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Two New Agents for the Treatment of Obesity

By: Nathan Trustman, PharmD Candidate c/o 2013, AMSCOP at LIU

Obesity is defined as having a body mass index (BMI) of 30 kg/m2 or greater. It is thought to be the result of an imbalance between energy intake and energy expenditure, possibly due to a number of genetic and environmental factors.1 It is estimated that 140 million people in the United States are either obese or overweight (BMI ≥ 25 kg/m2).1 Americans spend about 60 billion dollars trying to lose weight each year.2 The prevalence of many serious diseases including coronary artery disease, atrial fibrillation, congestive heart failure (CHF), type 2 diabetes mellitus, dyslipidemia, osteoarthritis, obstructive sleep apnea, gallstones, and many different cancers are all increased in obese patients.1,3,4   A decrease of 5-10% in body weight can decrease a patient’s risk of developing these comorbidities and in addition improve quality of life.1 Non-pharmacologic therapy, including reduced caloric intake (total daily intake of about 800 to 1,200 kcal), increased physical activity (at least 30 minutes of moderate physical activity on most days), and behavioral modification (behavioral contracting or describing goals and benefits of therapy, and support from family and friends), are recommended as first line for every patient for the treatment of obesity for at least six months.1 However, drug therapy is often necessary if adequate weight loss is not achieved.

The agents for the treatment of obesity can be organized into two categories: agents for short-term management (12 weeks) and those for long-term management.2,3 Agents such as diethylpropion and phentermine (Adipex-P®) are used for short-term management in the US. Most patients will regain the lost weight after they discontinue the drug, which is a major flaw. On the other hand, there are the long-term agents. Until recently, the only agent indicated for long-term use was orlistat (prescription only Xenical® or over-the-counter Alli®).

While diethylpropion, phentermine, and orlistat have been effective over the years, a number of anti-obesity drugs have been withdrawn from the market due to dangerous side effects. In the US, these include fenfluramine (withdrawn in 1997 due to heart disease and pulmonary hypertension), dexfenfluramine (withdrawn in 1997 due to heart disease and pulmonary hypertension) and sibutramine (withdrawn in 2010 due to increased risk of heart attack and stroke in high-risk cardiac patients).3

In the past year, two new agents have been approved for chronic weight management: lorcaserin (Belviq®), approved on June 27 2012, and phentermine/ topiramate extended-release (Qsymia™), approved on July 17 2012.5,6 (Table 1 shows the dosage form, strength, and usual doses of the two new agents. Table 2 compares the efficacy of the two.)

Lorcaserin selectively activates serotonin 2C (5-HT2C) receptors on anorexigenic pro-opiomelanocortin neurons located in the hypothalamus. Activation of these receptors is thought to decrease food consumption and promote satiety.5 Because it is a serotonergic agent, the drug has the ability to cause serotonin syndrome when used with other serotonergic agents, such as SSRIs, SNRIs, MOA-Is, triptans, dextromethorphan, and St. John’s Wort. Reviewing the patient’s medication profile, inquiring about OTC product use and counseling the patient about the signs and symptoms of serotonin syndrome (flushing, fever, racing heartbeat, and confusion) is essential in order to avoid this adverse effect.5 

Lorcaserin, a schedule IV drug, is contraindicated in pregnancy (category X) so female patients of childbearing age must be counseled to use appropriate birth control. The weight loss agent comes in a 10 mg oral tablet and the recommended dose is 10 mg twice a day without regards to meals. Counseling should contain information on how to monitor the effectiveness of the drug. Patients who do not achieve at least a 5% weight loss in the first 12 weeks of therapy should discontinue the drug because it is likely ineffective in that particular patient.5

Efficacy and safety was shown in three double-blind, placebo-controlled, phase III clinical trials (BLOOM, BLOSSOM and BLOOM-DM).3,7,8 All three studies included patients who were either obese or overweight (BMI = 27 – 45 kg/m2). In both the BLOOM and BLOSSOM studies, the standard dose of lorcaserin provided just over 47% of study participates at least a 5% weight loss and a mean weight loss of 5.8 kg in one year. This was statistically significant when compared to placebo (p < 0.001 for both).7,8

The BLOOM study was extended for another year to determine if patients would need to continue lorcaserin to maintain the 5% or greater weight loss they achieved in the first year. This notion was confirmed based on year two results of the study, revealing that the 67.9% of the patients who remained on lorcaserin maintained their weight loss compared to the 50.3% of patients who maintained their weight loss after switching to the placebo (p < 0.001). The BLOSSOM study, which compared lorcaserin 10 mg twice daily dosing to 10 mg once daily dosing, showed that the twice daily dosing was statistically more efficacious based on mean weight loss (-5.8 kg vs. -4.7 kg, p < 0.001) and the percent of patients with at least a 5% weight loss in one year (47.2% vs. 40.2%, p <0.001) 8 Because of this study, the standard dose of lorcaserin is 10 mg twice daily

