Pharmacotherapy in obesity: a systematic review and meta-analysis of randomized controlled trials of anti-obesity drugs

ABSTRACT

Introduction: Obesity poses a significant increase in morbidity and mortality and thus five anti-obesity drugs have been approved currently by US FDA. Several phase 3 trials have shown a significant improvement in cardio-metabolic profile including significant weight reduction with these agents compared to placebo.

Areas covered: We systematically searched the database of PubMed, Embase, The Cochrane Library and The ClinicalTrials.gov up to 30 September 2019 and retrieved all the randomized controlled trials (RCTs) that were conducted with these five drugs for ≥1 year and explicitly reported their efficacy versus placebo. Subsequently, we have conducted the meta-analysis to primarily study the effect of these anti-obesity drugs on weight reduction. We additionally reviewed the effect of these drugs on other cardio-metabolic parameters including key adverse events.

Expert opinion: This meta-analysis finds a significant reduction in body weight with orlistat (N = 10,435; ∆ −3.07 Kg, 95% CI, −3.76 to −2.37), phentermine plus topiramate (N = 2985; ∆ −9.77 Kg; 95% CI, −11.73 to −7.81), lorcaserin (N = 16,856; ∆ −3.08 Kg; 95% CI, –3.49 to –2.66), naltrexone plus bupropion (N = 3239; ∆ −4.39 Kg; 95% CI, −5.05 to −3.72) and liraglutide (N = 4978; ∆ −5.25 Kg; 95% CI, −6.17 to −4.32), compared to placebo (all p < 0.00001).

KEYWORDS:

• Obesity
• anti-obesity drugs
• orlistat
• lorcaserin
• phentermine plus topiramate
• naltrexone plus bupropion
• liraglutide 3.0 mg

Article highlights

• Obesity poses a major public health risk, as it is frequently associated with significant increase in morbidity and mortality.

• Currently, five anti-obesity drugs have been approved by US FDA for long-term use. The weight lowering potential of these five anti-obesity drugs appears to be in following descending orders – phentermine/topiramate > liraglutide 3.0 mg > naltrexone/bupropion > lorcaserin = orlistat.

• The ease of dosing and better tolerability put lorcaserin and orlistat at a better position, compared to others, nonetheless, the weight lowering potential of both these agents are modest at its best and definitely lesser than other approved anti-obesity drugs. Additionally, non-responders to orlistat and lorcaserin are comparatively higher than others. No cardio-vascular outcome trial (CVOT) is available till date for orlistat; however, lorcaserin has demonstrated CV safety in CAMELLIA-TIMI 61, against placebo. Therefore, lorcaserin should be the preferred agent in people with established cardiovascular disease or high CV risk.

• While phentermine/topiramate has shown most robust reduction in body weight compared to other anti-obesity agents, increased neuro-psychiatric adverse events require strict pharmacovigilance. Increased fetal toxicity (oral clefts) with topiramate also limits its use in female of reproductive age and need risk evaluation and mitigation strategy (REMS).

• Naltrexone/bupropion and liraglutide 3.0 mg have shown a moderate effect on body weight reduction. While the former increases systolic blood pressure (SBP) and heart rate (HR), the latter reduces SBP, but increases HR. The CV safety of naltrexone/bupropion is still unknown as their CVOT, the LIGHT study was unblinded prematurely, by the sponsors. Liraglutide 1.8 mg has shown significant reduction in CV outcome including reduction in CV death in LEADER trial in patients with type 2 diabetes and high CV risk, however, this benefit could not be entirely extrapolated to liraglutide 3.0 mg use in subjects with obesity without type 2 diabetes and a high CV risk. Nevertheless, liraglutide 3.0 mg should be the preferred agent in obese type 2 diabetes subjects.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

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Additional information

Funding

This paper was not funded.