Review of the pharmacologic arsenal for the war on obesity

Abstract

Obesity has become a highly prevalent chronic condition that is associated with significant morbidity and mortality. Studies have demonstrated that even as little as 5% to 10% of weight loss is associated with an improvement in cardiovascular risk factors and a reduction in the incidence of type 2 diabetes in high-risk patients. Prior to the recent approval of lorcaserin and extended-release phentermine/topiramate, there had been no new pharmacologic agents approved for the treatment of obesity for 13 years. This article reviews the pharmacologic treatment of obesity including past treatment options, lessons learned in recent years, current short- and long-term treatment options, and future direction. Formulary considerations of currently available agents are discussed.

Obesity has become a highly prevalent chronic condition that is associated with significant morbidity and mortality. According to the 2009–2010 data from the National Health and Nutrition Examination Survey (NHANES) of the US population, 78 million (35.7%) adults and 12.5 million (16.9%) children and adolescents were obese, while more than two-thirds of the US population is overweight. The World Health Organization defines overweight in adults as a body mass index (BMI) of 25–29.9 kg/m² and obesity as a BMI of 30 kg/m² or higher.  Obesity is further subdivided into mild (30–34.9 kg/m²), moderate (35–39.9 kg/m²), and severe (40 kg/m² or higher).^1,2,3  Obesity in children is defined as a BMI greater than or equal to the age- and sex-specific 95thpercentile of the Centers for Disease Control and Prevention growth charts.^1,2

Obesity is undeniably linked to an increased risk of hypertension, dyslipidemia, coronary heart disease, type 2 diabetes mellitus (T2DM), stroke, cancer, gallstones, osteoarthritis, sleep apnea, and death, particularly in adults younger than 65 years.^3,4,5 Depending on age and race, obesity is associated with a 6- to 20-year decrease in life expectancy.⁵ Besides the negative impact on morbidity and mortality, the obesity epidemic has significant economic impact in the form of direct medical, productivity, transportation, and human capital costs. Productivity costs include absenteeism, presenteeism, premature mortality, loss of quality-adjusted life years, disability, and welfare loss.⁴ Finkelstein et al estimated that the medical burden of obesity has risen to almost 10% of all medical spending and amounted to $147 billion per year in 2008.  The per capita medical spending for the obese was estimated to be 42% higher than for someone of normal weight.⁶

Studies have demonstrated that even as little as 5% to 10% of weight loss is associated with an improvement in cardiovascular risk factors and a reduction in the incidence of T2DM in high-risk patients.³ According to the US Preventive Services Task Force, the most effective interventions involve both high intensity (12 to 26 sessions) multicomponent behavioral interventions and pharmacologic agents.⁵  Diet and exercise typically result in an average weight loss of 3.34 kg over the duration of the intervention and are associated with partial weight regain over the long-term.⁷ In addition to or instead of  lifestyle modifications, 1 in 3 Americans turns to the $1.6 billion industry of dietary supplements which are often touted as effective without dietary and lifestyle changes and are easily available for purchase without a prescription.⁸  Since dietary supplements are treated as food products and not evaluated by the FDA for efficacy and safety, healthcare providers need to be aware of their patient’s use of dietary supplements for weight loss. Bariatric surgery is typically reserved for patients with a BMI ≥40 kg/m² or BMI ≥35 kg/m² with obesity-related comorbidities.  In 2008, an estimated 350,000 bariatric surgeries were performed worldwide, with the majority (63%) performed in the United States and Canada.⁹ This article reviews past prescription treatment options, lessons learned in recent years, current short- and long-term prescription treatment options, and future direction. Formulary considerations of currently available agents will be discussed.