Both BLOOM and BLOSSOM showed that lorcaserin was well tolerated. The most common side effects included fatigue, headache, dizziness, dry mouth, and nausea. One of the major concerns with previous serotonin agonists used for weight loss (fenfluramine and dexfenfluramine) was valvulopathy or disease of the heart valves.  Both studies reported no difference in the incidence of valvulopathy with use of the new agent when compared to placebo, due to lorcaserin’s selectivity to the 5-HT2C receptor. On the other hand, non-selective 5-HT receptor agonists activate the 5-HT2B receptors on the mitral and aortic valves in the heart, which is the proposed mechanism for valvulopathy.

The final clinical trial, BLOOM-DM, studied the effects of lorcaserin on diabetic patients.3 The 52 week trial revealed that in the group given lorcaserin 10 mg BID, 37.5% achieved at least a 5% weight loss (compared to 16.1% in the placebo group, p < 0.001) and achieved a mean weight loss of 4.7 kg (compared to 1.6 kg in the placebo group, p < 0.001). The numbers were not as impressive as those for non-diabetics, because diabetics have much more difficulty losing weight. The additional weight loss aided by lorcaserin may be crucial in preventing microvascular and macrovascular complications in diabetic patients.

Phentermine/ topiramate extended-release (PHEN/TPM) causes weight loss through multiple mechanisms.6 Phentermine causes a release of catecholamines in the hypothalamus, resulting in a reduced appetite and decreased food consumption. Topiramate’s mechanism of action is not fully understood but it may be the product of a number of different pathways, including augmenting the activity of the neurotransmitter gamma-aminobutyrate, modulating voltage-gated ion channels, inhibiting AMPA/kainite excitatory glutamate receptors, and inhibiting of carbonic anhydrase. Agents with multiple mechanisms may have better long-term success because they may be able to circumvent the body’s counter-regulatory adaptive mechanisms.4 PHEN/TPM capsules include both an immediate release phentermine and delayed-release topiramate beads. PHEN/TPM should be taken once daily in the morning to avoid insomnia, but without regards to meals. The dose of the drug needs to be titrated up in the following way: 3.75 mg/23 mg once daily for 14 days, and then increased to 7.5 mg/46 mg once daily. If adequate weight loss is not achieved (at least 3% weight loss in 12 weeks), PHEN/TPM can be titrated up to a maximum dose of 15 mg/92 mg. The schedule IV medication should never be abruptly discontinued due to the risk of rebound seizures.

Like lorcaserin, PHEN/TPM is also contraindicated in pregnancy (category X). Currently patients can only obtain this drug from mail order pharmacies that are registered with the Qsymia Risk Evaluation and Mitigation Strategy (REMS) program. Female patients of childbearing age are required to take a pregnancy test before starting PHEN/TPM and then every month while still on the drug. The pharmacist must counsel female patients to be on appropriate birth control. If oral contraception is utilized, patients on PHEN/TPM may experience irregular bleeding due to the drug’s effects on altering the exposure of estrogen and progestin. However, this will not increase the risk of becoming pregnant, and the drug should not be stopped.  Other contraindications include glaucoma, hyperthyroidism and concomitant use of or within 14 days of taking monoamine oxidase inhibitors (MAO-Is).6

PHEN/TPM was shown to be safe and efficacious based on 3 double-blind, placebo-controlled, phase III clinical trials (CONQUER, EQUIP and SEQUEL).9-11 The CONQUER study included patients who were either obese or overweight (BMI = 27 – 45 kg/m2). Both the mid-dose (7.5 mg/46 mg) and maximum dose (15 mg/92 mg) were shown to cause more patients to achieve at least a 5% weight loss (21% vs. 62% vs. 70%, placebo, mid-dose and maximum dose respectively; p < 0.001 for both treatment groups compared to placebo) and a greater mean weight loss (-1.4 kg vs. -8.1 kg vs. -10.2 kg, placebo, mid-dose and maximum dose respectively; p < 0.001 for both treatment groups compared to placebo).9 PHEN/TPM was generally well tolerated, with dry mouth, paraesthesia, dysgeusia and insomnia as the most common side effects.

