Long-term effects of weight-reducing drugs in people with hypertension.

rationaleLong-term weight management drugs have the potential to reduce body weight and blood pressure in obese or overweight individuals. Being overweight or obese is often associated with hypertension, which is linked to an increased risk of cardiovascular mortality and morbidity. The effects of weight-reducing drugs on patient-relevant outcomes, especially in people with hypertension, are currently unclear. This review is the fourth update of one first published in July 2009.

objectivesPrimary 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

methodsFor 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. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) of at least 24 weeks' duration that compared approved long-term weight management drugs to placebo in non-pregnant adults with essential hypertension. OUTCOMES: Critical outcomes were all-cause mortality, cardiovascular morbidity and adverse events. Important outcomes were changes in systolic and diastolic blood pressure and changes in body weight. RISK OF BIAS: We assessed the risk of bias using the Cochrane RoB 1 tool. SYNTHESIS

methodsWe used standard Cochrane methods. For meta-analyses, we used risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. We undertook both fixed-effect and random-effects meta-analysis, presenting the random-effects results. We assessed the certainty of evidence using GRADE. INCLUDED STUDIES: We identified no additional trials of drugs included in the previous version of the review. We included two new RCTs evaluating the recently approved drugs semaglutide and tirzepatide. In total, eight RCTs reported results on different weight-reducing drugs compared to placebo in people with hypertension (approximately 13,000 hypertensive participants in total). The interventions evaluated were orlistat (4 trials, 3132 participants), phentermine/topiramate (1 trial, 1305 participants), naltrexone/bupropion (1 trial, 8283 participants), semaglutide (1 trial, 274 participants) and tirzepatide (1 trial, 153 participants with stage 2 hypertension and 635 participants taking antihypertensive medication). Study duration ranged from six to 48 months. Seven of the eight trials were funded by the pharmaceutical industry. We were unable to include any liraglutide results, as no RCTs have provided separate data for participants with hypertension. Rimonabant, sibutramine and lorcaserin are no longer considered relevant, since their marketing approval has been withdrawn. SYNTHESIS OF

resultsOrlistat versus placebo Orlistat may have little to no effect on all-cause mortality compared to placebo, but the evidence is very uncertain (3 versus 0 deaths; 3 trials, 1488 participants; very low certainty evidence). Orlistat may have little to no effect on cardiovascular morbidity compared to placebo, but the evidence is very uncertain (1.9% versus 0.7% in one trial and 17% versus 19% in another trial; 2 trials, 1721 participants; very low certainty evidence). Orlistat probably increases serious adverse events (SAEs) compared to placebo (RR 1.45, 95% CI 1.10 to 1.91; 3 trials, 1476 participants; moderate-certainty evidence). There may be little to no difference in all adverse events (AEs) between orlistat and placebo, but the evidence is very uncertain (RR 1.13, 95% CI 0.84 to 1.54; 2 trials, 1386 participants; very low-certainty evidence). Phentermine/topiramate versus placebo Phentermine/topiramate may have little to no effect on all-cause mortality compared to placebo, but the evidence is very uncertain (no deaths in either group; 1 trial, 1305 participants; very low-certainty evidence). Phentermine/topiramate may have little to no effect on cardiovascular morbidity compared to placebo, but the evidence is very uncertain (treatment-emergent cardiac events: high-dose versus placebo: RR 2.39, 95% CI 0.82 to 6.69; 1 trial, 1044 participants; low-dose versus placebo: RR 1.51, 95% CI 0.43 to 5.27; 1 trial, 785 participants; both very low-certainty evidence). Phentermine/topiramate may have little to no effect on SAEs compared to placebo, but the evidence is very uncertain (RR 0.85, 95% CI 0.49 to 1.48; 1 trial, 1305 participants; very low-certainty evidence). Phentermine/topiramate probably increases all AEs compared to placebo (RR 1.13, 95% CI 1.08 to 1.20; 1 trial, 1305 participants; moderate-certainty evidence). Naltrexone/bupropion versus placebo Naltrexone/bupropion may have little to no effect on all-cause mortality (RR 0.99, 95% CI 0.70 to 1.40; 1 trial, 8283 participants; very low-certainty evidence) and cardiovascular morbidity (RR 1.11, 95% CI 0.87 to 1.41; 1 trial, 8283 participants; very low-certainty evidence) compared to placebo, but the evidence is very uncertain. There is probably little to no difference between naltrexone/bupropion and placebo in SAEs (RR 1.05, 95% CI 0.96 to 1.14; 1 trial, 8283 participants; moderate-certainty evidence), but naltrexone/bupropion probably increases all AEs compared to placebo (RR 1.69, 95% CI 1.58 to 1.80; 1 trial, 8283 participants; moderate-certainty evidence). Semaglutide versus placebo No results were reported for all-cause mortality, cardiovascular morbidity, SAEs and AEs. Tirzepatide versus placebo No results were reported for all-cause mortality, cardiovascular morbidity, SAEs and AEs. AUTHORS'

conclusionsThere 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.

fundingThis 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.