PAST LESSONS

Centrally acting and sympathomimetic agents have long been the pharmacologic focus for weight loss. While the exact mechanism is unknown, sympathomimetic anorectics are  thought to reduce appetite and increase satiety by releasing catecholamines in the hypothalamus.¹⁰ Agents approved in the United States include the following controlled substances: phentermine (C-IV), diethylpropion (C-III), benzphetamine (C-III), phendimetrazine (C-III) and methamphetamine (C-II). However, except phentermine, these sympathomimetics are no longer used in practice.  It is also important to note that all centrally acting and sympathomimetic agents have been removed from the market in Europe since early 2000.¹¹

The devastating fallout of the combination of fenfluramine/dexfenfluramine and phentermine, commonly known as “fen-phen,” marked the beginning of a wakeup call to the pharmacologic war on obesity. Even though fenfluramine, a serotonin-releasing agent, was approved in 1973, it was not until the early 1990s that the combination with phentermine caught the attention of the mass American audience. Dexfenfluramine, an isomer of fenfluramine, was approved in 1996. In 1996, Time reported a record number of 85,000 prescriptions of dexfenfluramine in combination of phentermine were written in 1 week.¹² Fenfluramine and dexfenfluramine were pulled from the market in 1997 due to the link to life-threatening primary pulmonary hypertension and cardiac valvulopathy.

Sibutramine is a serotonin-norepinephrine reuptake inhibitor structurally related to amphetamines. Approved in 1996, sibutramine was considered a safer alternative to fenfluramine and dexfenfluramine, although increase in blood pressure, pulse rate, or both were known adverse effects. The Sibutramine Cardiovascular Outcomes (SCOUT) trial found that long-term use (mean duration, 3.4 years) of sibutramine in patients with preexisting cardiovascular conditions was associated with an increase in nonfatal myocardial infarction and stroke.¹³ Subsequently, sibutramine was withdrawn from the market worldwide in 2010.

Rimonabant, a centrally acting cannabinoid CB1 receptor inverse agonist, was the first of its class available for the treatment of obesity in Europe in 2006. Rimonabant, once a promising agent for obesity and smoking cessation, was rejected by FDA in 2007. Reports of severe depression and suicidal thoughts associated with the use of rimonabant appeared soon, ultimately leading to its being withdrawn from the European market in 2008.

SHORT-TERM TREATMENT OPTIONS

Phentermine was approved by FDA in 1959 as adjunct therapy to diet and exercise for obese patients.¹⁴ In a meta-analysis examining 6 studies with an average duration of 13.2 weeks, subjects receiving phentermine lost an additional 3.6 kg over placebo.¹⁵ While most clinical trials examining the use of sympathomimetic drugs in weight loss were typically of short duration, the results from one of the longer trials of phentermine showed a mean weight loss of 12.2 kg compared to 4.8 kg in the placebo group, for a placebo-subtracted weight loss of 7.4 kg over a duration of 36 weeks (P>0.001). Therefore, over 36 weeks, continuous use or intermittent use of phentermine is effective in reducing weight.¹⁶

Diethylpropion has been approved for the treatment of obesity since 1959.¹⁴ A meta-analysis examining 13 studies of varying duration (6 to 52 weeks) from 1965 to 1983 found that weight loss attributed to diethylpropion was 3.0 kg (placebo-subtracted).¹⁵ Benzphetamine was approved by FDA in 1960. According to a meta-analysis that reviewed 3 studies with an average duration of 8.9 weeks, the effect of benzphetamine on weight loss was a placebo-subtracted 3.3 kg.¹⁵ Phendimetrazine was approved by FDA prior to 1962 and has a placebo-subtracted weight loss of 2.9 kg.¹⁷

Meta-analyses show that sympathomimetic agents produce a comparable weight loss, approximately 3 kg, when used as short-term therapy.  While weight loss using sympathomimetics typically plateaus, the loss is maintained for the duration of the treatment, indicating an absence of tolerance.¹⁸ Adverse effects of sympathomimetics are typically mild and can include insomnia, dry mouth, constipation, increased blood pressure, palpitations, and dizziness.¹⁴ Although sympathomimetics have been long established as effective agents for short-term weight loss, their long-term efficacy and safety has not been evaluated. Generally, the sympathomimetics have relatively mild side effects and are available as generic products, which has a cost advantage. However, their indication for short-term use and plateau effect on weight loss reduces their potential for chronic use and long-term weight loss.