In the EQUIP study, PHEN/TPM was shown to be efficacious in patients who belong to obesity class II and III (BMI ≥ 35 kg/m2).  At the maximum dose, 66.7% of patients achieved a 5% weight after one year, compared to 17.3% in the placebo group (p < 0.0001).10  The SEQUEL study, a 52-week extension of the CONQUER study, aimed to determine if patients would need to continue PHEN/TPM to maintain the 5% or greater weight loss they achieved in the first year. More patients who remained on PHEN/TPM maintained their weight loss from the first year of therapy (79.3% vs. 30%; p < 0.0001).11

Both lorcaserin and phentermine/topiramate appear to be efficacious and safe for chronic weight management as adjuncts to diet and exercise in patients with a BMI of 30 kg/m2 or a BMI of 27 kg/m2 or greater in the presence of at least one risk factor (hypertension, type 2 diabetes mellitus, or dyslipidemia).  Advantages common to both agents include greater weight loss compared to orlistat, and positive effects on patients’ lipid panels, blood pressure, and HbA1C in long term management, as evidenced by the safe and efficacious use for long-term management (108 weeks).7-11 The placebo-controlled clinical trials suggest that PHEN/TPM may cause more weight loss than lorcaserin; however, no head-to-head studies have been conducted.12 PHEN/TPM may be the preferred agent in patients with class II or III obesity.  Because agents (SSRIs and SNRIs) commonly used in depression can interact with lorcaserin resulting in serotonin syndrome, PHEN/TRM may be preferred over lorcaserin in patients with depression, even though Lorcaserin has less potential for adverse side effects and higher tolerability. Both of these agents will provide clinicians with more options for obese patients in need of pharmacotherapy. It is important to remember that the goal of pharmacotherapy when using these agents is not to alter the patient’s body for cosmetic reasons, but rather to reduce the risk of acquiring or exacerbating obesity-related comorbidities and to improve the quality of life.


Table 1. Comparison based on dosage forms and strengths and the usual dose.2,5,6,12

Drug Dosage forms and strengths Usual dose
Lorcaserin 10 mg tablets 10 mg BID
PHEN/TPM Capsules in the following strengths (PHEN/TPM):

  • 3.75 mg/23 mgα
  • 7.5 mg/46 mg
  • 11.25 mg/69 mgα
  • 15 mg/92 mg
3.75 mg/23 mg (PHEN/TPM) QD for 14 days then increased to 7.5 mg/46 mg (PHEN/TPM) QDβ

QD = once daily, BID = twice daily, TID = three times a day, PHEN/TPM = phentermine/ topiramate extended-release

αFor titration purposes only

βIf a patient has not lost at least 3% of baseline body weight in 12 weeks on 7.5 mg/46 mg, discontinue the drug or escalate the dose by increasing to 11.25 mg/69 mg (PHEN/TPM) QD for 14 days and then increasing to 15 mg/92 mg (PHEN/TPM) QD.  Patients who do not achieve at least a 5% weight loss in 12 weeks using the maximum dose should discontinue the drug


Table 2. Comparison based on percent of patients to achieve at least 5% weight loss in one year and mean weight loss in one year.7,9


At least 5% weight loss in one year

Mean weight loss in one year



-5.8 kg


62% (mid-dose)

70 % (max dose)

-8.1 kg (mid-dose)

-10.2 kg (max dose)

PHEN/TPM = phentermine/ topiramate extended-release, mid-dose = 7.5 mg/46 mg, max dose = 15 mg/92 mg



  1. Chen JT, Sheehan AH, Yanovski JA, Calis KA. Chapter 154. Obesity. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. Accessed July 7, 2013.
  2.  Hester SA. PL Detail-Document, Drugs for Weight Loss. Pharmacist’s Letter/Prescriber’s Letter. July 2013.
  3.  Kang JG, Park CY. Anti-Obesity Drugs: A Review about Their Effects and Safety. Diabetes Metab J. 2012 Feb;36(1):13-25.
  4.  Shin JH, Gadde KM. Clinical utility of phentermine/topiramate (Qsymia™) combination for the treatment of obesity. Diabetes Metab Syndr Obes. 2013 Apr 8;6:131-9.
  5.  Product Information: BELVIQ® oral tablets, lorcaserin oral tablets. Arena Pharmaceuticals GmbH, Zofingen, Switzerland, 2012.
  6.  Product Information: QSYMIA® capsules, phentermine/ topiramate extended-release capsules. VIVUS, Inc., Mountain View, CA, 2012.
  7.  Smith SR, Weissman NJ, Anderson CM et al. Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363: 245-56.
  8.  Fidler MC, Sanchez M, Raether B et al. BLOSSOM Clinical Trial Group. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab 2011;96:3067-77.
  9.  Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341–1352.
  10.  Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20(2):330–342.
  11.  Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a random­ized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95(2):297–308.
  12.  McClendon KS. “Phentermine/Topiramate ER (Qsymia): Second New Obesity Medication Approved in 2012” (update). In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2012. Accessed July 10, 2013.
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