Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients (CAMELLIA–TIMI 61)

Trial References

Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients – Thrombolysis in Myocardial Infarction 61 (CAMELLIA–TIMI 61)

Expert Comment

Amelia Carro. Hospital Universitario Vall d’Hebrón. Universidad Autónoma de Barcelona, Barcelona, Spain.

Background

Obesity is a major correlate of cardiovascular disease. Weight loss improves cardiovascular risk factors and has the potential to improve outcomes. In clinical trials, several drugs have demonstrated weight loss with favourable effects on glucose tolerance, lipid profile and blood pressure. However, some of them share the serotonergic and sympathomimetic mechanisms that proved harmful in the cases of fenfluramine and sibutramine (heart valve disease, pulmonary hypertension, cardiovascular events). Given these risks, randomized cardiovascular outcomes trials are needed to establish the safety and potential benefit of these drugs. Lorcaserin works by binding to 5-HT2C receptors in the hypothalamic POMC (proopiomelanocortin) pathway with an affinity that is 100 times that of 5-HT2B receptors and 18 times that of 5-HT2A receptors. The 5-HT2B receptor is expressed on cardiac cells and has been implicated as the cause of fenfluramine-associated valvulopathy and pulmonary hypertension¹. Avoiding 5-HT2A cross-reactivity is also important, as this receptor is implicated in psychosis². Activation of the 5-HT2C receptor promotes anorexia by activating central melanocortin pathways³. Post hoc analysis of the BLOOM and BLOSSOM trials showed numerically (non-significant) lower rates of cardiovascular death, myocardial infarction, hospitalization for unstable angina, or stroke in patients treated with lorcaserin (OR: 0.63, 95% CI: 0.19-2.12)⁴. Hence, the randomized, parallel CAMELLIA-TIMI-61 trial was designed with the aim to evaluate the cardiovascular safety and efficacy of lorcaserin (n=6000; 10 mg twice daily) compared with placebo (n=6000) among overweight and obese patients (body mass index >27 kg/m2) with cardiovascular disease or multiple cardiovascular risk factors.

The primary safety outcome focused on major cardiovascular events (cardiovascular death, myocardial infarction, or stroke) and was evaluated after a mean follow-up of 3.3 years. This composite endpoint occurred in 2.0% per year in the lorcaserin group compared with 2.1% per year in the placebo group (hazard ratio, 0.99; 95% CI, 0.85 to 1.14; p<0.001 for noninferiority). Since the condition for noninferiority was met, further analyses focused on superiority testing for the primary cardiovascular efficacy endpoint (major cardiovascular events, heart failure, or hospitalization for unstable angina or revascularization); no significant difference was found with lorcaserin (4.1% per year) versus placebo (4.2% per year) (occurred in 4.1% per year in the lorcaserin group compared with 4.2% per year in the placebo group (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.55). Secondary outcomes included:

• Weight loss: ≥5%: 38.7% (lorcaserin) vs. 17.4% (placebo) (p < 0.001)
• Cardiovascular death: 0.5% per year (lorcaserin) vs. 0.5% per year (placebo) (p=NS)
• Heart failure: 0.8% per year (lorcaserin) vs. 0.8% per year (placebo) (p=NS)
• New-onset diabetes: 3.1% per year (lorcaserin) vs. 3.8% per year (placebo)(p < 0.05)

As in other reports on its use, the side effects of headache, fatigue, dizziness, diarrhea, and nausea led to twice the number of discontinuations in the lorcaserin group as in the placebo group, although the total rates of discontinuation were similar in the two groups.

Conclusion:

Lorcaserin reduced weight among overweight and obese patients with cardiovascular disease or major risk for cardiovascular disease. Compared with placebo, this sustained reduction in weight did not increase adverse cardiovascular events at a median of 3.3 years. This drug represents an addition to the currently available options for weight loss including lifestyle modification and bariatric surgery. However, whether this trial will lead to enhanced utilization of lorcaserin by providers is uncertain, as is the ultimate role of this drug in the treatment of patients who are overweight or obese.

References

1. Roth BL. Drugs and valvular heart disease. N Engl J Med. 2007;356:6-9
2. Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, et al. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther.2008;325:577-587.
3. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart J, et al. Activation of central melanocortin pathways by fenfluramine. Science.2002;297:609-611.
4. Aronne L, Shanahan W, Fain R, Glicklich A, Soliman W, Li Y, et al. Safety and efficacy of lorcaserin: a combined analysis of the BLOOM and BLOSSOM trials. Postgrad Med. 2014;126(6):7-18.