LONG-TERM TREATMENT OPTIONS

Orlistat

Orlistat 120 mg was approved by the FDA in 1999 for obesity management when used in conjunction with a reduced-calorie diet and to reduce the risk of regaining weight after previous weight loss.¹⁹ In 2007, orlistat 60 mg was approved as a non-prescription weight loss agent in overweight adults 18 years and older, in combination with a low-fat and reduced-calorie diet.  While most weight loss occurs in the first 6 months, the orlistat 60 mg over-the-counter version does not have a duration of use limit. Orlistat causes weight loss by reversibly inhibiting gastrointestinal (GI) lipases to reduce fat absorption by approximately 30%.¹⁹ Since orlistat inhibits GI lipases, it needs to be taken with each meal to prevent fat absorption from the food. The effects of orlistat plus dietary intervention was studied in obese patients to evaluate the effect of reducing dietary fat absorption on body weight, blood pressure, serum lipids, glucose, and insulin levels. Within 1 year, patients treated with orlistat lost significantly more weight than those treated with placebo (8.8 kg versus 5.8 kg, P<0.001) for a placebo-subtracted weight loss of 3.0 kg. Blood pressure was slightly decreased in the orlistat group, which was statistically significant in comparison to placebo (Table). Treatment with orlistat was also shown to improve fasting low-density lipoprotein (LDL) by 8 mg/dL, but no significant improvements in high-density lipoprotein (HDL) or triglycerides was seen. Fasting serum insulin levels decreased by a statistically significant placebo-subtracted 17.5 pmol/L, and fasting serum glucose levels increased less for the orlistat group than for those who had received placebo.²⁰

The XENDOS study observed the long-term effect of orlistat plus lifestyle changes on the onset of T2DM and change in body weight in obese patients over a 4-year period. Weight loss was more pronounced within the first year of orlistat therapy with lifestyle modification and then after the first year, showed a steady increase in weight regain towards baseline over the next 3 years. Weight loss after the first year with orlistat was 4.4 kg more than with placebo (10.6 kg vs. 6.2 kg; P<0.001), and was 2.8 kg more than with placebo (5.8 kg vs. 3.0 kg; P<0.001) after 4 years.²¹

Since orlistat has been shown to reduce the absorption of some fat-soluble vitamins, patients should supplement their diet with a multivitamin containing fat-soluble vitamins at least 2 hours before or after taking orlistat. The common adverse effects reported for orlistat are associated with the fats that are not absorbed and include oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation, and fecal incontinence. The majority of the adverse effects occur during the first 3 months of therapy, and 50% of the adverse effects resolve within the first week, while some last for 6 months or longer.¹⁹ After the 4-year XENDOS trial, 52% of patients taking orlistat completed the trial compared with 34% of placebo recipients (P<0.0001), indicating an acceptable level of tolerability in exchange for weight loss.²¹

Lorcaserin

Thirteen years after the last long-term treatment for obesity was approved, lorcaserin gained FDA approval in 2012 as adjunct therapy to a reduced-calorie diet and exercise for chronic weight management in adults with a BMI ≥30 kg/m² or ≥27 kg/m² in the presence of at least 1 weight-related comorbid condition, including hypertension, dyslipidemia, or T2DM.²² The approved dose of lorcaserin is 10 mg twice daily, and it should be discontinued if a 5% weight loss is not achieved after 12 weeks of therapy.²² Lorcaserin is a serotonin 2C (5-HT_2C) receptor agonist which decreases food consumption and increases satiety by selectively activating the 5-HT_2C receptors on the pro-opiomelanocortin neurons of the hypothalamus.²²

Three clinical trials led to the approval of lorcaserin; 2 studied obese patients without major medical conditions and 1 evaluated overweight or obese patients with T2DM. After 1 year of treatment, obese patients lost 5.8 kg with lorcaserin and 2.2 kg with placebo (P<0.001), for a placebo-subtracted weight loss of 3.6 kg. Patients who lost 5% or more of their body weight were continued either on lorcaserin or placebo during year 2. In year 2, 67.9% of those who continued lorcaserin maintained their weight loss compared with 50.3% who received placebo (P<0.001).²³ The BLOOM-DM trial evaluated the safety and efficacy of lorcaserin in overweight or obese patients with T2DM. Weight loss was 4.5 kg and 1.5 kg with lorcaserin 10 mg twice daily and placebo, respectively, for a placebo-subtracted weight loss of 3.0 kg (P<0.001). HbA_1c decreased by 0.9% for lorcaserin 10 mg bid and 0.4% for placebo over the 52-week trial (P<0.001).²⁴

