Pharmacotherapy for obesity: What you need to know

Lorcaserin

Lorcaserin (Belviq) was approved by the FDA in 2012 for chronic weight management. It suppresses appetite by activating the serotonin 2C receptor in the brain. Because it is selective for the 2C receptor, it does not appear to have the same detrimental effects on heart valves as occurred with less-selective serotonergic agents such as fenfluramine and dexfenfluramine.³¹

Dosage. The recommended dosage for lorcaserin is 10 mg twice daily. Lorcaserin is a schedule IV controlled substance because of studies that showed increases in positive subjective measures such as euphoria in patients taking the drug. The incidence of euphoria was similar to that seen with zolpidem.³²

Efficacy. Lorcaserin was approved on the basis of 2 trials in nondiabetic obese and overweight adults who did not have diabetes but who had a weight-related condition,^33,34 and in a third trial in obese and overweight adults with type 2 diabetes mellitus who were taking oral hypoglycemic agents.³⁵ In these trials, lorcaserin use resulted in a modest 4.7- to 5.8-kg weight loss compared with 1.6 to 2.2 kg in the placebo group.^33–35 There was a high dropout rate in all 3 of these studies (33% to 45% of participants).

A pilot study that added phentermine to lorcaserin yielded double the weight loss from lorcaserin alone.³⁶ This drug combination warrants further investigation.

Contraindications. Lorcaserin should not be given to patients who have severe renal insufficiency (creatinine clearance < 30 mL/min) or severe hepatic impairment, or who are pregnant.

Adverse effects. Common adverse reactions include dry mouth, dizziness, somnolence, headache, and gastrointestinal disturbances (nausea, constipation, or diarrhea).³⁷

Patients with type 2 diabetes mellitus should be monitored for hypoglycemia.

Lorcaserin should be used with extreme caution in patients taking other serotonergic agents because of the risk of the serotonin syndrome.

A theoretic potential for increased risk of breast cancer also exists with lorcaserin. When rats were given supraphysiologic doses of lorcaserin (more than 50 times higher than recommended in humans), fibroadenomas and adenocarcinomas occurred at higher rates.³⁸ Breast cancer data were not reported in the 3 randomized trials discussed above.^33–35

Naltrexone-bupropion

The combination of naltrexone and bupropion was approved by the FDA in 2014 under the brand name Contrave. Both drugs are approved for monotherapy in conditions other than obesity.

Naltrexone is a mu opioid receptor antagonist approved to treat alcohol and opioid dependency. Bupropion is a dopamine-norepinephrine reuptake inhibitor approved to treat depression and to help with smoking cessation. Combining the drugs produces weight loss and metabolic benefits through effects on 2 areas of the brain that regulate food intake: the hypothalamus (appetite) and the mesolimbic dopamine circuit (reward system).

Dosage. Naltrexone-bupropion comes as an extended-release tablet of 8/90 mg. The maintenance dose of 2 tablets twice daily is reached at week 4 through a specific dose-titration regimen (Table 1). The dose should be adjusted if patients have renal or hepatic impairment or if they are also taking a CYP2B6 inhibitor.

Efficacy. FDA approval was based on the results of 4 clinical trials.^39–42 Using a modified intention-to-treat analysis, Yanovski and Yanovski⁴³ calculated that at 1 year, placebo-subtracted mean weight loss was 4.6% (4.9 kg), and mean total weight loss was 6.8% (7.3 kg) across the studies. Attrition rates, however, were high, ranging from 42% to 50%.

Cardiometabolic effects in 2 of the trials^40,41 included decreased waist circumference, triglyceride levels, and C-reactive protein levels, and increased high-density lipoprotein levels at the initial dose. At the maintenance dose, additional lowering of fasting plasma insulin and glucose levels occurred along with lower levels of the homeostatic model assessment of insulin resistance. In the COR-Diabetes Study Group trial, patients with type 2 diabetes mellitus had decreased hemoglobin A_1c levels without an increase in hypoglycemia and an increased likelihood of reaching the target hemoglobin A_1c level below 7%.³⁹

Contraindications. Naltrexone-bupropion is contraindicated for patients who have uncontrolled hypertension, seizure disorder, eating disorder, or end-stage renal failure; who are pregnant; or who have been treated with a monoamine oxidase inhibitor within 14 days. It should not be used with other bupropion-containing products or in patients who have taken opioids chronically or have acute opiate withdrawal.

Because of its bupropion component, this product carries an FDA black-box warning about possible suicidal thoughts and behaviors and neuropsychiatric reactions.

Adverse effects. The adverse reactions most commonly associated with naltrexone-bupropion were nausea (32.5%), constipation (19.2%), headache (17.6%), vomiting (10.7%), dizziness (9.9%), insomnia (9.2%), dry mouth (8.1%), and diarrhea (7.1%).⁴⁴

Liraglutide

Liraglutide, previously FDA-approved to treat type 2 diabetes mellitus under the brand name Victoza, received approval in 2014 in a higher-dose formulation (Saxenda) to treat obesity.

Liraglutide is a glucagon-like peptide-1 receptor agonist that stimulates glucose-dependent insulin release from the pancreatic islet cells, slows gastric emptying, regulates postprandial glucagon, and reduces food intake.

Dosage. Liraglutide is given as a once-daily injection in the abdomen, thigh, or arm. The initial dosage is 0.6 mg daily for the first week and can be titrated up by 0.6 mg weekly to a target dose of 3 mg daily. If a patient does not lose 4% of baseline body weight after 16 weeks on the target dose, the drug should be discontinued because it is unlikely to lead to clinically significant weight loss.

Efficacy. Liraglutide for weight management (3 mg once daily) was evaluated in a large (N = 3,731), randomized, double-blind, placebo-controlled international trial.⁴⁵ Participants did not have diabetes mellitus, but 60% had prediabetes. Liraglutide or placebo was given for 56 weeks, along with lifestyle counseling. At the end of the study, the liraglutide group had lost a mean of 8.4 kg vs 2.8 kg in the placebo group. Additionally, 63% of the liraglutide group lost at least 5% of body weight vs 27% in the placebo group, and 33% lost at least 10% of body weight vs 10% in the placebo group.

A 2-year extension found systolic blood pressure decreased with no change in pulse, and the prevalence of prediabetes and metabolic syndrome decreased by 52% and 59%, respectively.⁴⁶ At 2 years, mean scores for physical function, self-esteem, and work had improved more in the liraglutide group than the placebo group.⁴⁷

Adverse effects. The most common adverse reactions with liraglutide were nausea, vomiting, diarrhea, constipation, hypoglycemia, and loss of appetite. In most cases, nausea and vomiting were tolerable, transient, and associated with greater weight loss but not with decreased quality-of-life scores. Serious adverse reactions included pancreatitis, gallbladder disease, renal impairment, and suicidal thoughts.