Pharmacotherapy for Obesity: Filling a Therapeutic Gap

Weight gain prevention should be part of clinical practice, with recognition of slow increases in body weight. Once obesity occurs, it is difficult to reverse, as in general the body defends a certain weight set point. A 5% to 10% weight reduction is desirable in terms of cardiometabolic benefit. Changes in diet and lifestyle may lead to a reduction of up to 5% of body weight. Lap band surgery may lead to a 15% to 20% reduction in weight. Other surgical options such as sleeve gastrectomy may lead to up to a 35% weight loss. There remains a gap for nonsurgical therapies beyond diet and lifestyle changes that lead to body weight reductions between 5% and 15%.

Phentermine/topiramate ER and lorcaserin have recently received FDA approval as an adjunct to diet and lifestyle changes for chronic weight management. A combination of naltrexone and bupropion is in development, and is currently in phase III trials. Another medication, liraglutide, may soon receive an indication for aiding weight reduction.

Phentermine is a sympathomimetic amine that increases norepinephrine release. Topiramate increases gamma-aminobutyric acid (GABA) activity, decreases AMPA/kainate glutamate receptor stimulation, and inhibits carbonic anhydrase. GABA is an important neurotransmitter because it may affect areas of the brain that regulate energy balance. A study by Vong et al found that leptin works on GABAergic neurons, and reduces inhibitory tone of proopiomelanocortin POMC neurons. This may be the weight-reducing mechanism of topiramate.

Phentermine/topiramate has been evaluated in several major trials that ranged from 1 to 2 years in duration. EQUIP included 227 patients with a body mass index (BMI) greater than 30, CONQUER included 2487 patients with a BMI over 30 and obesity-related comorbidities, and SEQUEL included 676 patients with a BMI greater than 30 and obesity-related comorbidities. The dosages of topiramate used were much lower than those used in epilepsy and migraine treatment. In EQUIP, over 108 weeks, the lower dose of topiramate led to a 3.5% weight reduction, and the higher dose of topiramate led to a 9.3% weight reduction. The lower and higher doses of phentermine/topiramate ER led to weight losses of 10.8% and 11.4%, respectively. Placebo led to a 2.5% weight loss. In EQUIP and CONQUER there were substantial and significant decreases in blood pressure and markers of dyslipidemia.

Patients enrolled in the SEQEL trial were randomized to receive lower-dose phentermine/topiramate ER combination therapy, higher-dose phentermine/topiramate ER combination therapy, or placebo. The results of SEQUEL showed that blood pressure was reduced about the same amount in all 3 groups; however, the percentage of blood pressure prescriptions went down 3.5% and 9.8% in the lower and higher dose groups, respectively. By contrast, the blood pressure prescription percentage went up 3.5% in the placebo group. Lipid therapy increased by 17% in the placebo group, 5.2% in the lower-dose group, and 4.7% in the higher-dose group. Glycated hemoglobin (A1C) levels went down, and the number of prescriptions used to treat diabetes was reduced.

Therapy with phentermine/topiramate ER should be initiated with a low dose for 2 weeks, and the dose should be gradually increased. Dose reduction may be necessary in patients with liver or kidney impairment. After 12 weeks of therapy, the dose may be further increased in patients not achieving a 3% weight loss. If a patient has not lost at least 5% of baseline body weight after 12 additional weeks of therapy, the patient and clinician should reconsider therapy.

Side effects associated with phentermine/topiramate ER include dry mouth, headache, dizziness, cognitive impairment, paresthesias, fetal toxicity (increase in oral cleft palate), and an increase in heart rate (about 2 beats per minute). Acute myopia and secondary angle glaucoma may occur. Sleep disorders may also occur. However, there was no increased incidence of depression or anxiety or increase in risk of suicide with treatment, despite the fact that around 20% of patients in the study used psychiatric medication.

The FDA has required a Risk Evaluation and Mitigation Strategy (REMS) for phentermine/topiramate ER. The purpose of the REMS for phentermine/topiramate ER is to inform clinicians and patients about the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to phentermine/topiramate ER during the first trimester of pregnancy; the importance of pregnancy prevention for females of reproductive potential receiving phentermine/topiramate ER; and the need to discontinue phentermine/topiramate ER immediately if pregnancy occurs.

The BLOOM study demonstrated the efficacy of lorcaserin 10 mg once daily versus placebo. Nearly 50% of patients lost 5% or more of overall body weight. Nearly 20% of patients lost 10% of overall weight with lorcaserin. Lorcaserin also reduced blood pressure, triglycerides, low-density lipoprotein cholesterol, and other clinical endpoints. In the BLOOM-DM trial, which enrolled patients with a BMI of 30 or greater and diabetes mellitus, lorcaserin at a dose of 10 mg twice daily led to a loss of body weight from baseline. Other evaluated groups included patients that received placebo, and patients that received once-daily doses of lorcaserin. Treatment with lorcaserin led to a 0.5 percentage-point reduction in A1C levels with lorcaserin 10 mg twice daily.

Headaches occured more commonly with lorcaserin therapy than with placebo. Nausea, dizziness, sinus infections, depression, anxiety, and cognitive impairment were associated with lorcaserin therapy. There have been reports of psychiatric side effects. However, there have been no reports of valvulopathy.

Combination therapy with naltrexone/bupropion is currently being evaluated. Trials with naltrexone/bupropion at 2 different doses, with the highest dose showing an approximately 16% loss in total body weight with treatment. Another drug, liraglutide, is already FDA-approved for type 2 diabetes, but is currently being studied for the additional indication of reduction in body weight. Liraglutide use may lead to a substantial weight reduction of around 10% of total body weight at higher doses.

The era of new pharmacotherapy for obesity has begun. Pharmacotherapy can help patients achieve a 10% or greater weight loss, and long-term treatment may also be a possibility with these new therapies.