Lorcaserin was developed based on the rationale that fenfluramine acted indirectly on 5-HT_2C receptors to promote weight loss.¹¹ The active metabolite of fenfluramine has high affinity for 5-HT_2B and 5-HT_2C receptors. It is thought that fenfluramine’s increased activity on the 5-HT_2B receptor, predominantly found in cardiac tissue, contributed to the cardiac valvulopathy.²⁵ Both drugs act on serotonin receptors, but lorcaserin is more selective for the 5-HT_2C receptor than the 5-HT_2B receptor. However, extensive testing and echocardiography was performed throughout the studies to identify patients in whom valvulopathy developed. After 1 and 2 years of treatment, valvulopathy had developed in 2.7% and 2.6% versus 2.3% and 2.7% of patients receiving lorcaserin and placebo, respectively (P=0.70).²³

There was little risk of cardiac damage shown by the results of the extensive echocardiographic monitoring; the most common adverse events reported were blurred vision, dizziness, somnolence, headache, and GI effects. Within the first year, 55.4% of the lorcaserin group and 45.1% of the placebo group completed the study; 7.1% and 6.7% discontinued due to adverse effects, respectively.²³ The abuse potential for lorcaserin is a concern since 5-HT_2A receptor agonists are associated with hallucinogenic effects.¹¹ Whereas a study evaluating the abuse potential of lorcaserin found that higher (single) doses (40 and 60 mg) of lorcaserin were associated with effects described as “detached,” “spaced out,” “floating,” and hallucinations, the researchers demonstrated that lorcaserin, at supratherapeutic doses, is associated with primarily negative subjective effects and presents low abuse potential.²⁶ Lorcaserin is currently under evaluation for scheduling by the Drug Enforcement Administration (DEA) and is expected to be scheduled as a C-IV medication.¹¹

Phentermine/topiramate ER

Each component drug was previously approved by FDA; the phentermine and topiramate ER combination was approved in 2012 as adjunctive therapy to diet and exercise in obese patients or overweight patients with the presence of a weight-related comorbidity such as hypertension, T2DM, or dyslipidemia. Phentermine was previously approved for short-term treatment only. Topiramate was previously approved for epilepsy and migraine. The exact mechanism of action of topiramate on weight loss is not known. It is thought that topiramate suppresses appetite and decreases food consumption through a variety of pharmacologic effects including augmenting the activity of gamma-aminobutyrate, modulating voltage-gated ion channels, and inhibiting carbonic anhydrase and AMPA/kainite excitatory glutamate receptors.²⁷

The phentermine/topiramate ER combination requires titration from the 3.75 mg/23 mg daily dosage to the 7.5 mg/46 mg daily dosage over a 14-day period. If the patient has not lost at least 3% of their body weight after 12 weeks on the 7.5 mg/46 mg daily dosage, the medication should be discontinued or the dosage escalated. To escalate the dosage,  11.25 mg/69 mg should be used daily over 14 days to titrate up to a 15 mg/92 mg daily dosage. If the patient has not lost at least 5% of baseline body weight after 12 additional weeks of therapy, the medication should be discontinued. However, since topiramate is an antiepileptic, to avoid precipitating a seizure, the 15 mg/92 mg daily dosage should be taken every other day for 1 week to titrate off.²⁷

