An update on weight-loss medications

Adarsh K. Gupta, DO, MS, FACOFP, Department of Family Medicine, Center for Medical Weight Loss & Metabolic Control, UMDNJ-SOM, 61 Meetinghouse Cir, Sicklerville, NJ 08081- 4896.

E-mail address: adarshgupta@gmail.com.

An update on weight-loss medications

To the Editor:

This is an update to the article published in September/ October 2012th issue of Osteopathic Family Physician entitled “Diabetes obesity: Link how to lower your risk of diabetes with weight management.” As that article was originally submitted to osteopathic family physicians, there have been updates on the weight-loss medications. The Food and Drug Administration (FDA) recently approved 2 new drugs as adjuncts to a reduced calorie diet and increased physical activity for long-term weight manage- ment in adults who are obese (defined as having a body mass index 430) or overweight (body mass index 427) with at least 1 weight-related coexisting condition.

Belviq (lorcaserin, Arena pharmaceuticals) is the selec- tive agonist of the serotonin (5-hydroxytryptamine) 2C (5- HT2C) receptor.1 Qsymia (phentermine plus extended- release topiramate, Vivus) is a fixed-dose combination of a sympathomimetic amine, phentermine, which is an anorectic agent, and the antiepileptic drug topiramate.2 Both medications reduce appetite and in some people induce a negative energy balance.

Both drugs produced meaningful weight loss as defined by the FDA criteria3 in the 1-year placebo-controlled clinical trials in which all participants received instruction in lifestyle modification. Compared with placebo, both drugs showed favorable changes in cardiometabolic factors, eg, blood pressure, waist circumference, and cholesterol levels. Both drugs also improved hemoglobin A1 C in overweight and obese patients with type II diabetes.

‌Belviq (lorcaserin)

It is a selective agonist of the 5-HT2C serotonin receptor. At clinically effective doses Belviq does not activate the 5- HT2B receptor, which appears to be the receptor primarily responsible for the cardiac valvular disease associated with fenfluramine. In 1997, fen-phen was withdrawn because fenfluramine caused heart valve damage. This effect is assumed to be related to activation of 5-HT2B receptor on the heart tissue. When used at the approved dose of 10 mg twice a day, Belviq does not appear to activate the 5-HT2B receptor.

In clinical trials of 1-year duration, echocardiographic criteria for valvular regurgitation doubled up for 2.4% of the patients receiving Belviq and 2% of the patients receiving placebo after 1 year (mild or greater aortic regurgitation or moderate or greater mitral regurgitation or both); none of these patients were symptomatic.

The safety and efficacy of the coadministration of these drugs with other products for weight loss have not been established. The effect of Belviq on cardiovascular morbid- ity and mortality has not been established as well.

Prescribers and patients should adhere to the recommen- dations on the labels regarding patient’s initial weight-loss response to the treatment on the basis of FDA analysis of the clinical trial data. It was determined that if after 12 weeks of treatment with Belviq a patient has not lost at least 5% of the baseline body weight, use of the drug should be discon- tinued as it is unlikely that the patient will achieve meaningful weight loss with continued treatment.

The contraindications of this drug include pregnancy, concomitant use of medications that increase serotonin levels or activate serotonin receptors to avoid serotonin syndrome. Caution is advised while using this drug in patients with congestive heart failure (these patients may already have overexpression of 5-HT2B receptors).

Additionally, Belviq may increase the risk of psychiatric disorder (euphoria and dissociation) and cognitive impair- ment if the dose is increased from the recommended dose of 10 mg twice a day. This drug will be available in the market after FDA decides the Drug Enforcement Administration schedule.

Qsymia (phentermine plus extended-release topiramate)

Qsymia is a combination of phentermine and extended- release topiramate. Preliminary data suggest that the women who received topiramate during pregnancy were more likely to have infants born with an orofacial cleft.4 If Qsymia is used during pregnancy or if the patient becomes pregnant while taking Qsymia, treatment should be discontinued immediately and the patient should be informed of the potential hazard to a fetus. Women in the reproductive age group should have a negative pregnancy test before starting Qsymia and monthly pregnancy tests should be performed thereafter during Qsymia therapy. They should use effective contraception during Qsymia therapy. It is for this reason, risk evaluation and mitigation strategy (REMS) is required before prescribing Qsymia by physicians. The REMS includes a medication guide, a patient brochure, and a formal training program for prescribers, all of which inform patients and prescribers of the teratogenic risk and stress the need for women in the reproductive age group to use effective forms of contraception. The REMS also permits only specially certified pharmacist to dispense Qsymia.

