Behavioral Modification and Lorcaserin for Overweight and Obesity Management - BLOOM

Description:

Activation of 5-HT2C receptors (serotoninergic) has been shown to be associated with decreased food intake in basic science studies. An earlier phase II trial involving lorcaserin, a selective 5-HT2C receptor agonist, demonstrated dose-dependent weight loss with its use. BLOOM was a phase III trial designed to study the safety and efficacy of lorcaserin for weight management in obese patients.

Hypothesis:

Lorcaserin would be safe and effective for weight management, as compared with placebo, in obese patients.

Study Design

  • Blinded
  • Crossover
  • Parallel
  • Placebo Controlled
  • Randomized

Patient Populations:

Inclusion criteria:

  • Age 18-65 years
  • BMI 30-45 kg/m2 or 27-45 kg/m2 with at least one of the following: 
    o Hypertension
    o Hyperlipidemia
    o Cardiovascular disease
    o Impaired glucose tolerance
    o Sleep apnea

Total number of patients: 3,182

Duration of follow-up: 2 years

Mean patient age: 44.1 years

Percentage female: 83.5%

 

Exclusions:

  • Moderate or severe mitral regurgitation
  • Mild or more severe aortic regurgitation
  • Diabetes mellitus
  • Systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg
  • Depression needing treatment within the preceding 2 years
  • Pregnancy or lactation

Primary Endpoints:

  • Proportion of patients with ≥5% reduction in body weight from baseline at the end of year 1 
  • Change in weight between baseline and year 1 
  • Proportion of patients with ≥10% reduction in body weight from baseline at the end of year 1 
  • Proportion of patients with ≥5% reduction in body weight from baseline at the end of year 1, and who maintained this at the end of year 2

Secondary Endpoints:

  • Changes from baseline in lipids, glycemic variables, physical measures, inflammatory markers of cardiovascular risk, and quality of life

Drug/Procedures Used:

During the first year, patients were randomized to receive either lorcaserin 10 mg twice daily, or placebo. At the beginning of the second year, one-third of the patients in the lorcaserin arm crossed over to the placebo arm.

Concomitant Medications:

All patients underwent standardized nutritional and exercise counseling. All patients were advised to exercise moderately for 30 minutes daily, and to reduce daily caloric intake by 600 kcal below the individual World Health Organization estimate for daily requirements.

Principal Findings:

A total of 3,182 patients were randomized, 1,595 to lorcaserin and 1,587 to placebo. Baseline characteristics were fairly comparable between the two groups. The mean weight was about 100 kg, with a mean body mass index (BMI) of 36.2 kg/m2, and a mean waist circumference of 109.4 cm. Baseline mean laboratory values included low-density lipoprotein cholesterol of 113 mg/dl, fasting glucose of 94.2 mg/dl, glycated hemoglobin of 5.6, and a high-sensitivity C-reactive protein (hs-CRP) of 5.6 mg/L. Rates of completion of study medication at year 1 were low: 55.4% versus 45.1% in the lorcaserin and placebo arms, respectively. Only about 7% of these patients discontinued the study due to side effects.

Lorcaserin was associated with a significant proportion of patients with ≥5% (47.5% vs. 20.3%, p < 0.001), and ≥10% (22.6% vs. 7.7%, p < 0.001) weight loss from baseline. The average weight loss was 5.8% versus 2.2% of baseline weight in the lorcaserin and placebo arms, respectively. Weight loss was noted as early as 4-8 weeks following drug initiation. Among patients with >5% weight loss from baseline, a greater proportion of patients in the lorcaserin arm who continued to receive the study medication maintained their weight loss, as compared with those who crossed over to the placebo arm (67.9% vs. 50.3%, p < 0.001).

Other measures such as waist circumference (-6.8 cm vs. -3.9 cm, p < 0.001), BMI (-2.1 vs. -0.8, p < 0.001), systolic blood pressure (-1.4 mm Hg vs. -0.8 mm Hg, p = 0.04), diastolic blood pressure (-1.1 mm Hg vs. -0.6 mm Hg, p = 0.01), total cholesterol (-0.9% vs. 0.6%, p = 0.001), triglycerides (-6.2% vs. 0.1%, p < 0.001), fasting glucose (-0.8 mg/dl vs. 1.1 mg/dl, p < 0.001), and hs-CRP (-1.19 mg/L vs. -0.17 mg/L, p < 0.001) were significantly improved in the lorcaserin arm at the end of 1 year. Safety endpoints at 1 year were similar between the two arms, including pulmonary artery systolic pressure (-0.9 vs. -0.2 mm Hg, p = 0.14) and Beck Depression Inventory II (-1.1 vs. -0.9, p = 0.26), although heart rate was marginally lower in the lorcaserin arm (-2.0 vs. -1.6 bpm, p = 0.05).

The incidence of adverse events, including serious adverse events, was similar between the two arms. The most frequent adverse events in the lorcaserin arm were headache, upper respiratory infection, nasopharyngitis, dizziness, and nausea. Serious side effects such as cardiac were infrequent. Food and Drug Administration (FDA)-defined valvulopathy at the end of the first and second years was similar between the two arms. Psychiatric events were very infrequent.

Interpretation:

The results of the BLOOM trial indicate that lorcaserin, a novel 5-HT2C receptor agonist, results in greater weight loss and an improvement in metabolic markers in obese patients, as compared with placebo, over 2 years of follow-up. Serious side effects are rare.

Fenfluramine and dexfenfluramine, which were marketed for weight loss, were nonselective 5-HT2 receptor agonists, but gained notoriety due to an increased risk of serotonin-associated valvulopathy. Lorcaserin is a newer drug, with higher affinity for 5-HT2C receptors, whereas serotonin-associated valvulopathy is thought to occur via 5-HT2B receptor activation. Hence, it is unlikely to be associated with this side effect, which was confirmed in this trial.

Limitations of this trial include the relatively short duration to assess for infrequent but serious side effects (such as psychiatric side effects), and the high rate of study drug discontinuation. Also, patients with diabetes or hypertension were excluded, which are significant coexisting conditions in obese patients. In addition, it should be noted that patients in this trial received intense nutritional and exercise counseling, which should be the cornerstone for weight management in obese patients. Lorcaserin has the potential to be an adjunct in obese patients in whom exercise and nutritional counseling alone has failed or is inadequate.

References:

Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363:245-56.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Statins, Heart Failure and Cardiac Biomarkers, Diet, Hypertension, Sleep Apnea

Keywords: Receptor, Serotonin, 5-HT2C, Follow-Up Studies, Hyperlipidemias, Counseling, Headache, Benzazepines, Hemoglobin A, Glycosylated, Dexfenfluramine, Waist Circumference, Cholesterol, Dizziness, United States Food and Drug Administration, Nasopharyngitis, Hypertension, Depression, Nausea, Weight Loss, Diet, Reducing, Heart Rate, Receptor, Serotonin, 5-HT2B, Sleep Apnea Syndromes, Lipoproteins, LDL, C-Reactive Protein, Body Mass Index, Serotonin, Fenfluramine, Triglycerides, Diabetes Mellitus


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