic pressure). Blood pressure is considered to be high when systolic pressure is over 140 and/or diastolic pressure is over 90. The risk of developing high blood pressure (hypertension) increases with age.
Why is hypertension a problem?
Hypertension can increase the risk of developing serious health problems, such as heart attack or stroke. Lowering blood pressure in people with hypertension reduces the number of people who develop diseases of the heart and blood vessels (cardiovascular diseases), which leads to fewer deaths and cardiovascular problems.
Is there a link between being overweight and hypertension?
Being overweight is associated with increased blood pressure. Hypertension treatment guidelines recommend maintaining a healthy weight and losing weight when needed. Some people may take medicine specifically to help reduce their weight.
What did we want to find out?
We wanted to find out if weight-loss medicines could reduce the negative effects of hypertension on people's health.
What did we do?
We updated a systematic review. We looked for studies on how weight-loss medicines affect people with hypertension. We wanted to know how many people experienced unwanted events (e.g. side effects), how many developed heart disease or stroke, and if any died.
We looked for studies called 'randomised controlled trials', which usually give the most reliable evidence about the effects of a treatment. We rated how certain we were about the evidence, taking into account how the studies were done, how many people took part and whether results were consistent. All studies compared a weight-loss medicine with a placebo, which is a 'dummy' medicine, one that looks like the same medicine but is inactive.
What did we find?
We added two new studies of medicines recently approved for weight reduction, so, in total, this updated review includes eight studies. They involved around 13,000 people with hypertension (average age 46 to 62 years). Three studies were conducted in the USA, three in European countries and two were multinational. The studies lasted between six and 48 months. Pharmaceutical companies funded seven of the eight studies.
For people with hypertension, three drugs that are approved to help people lose weight over time (orlistat, phentermine/topiramate and naltrexone/bupropion) may make little to no difference to how many people die or how many people have heart problems, but we are very uncertain about the results. People taking orlistat, phentermine/topiramate and naltrexone/bupropion probably have more serious unwanted events than those taking placebo. However, there may be little to no difference in unwanted events in general between orlistat and placebo, and little to no difference in serious unwanted events between phentermine/topiramate and placebo, but we are very uncertain about these results. The most common unwanted events were digestive problems (for orlistat, phentermine/topiramate), and dry mouth and skin tingling or numbness (for naltrexone/bupropion).
The studies that investigated semaglutide or tirzepatide did not present information on the number of deaths, heart problems or safety issues in people with hypertension.
What are the limitations of the evidence?
We are not confident in the evidence regarding overall deaths and heart problems for orlistat, phentermine/topiramate or naltrexone/bupropion, or regarding serious unwanted events for phentermine/topiramate, because of our concerns about how the studies were conducted and the low number of the events. We are not confident in the evidence about all unwanted events for orlistat because of our concerns about how the studies were conducted and because the results were inconsistent across different studies. We have more confidence in the evidence regarding serious unwanted events for orlistat and naltrexone/bupropion, and regarding all unwanted events for phentermine/topiramate or naltrexone/bupropion, but we do not have high certainty about these because of our concerns about how some of the studies were conducted.
How up to date is this evidence?
We included evidence published up to 22 April 2024.
Read the full abstract
This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be able to help in this respect.
Objectives
Primary objective
To assess the effects of drugs approved for long-term weight management on all-cause mortality, cardiovascular morbidity and adverse events in adults with essential hypertension.
Secondary objective
To assess the effects of drugs approved for long-term weight management on changes in systolic and diastolic blood pressure and body weight in adults with essential hypertension.
Search strategy
For this updated review, the Cochrane Hypertension Information Specialist searched the following databases to 22 April 2024: the Cochrane Hypertension Specialised Register, Cochrane CENTRAL, MEDLINE, Embase and trial registries, with no language restrictions. We also checked references, searched citations, and contacted manufacturers and authors of relevant papers.
Selection criteria
Randomised controlled trials of at least 24 weeks' duration in adults with hypertension that compared approved long-term weight-loss medications to placebo.
Data collection and analysis
Two review authors independently selected studies, assessed risks of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of the heterogeneity.
Main results
This third update of the review added one new trial, investigating the combination of naltrexone/bupropion versus placebo. Two medications, which were included in the previous versions of this review (rimonabant and sibutramine) are no longer considered relevant for this update, since their marketing approval was withdrawn in 2010 and 2009, respectively. The number of included studies in this review update is therefore six (12,724 participants in total): four RCTs comparing orlistat to placebo, involving a total of 3132 participants with high blood pressure and a mean age of 46 to 55 years; one trial comparing phentermine/topiramate to placebo, involving 1305 participants with high blood pressure and a mean age of 53 years; and one trial comparing naltrexone/bupropion to placebo, involving 8283 participants with hypertension and a mean age of 62 years. We judged the risks of bias to be unclear for the trials investigating orlistat or naltrexone/bupropion. and low for the trial investigating phentermine/topiramate. Only the study of naltrexone/bupropion included cardiovascular mortality and morbidity as predefined outcomes.
There were no differences in the rates of all-cause or cardiovascular mortality, major cardiovascular events, or serious adverse events between naltrexone/bupropion and placebo. The incidence of overall adverse events was significantly higher in participants treated with naltrexone/bupropion. For orlistat, the incidence of gastrointestinal side effects was consistently higher compared to placebo. The most frequent side effects with phentermine/topiramate were dry mouth and paraesthesia. After six to 12 months, orlistat reduced systolic blood pressure compared to placebo by mean difference (MD) −2.6 mm Hg (95% confidence interval (CI) −3.8 to −1.4 mm Hg; 4 trials, 2058 participants) and diastolic blood pressure by MD −2.0 mm Hg (95% CI −2.7 to −1.2 mm Hg; 4 trials, 2058 participants). After 13 months of follow-up, phentermine/topiramate decreased systolic blood pressure compared to placebo by −2.0 to −4.2 mm Hg (1 trial, 1030 participants) (depending on drug dosage), and diastolic blood pressure by −1.3 to −1.9 mm Hg (1 trial, 1030 participants) (depending on drug dosage). There was no difference in the change in systolic or diastolic blood pressure between naltrexone/bupropion and placebo (1 trial, 8283 participants). We identified no relevant studies investigating liraglutide or lorcaserin in people with hypertension.
Authors' conclusions
There have been multiple developments in the domain of medications for long-term weight reduction in recent years. Several pharmaceutical products have been removed from the market due to safety concerns, whilst new drugs have been introduced. Our critical outcomes of death and cardiovascular complications were not the focus of the trials included in this review but were sometimes presented as part of an ‘adverse events’ outcome, with the resultant data providing only very low certainty evidence. Overall, the evidence for people with hypertension remains insufficient to draw conclusions regarding the benefits of pharmacological weight loss in terms of reducing the risk of mortality or cardiovascular morbidity. Further trials are needed. Moreover, separate results for participants with hypertension should be made available from any completed trials involving both normotensive and hypertensive people.
Funding
This Cochrane review had no dedicated funding.
Registration
Protocol and previous version DOIs: 10.1002/14651858.CD007654; 10.1002/14651858.CD007654.pub2; 10.1002/14651858.CD007654.pub3; 10.1002/14651858.CD007654.pub4; 10.1002/14651858.CD007654.pub5