The effect of Qsymia on weight loss in conjunction with reduced calorie intake and increased physical activity was studied in 2 randomized, double-blind, placebo-controlled studies in obese patients (study 1) and in obese and overweight patients with 2 or more significant comorbidities (study 2). The percentages of patients who lost weight greater than or equal to 5% body weight were 17% in the placebo group, 45% in Qsymia 3.75-mg/23-mg dose group, and 67% in Qsymia 15-mg/92-mg dose group in study 1. In study 2, these percentages were 21% in the placebo group, 62% in Qsymia 7.5-mg/46-mg group, and 70% in Qsymia 50-mg/92-mg group.

‌Qsymia is contraindicated in pregnancy, glaucoma, hyperthyroidism, and with known hypersensitivity or idiosyncrasy to sympathomimetic amines. It is also contra- indicated during or within 14 days of taking monoamine oxidase inhibitors. The adverse reaction that needs to be monitored during the treatment phase is elevation in heart rate, suicidal behavior and ideation, acute angle-closure glaucoma, mood and sleep disorders, cognitive impairment, and metabolic acidosis. Although the Qsymia was asso- ciated with mean increases in heart rate of 0.6 bpm and 1.7 bpm at doses of 7.5 mg/46 mg and 15 mg/92 mg, respectively, the study participants had greater reduction in systolic blood pressure, diastolic blood pressure, and triglycerides compared with placebo. Taking into account the magnitude of the weight loss and the favorable changes in metabolic profile, the FDA concluded that the benefit-risk balance was positive and supported the approval of this drug.

Qsymia is taken once daily in the morning to avoid the possible side effect of insomnia. Recommended starting dose for Qsymia is 3.75 mg/23 mg (phentermine 3.75 mg/ topiramate 23-mg extended release) daily for 14 days; then increase the dose to 7.5 mg/46 mg daily. If after 12 weeks of treatment with Qsymia at 7.5-mg/46-mg dose the patient has not lost at least 3% of the baseline weight, the drug should

be discontinued or the dose increased. To escalate the dose,increase the dose of Qsymia to 11.25 mg/69 mg daily for 14days followed by 15 mg/92 mg daily. If patient does notlose at least 5% of the baseline weight during an additional12 weeks of treatment on the maximum daily dose of15 mg/92 mg, the drug should be discontinued because thepatient is unlikely to achieve meaningful weight loss withcontinued treatment. To discontinue the treatment, the15 mg/92 mg dose should be taken every other day for atleast 1 week prior to stopping it, because of the possibilityof this precipitating a seizure (topiramate withdrawal).Finally, as with any new drug, there may be yet unknownbenefits and risk associated. Both the drugs should be usedwith caution while monitoring the patient for potentialadverse reactions. Any antiobesity drugs should always beused in conjunction with a healthy eating lifestyle program

12 weeks of treatment on the maximum daily dose of 15 mg/92 mg, the drug should be discontinued because the patient is unlikely to achieve meaningful weight loss with continued treatment. To discontinue the treatment, the 15 mg/92 mg dose should be taken every other day for at least 1 week prior to stopping it, because of the possibility of this precipitating a seizure (topiramate withdrawal).

Finally, as with any new drug, there may be yet unknown benefits and risk associated. Both the drugs should be used with caution while monitoring the patient for potential adverse reactions. Any antiobesity drugs should always be used in conjunction with a healthy eating lifestyle program.

‌References

1. FDA Briefing Information: Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, May 10, 2012. Available at:

   /http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMee tingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCom mittee/UCM303198.pdfS.

2. FDA Briefing Information: Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, February 22, 2012. Available at: /http://www.fda.gov/downloads/AdvisoryCommittees/Committees MeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisory Committee/UCM292315.pdfS.

3. Guidance for Industry: Developing Products for Weight Management (Draft). Silver Spring, MD: Food and Drug Administration, 2007. Available at: /http://www.fda.gov/downloads/Drugs/GuidanceCom plianceRegulatoryInformation/Guidances/UCM071612.pdfS.

4. Margulis AV, Mitchell AA, Gilboa SM, et al: Use of topiramate in pregnancy and risk of oral clefts. Am J Obstet Gynecol. 2012