Pharmacology Update
July 15, 2012 4 minutes read
Pharmacology Update
Lorcaserin HCl Tablets (Belviq®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
THE FDA HAS APPROVED THE FIRST NEW WEIGHT LOSS DRUG in more than a decade. Lorcaserin is a selective agonist of the serotonin 2C receptor (5-HT2C). Activation of this receptor is associated with decreased food intake. In 2010, the FDA advisory panel did not recommend approval due to safety concerns but subsequently decided that the benefits outweigh the risks. This product will be manufactured by Arena Pharmaceuticals and distributed by Eisai Inc. as Belviq.
Indications
Lorcaserin is indicated for chronic weight management in conjunction with a reduced-calorie diet and increased physical activity in obese adults or overweight adults with at least one comorbidity.1 Obese is defined as initial body mass index (BMI) of 30 kg/m2 or greater. Overweight with comorbidity is defined as a BMI of 27 kg/m2 with hypertension, dyslipidemia, or type 2 diabetes.
Dosage
The recommended dose is 10 mg twice a day without regard to meals.1 If a 5% weight loss is not achieved by week 12, the drug should be discontinued.
Potential Advantages
Lorcaserin is a selective inhibitor of 5-HT2C with minimal affinity for 5-HT2A and 5-HT2B. Previous nonselective serotonin agonists such as fenfluramine and dexfenfluramine have been associated with cardiac valvulopathy, but current evidence suggests no increased risk with lorcaserin.
Potential Disadvantages
The most common adverse events were headache, dizziness, fatigue, and nausea.1 Hypoglycemia has been reported with type 2 diabetic subjects. Less frequent or even rare but potentially serious adverse events include serotonin syndrome or neuroleptic malignant syndrome-like reaction and pulmonary hypertension.1
Comments
The safety and efficacy of lorcaserin was studied in three randomized, double-blind, placebo-controlled trials of 52 to 104 weeks duration.1-4 Study 1 (BLOOM) randomized 3182 obese or overweight adults to lorcaserin 10 mg twice daily or placebo for 1 year and follow-up to 2 years.2 Study 2 (BLOSSOM) randomized 4008 similarly obese or overweight adults to lorcaserin 10 mg once daily, twice daily, or placebo.3 Study 3 (BLOOM-DM) randomized 604 adults with type 2 diabetes to lorcaserin 10 mg once daily, twice daily, or placebo.4 All subjects received nutritional and exercise counseling.
For studies 1 and 2, the mean 12-month weight loss for lorcaserin 10 mg twice daily was 5.8 kg ± 0.1 kg compared to 2.5 ± 0.1 kg for placebo with an adjusted difference of -3.3 kg (95% CI -3.6, -2.9).1 Forty-seven percent had a 5% or more loss of body weight compared to 22.6% for placebo (adjusted difference of 24.5%) and 22.4% had a ≥ 10% loss of body weight compared to 8.7% for placebo (adjusted difference 13.8%). Weight loss was higher in Caucasians than African Americans or Hispanic patients. Older (> 50 years) subjects lost more weight than younger subjects. In study 1, subjects who completed 1 year of participation continued for another year. The placebo group continued to receive placebo and the lorcaserin group was randomized to placebo or lorcaserin. Weight gain occurred in all groups but ended up below their year 1 baseline weight. At the end of week 104, the weight loss was -2.8 kg for placebo, -3.8 kg for lorcaserin to placebo, and -6.0 kg for lorcaserin.
Lorcaserin showed a small improvement in cardiovascular risk factors (e.g., lipids, fasting insulin) compared to placebo with the waist circumference and triglycerides showing the greatest improvement (-2.5 cm, -4.8%). For type 2 diabetics (study 3), mean weight loss at 1 year was -4.7 kg for lorcasarin 10 mg twice daily compared to -1.6 kg for placebo (adjusted -4.5%). Five percent loss in body weight occurred in 37.5% of subjects taking lorcasarin compared to 16.1% for placebo (adjusted difference of 21.3%). For 10% loss of body weight, the percentages were 16.3%, 4.4%, and 11.9%, respectively. Cardiovascular risk factors also improved in this population compared to placebo, with fasting glucose (-15.5 mg/dL), triglycerides (-5.9%), HDL-cholesterol (+3.6%), and waist circumference (-2.2%) showing the greatest improvements. The rate of echocardiographic valvulopathy was not significantly different between the lorcasarin group and placebo group. Rates were 2.6% vs 2.7% at year 2 in study 1 and 2.0% for each group in study 2. However, in the smaller study (BLOOM-DM) 2.9% (6/256) in the lorcaserin (10 mg twice daily) group and 0.5% (1/252) in the placebo group had new echocardiographic valvulopathy.4 This did not reach statistical significance (P = 0.122). Lorcaserin is generally well tolerated; 8.6% of subjects prematurely discontinued treatment due to adverse events compared to 6.7% for the placebo-treated subjects.1
Clinical Implications
Lorcaserin is the first weight-loss drug to be approved in more than a decade. The weight loss achieved is rather modest (3.3 kg compared to control at 1 year and an absolute difference of 25% with a 5% loss of body weight). The effectiveness appears to be similar to that reported in placebo-controlled trials with orlistat (120 mg three times daily).5 The FDA Guidance for Industry: Developing Products for Weight Management indicates that the primary efficacy endpoint should show a statistical difference of 5% or at least 35% and approximately double the proportion of subjects in the drug group achieve a loss of 5% or greater in baseline body weight compared to the control group. Lorcaserin met the second criteria but not the first. The long-term safety of lorcaserin remains to be determined. The drug manufacturer will be required to conduct postmarketing studies, including long-term assessment of risks for adverse cardiovascular events.
References
1. Belviq® Prescribing Information. San Diego, CA: Arena Pharmaceuticals; June 2012.
2. Smith SR, et al. N Engl J Med 2010;363:245-256.
3. Fidler MC, et al. J Clin Endocrinol Metab 2011;96: 3067-3077.
4. O’Neil PM et al. Obesity 2012;20:1426-1436.
5. Curran MP, Scott LJ. Drugs 2004;64:2845-2864.
6. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071612.pdf. Accessed June 30, 2012.
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