FDA-Approved Drugs and Lifestyle Changes for Obesity

Orlando—According to the Centers for Disease Control and Prevention, 34.9% of adults in the United States are obese, while the estimated obesity-related costs are $147 billion per year. The prevalence did not significantly increase from 2003 to 2004 to 2011 to 2012, although obesity remains a burden for patients and payers.

In 2012, the FDA approved lorcaserin and the combination of phentermine and topiramate extended-release (ER) to treat obesity. However, the agency noted that for the drugs to work properly, exercise and a proper diet must be implemented as well.

Salila Kurra, MD, assistant professor of clinical medicine, Columbia University, said that “weight loss medications do not work without lifestyle changes” and suggested obese patients exercise and have a better diet in order to lose weight.

Dr. Kurra, who spoke during a session at the NAMCP forum, said the most important factor in weight loss is reducing calories. She noted that for people to lose 1 pound per week, they must eat 500 fewer calories per day. The presentation was supported by educational grants from Eisai, Inc., and Vivus, Inc.

People are considered obese if their body mass index (BMI) is ≥30 kg/m² (Please see Table below). A larger BMI number is associated with an increased rate of death from all causes and from cardiovascular disease (CVD), according to Dr. Kurra. Medical complications of obesity include pulmonary disease, nonalcoholic fatty liver disease, gall bladder disease, gynecologic abnormalities, osteoarthritis, gout, idiopathic intracranial hypertension, stroke, cataracts, coronary heart disease, diabetes, dyslipidemia, hypertension, severe pancreatitis, phlebitis, and cancer.

Diets for Obesity

Dr. Kurra mentioned there are numerous diets that recommend various strategies, such as low fat, low carbohydrates, low glycemic, and high protein. However, she noted that if patients are adherent to diets, they would have comparable weight loss. She cited an article in Circulation that reviewed randomized, controlled trials comparing diets [2012;125(9):1157-1170]. The authors found that “caloric restriction rather than macronutrient composition is the key determinant of weight loss.”

Although adherence to diet is a better predictor of weight loss than the type of diet, Dr. Kurra said that most people do not adhere to their diets within 3 to 6 months of starting them. Physical activity is also important, according to Dr. Kurra. To prevent weight gain, she recommended people have 60 minutes of moderate intensity activity most days.

Other suggestions to help patients lose weight include having them keep track of what they eat, make sure they eat breakfast, limit alcohol consumption, do not drink juice or regular soda, and encourage them to purchase a pedometer with a goal of 10,000 steps per day.

If patients take other medications, however, they may have trouble losing weight. Dr. Kurra mentioned some drugs for psychiatric conditions, diabetes, and hypertension are associated with weight gain. For depression, she said weight gain is associated with monoamine oxidase inhibitors, such as isocarboxazid, phenelzine, selegiline, and tranylcypromine, and tricyclic antidepressants, such as amoxapine, clomipramine, and doxepin.

Patients with diabetes who take the following medications may also gain weight: insulin; sulfonylureas, such as glimepiride, glipizide, and glyburide; and thiazolidinediones, such as pioglitazone and rosiglitazone. Weight gain is also associated with hypertension medications, including beta-blockers and alpha-adrenergic antagonists.

History of Obesity Drugs

Through the years, the FDA has had several problems with approved obesity drugs. In 1947, the agency approved methamphetamine as the first prescription drug to treat obesity. However, the FDA limited its use in 1973, because it was concerned about the potential abuse of methamphetamine.

In 1996, the FDA approved dexfenfluramine, but the drug was pulled from the market a year later because of concerns regarding cardiac valve damage. In 1997, the FDA approved sibutramine. After the drug was found to be associated with a possible increase in cardiovascular risk, its manufacturer voluntarily withdrew sibutramine from the market in 2010.

Today, noradrenergic sympathomimetic drugs are approved for short-term use (up to 12 weeks) and 3 drugs are approved for long-term treatment of obesity: (1) orlistat; (2) lorcaserin; and (3) the combination of phentermine and topiramate ER. The FDA-approved noradrenergic sympathomimetic drugs are phentermine, diethylpropion, benzphetamine, and phendimetrazine. Dr. Kurra said there were 25 million prescriptions for phentermine in 2013, making it the most prescribed drug for obesity. She added that noradrenergic sympathomimetic drugs increase heart rate and blood pressure, are contraindicated in patients with CVD, and have abuse potential.