In the CONQUER trial, which examined the effect of phentermine/topiramate ER in overweight and obese patients with comorbidities, weight loss over 56 weeks was 1.4 kg, 8.1 kg, and 10.2 kg for placebo, 7.5 mg/46 mg, and 15 mg/92 mg phentermine/topiramate ER, respectively (P<0.0001). The placebo-subtracted weight loss was 6.7 kg for 7.5 mg/46 mg and 8.8 kg for 15 mg/92 mg dosages.²⁸ In the SEQUEL trial, weight loss was maintained after 2 years of phentermine/topiramate ER. Over 2 years, 15.3% of subjects on the 15 mg/92 mg dosage maintained a 20% or greater weight loss compared with 2.2% of subjects on placebo (P<0.0001). The researchers concluded that phentermine/topiramate ER improved cardiovascular and metabolic variables, and the subjects showed decreased rates of diabetes in comparison with placebo.²⁹

The most common adverse effects are dry mouth, paresthesia, constipation, insomnia, dizziness, taste disturbances, palpitations, headache, alopecia, and hypokalemia. The subjects that discontinued due to dose-related adverse effects were 9% for placebo, 12% for 7.5 mg/46 mg, and 19% for 15 mg/92 mg phentermine/topiramate ER.²⁸

Phentermine/topiramate ER is classified as C-IV by the DEA due to the potential for phentermine abuse, and utilizes a Risk Evaluation and Mitigation Strategy (REMS). The REMS is required since topiramate is known to cause birth defects. While many other antiepileptic drugs are known to cause birth defects in humans but do not require a REMS program, the anti-obesity drugs are predominantly targeted to women in their child-bearing years. Therefore, FDA’s safety concern and the required REMS program are well founded.¹¹ Due to the teratogenic risk, phentermine/topiramate ER is only available through certified mail-order pharmacies.²⁷

TREATMENTS IN DEVELOPMENT

Naltrexone and bupropion

The combination of naltrexone and bupropion is under investigation as a weight-loss agent and is currently in phase 3 trials. Naltrexone is an opioid antagonist with high affinity for the mu-opioid receptor. Bupropion is a weak dopamine and norepinephrine reuptake inhibitor.³⁰ It is thought that the sustained-release combination of naltrexone and bupropion (NBSR) induces weight loss by affecting the hypothalamic melanocortin system and the mesolimbic reward system. Bupropion stimulates the production of α-melanocyte–stimulating hormone (α-MSH), which binds to melanocortin-4 receptors, initiating a series of actions that result in increased energy expenditure and decreased desire for energy intake. Concurrently, bupropion stimulates release of β-endorphin, which initiates a negative feedback loop on the α-MSH–producing neurons, resulting in decreased α-MSH production. Naltrexone is theorized to block this negative feedback loop, resulting in increased action of α-MSH and its anorectic effect. Proposed dosing for NBSR is 8 mg naltrexone with 90 mg of bupropion tablets, 2 tablets twice daily for a total daily dose of 32/360 mg. Dosing should be titrated up from 1 tablet daily to 2 tablets twice a day over a period of 4 weeks to increase tolerability.³¹ Pooled data from phase 2 and phase 3 trials (N=3,239) revealed the most common adverse events are nausea (31.8%), constipation (18.1%), headache (17.1%), and vomiting (9.9%). Eighty-five percent of all patients receiving the study drug experienced at least 1 adverse event. Systolic and diastolic blood pressure increased 1 mm Hg at 4 and 8 weeks of treatment, which is consistent with the hemodynamic effects of bupropion. However, blood pressure at 56 weeks averaged 1 to 2 mm Hg below baseline.³¹

Naltrexone/bupropion has been studied in 2 phase-3 trials. Greenway et al showed that, when compared to placebo, NBSR 16/360 mg decreased weight by 6.7% (P<0.0001), and NBSR 32/360 mg decreased weight by 8.1% (P<0.0001), when taken along with a moderate- to low-calorie diet and mild exercise program.³² In another trial where patients were prescribed a more restrictive diet and more intense exercise regimen, patients receiving NBSR 16/360 mg and 32/360 mg lost 7.3% and 11.5% body weight, respectively (P<0.001).³³ A new drug application based on the data from these 2 trials was denied by FDA citing the lack of long-term cardiovascular safety data. The manufacturer announced the Light Study in June 2012, with an estimated completion in July 2017 to assess cardiovascular risks of NBSR.³⁴

