Lorcaserin and Phentermine Safe Combo in Weight-Loss Trial

Marlene Busko

November 10, 2014

In a 3-month safety study, combined therapy with the obesity agents phentermine plus lorcaserin (Belviq, Arena Pharmaceuticals/Eisai) did not exacerbate any serotonergic adverse effects seen with lorcaserin alone.

"The study is reassuring…in that the drug combination appears to be fairly safe, at least up to 12 weeks…and in the secondary efficacy outcome there was more than additive weight lost," coauthor Dr W Timothy Garvey (University of Alabama at Birmingham), who presented the findings at a late-breaking poster at the recent Obesity Week 2014 meeting, told Medscape Medical News.

"The [Food and Drug Administration] FDA has a caution about use of combinations of approved weight-loss drugs pending safety data, and this study is the first step in that direction," he said.

This is a valuable initial study, but longer drug-combination safety studies are needed, another expert noted.

"We really need to be sure regarding safety as we move forward," Dr Robert F Kushner (Northwestern University, Chicago, Illinois), a past president of the Obesity Society, who was not involved with this study, cautioned. Three months is not enough safety data, and the combination therapy was tested in only a small number of subjects, he stressed.

Nevertheless, "this is great pilot information to actually do more of a definitive, longer safety study, with a different trial design possibly, before we then give information to clinicians about how to use this," he commented.

Unknown Safety of Combining Weight-Loss Drugs

Phentermine and lorcaserin act via different mechanisms, and the safety of combining them is unknown, Dr Garvey explained. Lorcaserin activates specific serotonin 2C receptors in the hypothalamus, which may increase satiety, he observed.

Phentermine, meanwhile, stimulates the release of norepinephrine, and was approved by the US FDA in 1959 as a short-term appetite suppressant. It is also available in the United States as a new combination obesity product, joined with the antiepileptic drug topiramate as Qysmia (Vivus Pharmaceuticals), approved in 2012.

Neither of these newer obesity products, Belviq or Qsymia, has been approved in Europe due to safety concerns, however, and some in the United States have also questioned the safety of these agents.

The current study, Pilot Evaluation of Tolerability and Safety of Lorcaserin Plus Phentermine (PETAL), aimed to determine whether nine common potential serotonergic adverse events — headache, dizziness, nausea, fatigue, dry mouth, diarrhea, vomiting, insomnia, and/or anxiety — would be exacerbated by adding phentermine to lorcaserin.

The trial enrolled 238 patients at 12 sites in the United States. The patients were 18 to 60 years old, did not have type 2 diabetes, and had a body mass index (BMI) of 30 or higher, or a BMI of 27 plus hypertension, dyslipidemia, or sleep apnea.

The patients were randomized to one of three treatment groups: lorcaserin 10 mg, twice daily; lorcaserin 10 mg twice daily plus phentermine 15 mg daily (low-dose group); or lorcaserin 10 mg plus phentermine 15 mg, both taken twice daily (high-dose group). All patients also received a diet and exercise program.

Overall, combination therapy was well tolerated. A similar percentage of patients in each treatment group experienced one of the nine prespecified adverse effects: 37.2% of patients on monotherapy and 42.3% and 40.5% of patients taking low-dose and high-dose phentermine, respectively.

Common adverse effects were consistent with prior experience with these agents. Patients who received phentermine were more likely to have dry mouth, and pulse rate increased by 3 beats per minute with the higher dose.

The study dropout rate was 5% among patients taking lorcaserin alone and 2.6% and 10% among patients who were also taking low- and high-dose phentermine.

Although this trial was not powered to assess efficacy, patients receiving the combination therapy lost twice as much weight as those taking lorcaserin monotherapy.

At 12 weeks, patients who took lorcaserin plus low-dose or high-dose phentermine lost 7.0 kg and 7.6 kg, respectively, whereas patients taking lorcaserin alone lost 3.5 kg.

In the intent-to-treat population, 28% of patients receiving monotherapy, vs 59% and 70.9% of patients on combination therapy, lost 5% or more of their weight at 12 weeks.

"Further study is warranted to assess the efficacy and long-term safety of this combination," the authors conclude.

"This study has implications not only for this drug combination, but for a more comprehensive approach for drug-combination therapy in obesity — looking into the future — like we do for diabetes," Dr Garvey said.

"Obesity is a chronic disease, no different from diabetes, hypertension, or asthma, where we combine drugs," he concluded.

The PETAL study is sponsored by Eisai. Dr Garvey has served on advisory boards for Eisai, Novo Nordisk, Daiichi-Sankyo, Liposcience, Vivus, Takeda, Janssen, Boehringer-Ingelheim, and AstraZeneca and has conducted research for Eisai, Merck, Sanofi, AstraZeneca, and Weight Watchers. Dr Kushner is a consultant for Vivus.

Obesity Week 2014: The American Society for Metabolic and Bariatric Surgery and the Obesity Society Joint Annual Scientific Meeting; November 4, 2013; Boston, MA. Abstract 2053P

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