Dr. Kurra said that for drugs to be approved for long-term treatment, trials must show patients receiving the drug have at least a 5% mean weight loss compared with a placebo group. The studies must also indicate that at least 35% of patients receiving the drug lose at least 5% of their weight, and the portion must be double of the placebo group 1 year after treatment.

Orlistat, an oral drug, was approved in 1999 for use in adults and children 12 to 16 years of age. The medication is available in 120 mg (prescription) and 60 mg (over-the-counter [OTC]) strengths and is taken 3 times per day during or up to 1 hour after meals. Dr. Kurra mentioned that GlaxoSmithKline recently voluntarily recalled 60 mg of orlistat because of tampering with the OTC drug’s packaging.

Studies have found that patients receiving orlistat in trials lost approximately 9% of their weight after a year compared with 5.8% of patients who took placebo. In long-term studies, patients in the orlistat group had moderate decreases in diastolic blood pressure, fasting insulin levels, total cholesterol, and low-density lipoprotein cholesterol.

Dr. Kurra also discussed a 4-year, randomized, double-blind study of obese patients who took placebo or 120 mg of orlistat as an adjunct to lifestyle changes to prevent type 2 diabetes. Compared with the placebo group, patients in the orlistat group lost 2.4% more body weight and had a significantly decreased risk for developing type 2 diabetes.

Orlistat is associated with a few side effects, including considerable gastrointestinal side effects because the mechanism of action leads to increases in undigested stool triglycerides. Dr. Kurra said fewer than 10% of patients take the medication for at least a year and fewer than 2% take the drug for 2 years.

Newly Approved Agents

In 2012, the FDA approved 10 mg of lorcaserin twice daily based on 2 randomized, placebo-controlled trials that included overweight and obese patients who did not have diabetes. The drug is a selective serotonin receptor agonist and decreases food intake. Dr. Kurra said lorcaserin has the weight loss effects of fenfluramine, but it does not have the adverse cardiac effects associated with fenfluramine.

After 1 year in a phase 3 trial, 47.5% of patients receiving lorcaserin lost at least 5% of their body weight compared with 20.3% of patients in the placebo group (P<.001). Furthermore, the average weight loss was 5.81% in the lorcaserin group and 2.16% in the placebo group (P<.001). All patients underwent diet and exercise counseling.

After a year, patients continued to receive lorcaserin or were reassigned to receive placebo. Of the patients in the lorcaserin group who lost at least 5% of their weight, 67.9% of those who remained on lorcaserin in year 2 maintained their weight loss compared with 50.3% of those who switched to placebo.

There was no significant difference in valvulopathy between the groups; after a year, 2.3% of patients in the placebo group and 2.7% of patients in the lorcaserin group had developed valvulopathy (P=.70). Adverse effects associated with lorcaserin included headache, nausea, fatigue, and dizziness.

The FDA also approved phentermine plus topiramate ER in 2012 based on the results of 2 phase 3 trials. It is the first FDA-approved combination drug for obesity. The starting dose is 3.75 mg of phentermine plus 23 mg of topiramate, the recommended dose is 7.5 mg of phentermine plus 46 mg of topiramate, the titration dose is 11.25 mg of phentermine plus 69 mg of topiramate, and the top dose is 15 mg of phentermine plus 92 mg of topiramate.

Both phase 3 trials involving phentermine plus topiramate ER lasted 56 weeks. Compared with a placebo group, the phentermine plus topiramate ER group had a greater reduction in body weight and a greater proportion of patients achieved at least 5% weight loss.

Dr. Kurra said adverse effects associated with phentermine plus topiramate ER includes a potential for oral clefts in the offspring of women who become pregnant while taking topiramate. Before taking the drug, women with childbearing potential should have a negative pregnancy test, according to Dr. Kurra.

She also mentioned there are some concerns with phentermine plus topiramate ER and its long-term effect on cardiovascular events. In the trials, 56.1% of patients who received the top dose of phentermine plus topiramate ER had a resting heart rate increase of >10 beats per minute compared with 42.1% of patients in the placebo group.

Some insurers do not cover lorcaserin and phentermine plus topiramate ER, according to Dr. Kurra. She added that the average patient taking phentermine plus topiramate ER pays $100 per month out-of-pocket for the drug.