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General medicine
Lorcaserin in obesity: minimal benefits and ill-defined harms
  1. Igho J Onakpoya1,
  2. Jeffrey K Aronson2
  1. 1 Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
  2. 2 Centre for Evidence Based Medicine, University of Oxford, Oxford, UK
  1. Correspondence to Dr Igho J Onakpoya, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; igho.onakpoya{at}phc.ox.ac.uk

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A recent lorcaserin trial investigated ‘the long-term cardiovascular and metabolic safety and efficacy of lorcaserin’ in subjects at high cardiovascular risk. The large number of exclusions, the minimal weight reductions observed and the selective reporting of harms leave major uncertainties about lorcaserin’s benefit-harm profile

Lorcaserin has recently been hailed in news media as the new ‘holy grail’ in managing obesity. Is this true? Or are we being misled?

This claim is based on the results of a study of lorcaserin in 12 000 overweight or obese subjects with high cardiovascular risk profiles.1 The authors concluded that lorcaserin generated sustained weight loss without increased risks of major cardiovascular events. However, the benefits appear to have been exaggerated, and the harms downplayed or poorly reported.2

Lorcaserin (Belviq) is a selective 5HT2C receptor agonist, developed for use as a weight-reducing agent. In 2012, it gained US marketing approval for obesity after initial hesitancy by the Food and Drug Administration (FDA), because of concerns about harms.3 Concerns about the risks of tumours, psychiatric disorders and valvulopathies led the European Medicines Agency (EMA) to refuse the manufacturers of lorcaserin marketing approval.4

Minimal benefits

In the recent study, 33% and 15% of participants lost ≥5% body weight with lorcaserin and placebo, respectively: risk difference (RD) 0.18 (95% CI 0.17 to 0.20). This result is no better than weight reductions observed in our pooled analysis of three pivotal lorcaserin clinical trials (n=7784),5 and similar to other centrally acting medicines (we identified the pivotal trials by searching EMA and FDA databases, and combined the data using the random effects model of the Review Manager software).

Weight loss at 40 months was 4 kg with lorcaserin and 2.1 kg with placebo; the difference, 1.9 kg, may be statistically significant, but is clinically irrelevant. No information was given about the spread of weight changes in the population, for example, how many subjects gained weight rather than losing it.

We have combined this latest result with the results of three pivotal studies. The mean weight loss with lorcaserin compared with placebo was 2.77 kg (95% CI 1.55 to 3.98), a trivial loss in those who are overweight or obese.

Adverse events

In our pooled meta-analysis, adverse events were significantly more common with lorcaserin than placebo: RD 0.08 (95% CI 0.06 to 0.09, NNTH 13),5 as were nervous system and gastrointestinal adverse events: RD 0.14 (95% CI 0.11 to 0.17, NNTH 7) and RD 0.07 (95% CI 0.02 to 0.11, NNTH 16), respectively. Although the authors of the recent study reported that the frequencies of serious adverse events were not significantly different between the groups, they failed to report the overall frequencies of adverse events. Nor did they report the frequencies of nervous system and gastrointestinal adverse events; instead, they reported the rates of discontinuation attributed to those events.

Overall annual study discontinuation rates were 12% (lorcaserin) and 12.7% (placebo).1 However, this does not depict the true picture. Discontinuation rates over the 40 months of the study were much higher: 37.5% and 39.4%, respectively, comparable to the rates of discontinuations in our pooled analysis (34%–50%).5

The discontinuation rates due to adverse events were 7.2% (lorcaserin) and 3.7% (placebo): RD 0.035 (95% CI 0.03 to 0.04) NNTdiscont 28; this is greater than observed in our pooled analysis of three previous studies: RD 0.015 (95% CI 0.004 to 0.023; NNTdiscont 66). Medication adherence and reasons for non-adherence were neither mentioned in the trial registration document nor reported. This has economic and other implications that appear not to have been considered by trialists and drug regulators.6 7

External validity

The exclusion criteria in the recent study ran to 18 categories, including the use of other products intended for weight loss, a history or evidence of clinically significant disease, planned bariatric surgery and patients considered by the investigator to have insufficient motivation. It is hard to think of many patients in ordinary practice who would be eligible for treatment given these criteria.

Conclusions

Access to the clinical study reports of lorcaserin trial programmes should be granted, to allow researchers to conduct independent assessments of its benefits and harms.

EBM Verdict

EBM Verdict on: Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med 2018 Aug 26. doi: 10.1056/NEJMoa1808721.

  • Many centrally acting medicines have been withdrawn because of serious adverse effects, and their benefits are minimal. Lorcaserin causes minimal weight loss, its harms profile is as yet incompletely understood and it is unlikely to be a cost-effective intervention.

  • Overweight and obesity largely result from an imbalance between caloric intake and energy expenditure. Encouraging lifestyle changes that could correct this should therefore be the cornerstone of research and government policies. 

Supplementary file 1

Acknowledgments

Professor Carl Heneghan for criticism and proofreading of the manuscript, and Dr David Nunan for helpful comments.

References

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Footnotes

  • Contributors IJO and JKA both contributed equally to the text.

  • Competing interests IJO and JKA are coauthors of a previously published systematic review and meta-analysis that assessed the benefits and harms of centrally acting antiobesity medicines. IJO holds grant funding from the NIHR School of Primary Care Research (NIHR Evidence Synthesis working group Project No 390).

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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