Cetilistat

Cetilistat is a pancreatic and GI lipase inhibitor similar to orlistat, and is currently in phase 3 trials. Inhibition of lipase prevents the metabolism of dietary fat and therefore prevents absorption.³⁵ Dosages studied in phase 2 trials ranged from 60 to 240 mg 3 times daily. In a phase 2 trial (N=371), Kopelman et al found that compared to placebo, cetilistat 60 mg, 120 mg, and 240 mg taken for 12 weeks reduced weight by 3.3 kg (P<0.03), 3.5 kg (P=0.02), and 4.1 kg (P<0.001), respectively. Unpleasant side effects such as flatus with discharge and oily spotting occurred in up to 2.8% of patients. Cetilistat was also associated with a decrease in LDL of 3% to 11%.³⁵

In a phase 2 study (N=612), cetilistat was compared to orlistat and placebo in obese patients with diabetes. Patients were randomized to cetilistat 40 mg, 80 mg, or 120 mg 3 times daily, orlistat 120 mg 3 times daily, or placebo. At 12 weeks, weight loss for the cetilistat group was superior to placebo in the 80 mg and 120 mg groups (P=0.01 and P=0.0002, respectively). Cetilistat 80 mg and 120 mg were not significantly different from orlistat 120 mg. Of note, HbA_1c was reduced by 0.51% to 0.54% in the cetilistat 80- and 120-mg and the orlistat 120-mg groups, compared to a reduction of 0.37% in the placebo group. The most common adverse effects were GI-related, but rates for individual events were not reported. It was noted, however, that the total number of adverse events in the orlistat 120-mg group was significantly higher than in the cetilistat 120-mg group (P=0.0148).³⁶ Cetilistat is currently undergoing phase 3 trials in Japan.  

Exenatide and liraglutide

Exenatide and liraglutide are glucagon-like peptide 1 (GLP-1) receptor agonists, which act to enhance glucose-dependant insulin secretion, suppress glucagon production, and delay gastric emptying, and are currently approved in the United States as treatment for T2DM. Weight loss has long been an additional benefit for overweight patients with T2DM treated with these agents, with 2.5–3 kg weight loss noted in the diabetes trials for both agents.^37,38 For exenatide, an interim analysis of overweight patients with T2DM was conducted in 2006 on 314 patients to assess cardiovascular risk factors, HbA_1c, and weight over 82 weeks.³⁹ In addition to an average reduction of HbA_1c of 0.9%, exenatide therapy was associated with a decrease in weight from baseline (-4.4±0.3 kg). This set the stage for Rosenstock et al to examine the effect of exenatide and lifestyle modification on patients with and without prediabetes.⁴⁰ A total of 152 obese patients with an average weight of 108.6±23 kg were randomized to exenatide or lifestyle modifications for 24 weeks. At the end of the study, the treatment group lost significantly more weight than the control group (-5.1±0.5 kg vs -1.6±0.5 kg, respectively, P<0.001). However, there was a high withdrawal rate in this study-32% for placebo and 34% for exenatide-and withdrawal due to nausea was the most common reason in the exenatide group.

Liraglutide was evaluated in a 20-week open-label trial with orlistat as the active comparator in 564 patients in Europe.⁴¹ Patients were randomized to liraglutide 1.2, 1.8, 2.4, or 3.0 mg or placebo administered subcutaneously once daily or orlistat 120 mg 3 times daily. Patients had similar baseline body weight and BMI, but rates of diabetes varied between treatment groups, ranging from 1.1% to 6.3%. Placebo-subtracted weight losses were 2.1 kg for 1.2 mg (P=0.003), 2.8 kg for 1.8 mg (P<0.0001), 3.5 kg for 2.4 mg (P<0.0001), and 4.4 kg for 3.0 mg (P<0.0001) of liraglutide, respectively. Orlistat therapy resulted in a weight loss of 4.1 kg, and 2.4 mg and 3.0 mg of liraglutide were significantly superior to orlistat (P=0.003 and P<0.0001, respectively). The most common adverse events in the liraglutide group were GI-related (53.7–71.0%), with 4.2–9.7% of patients withdrawing due to adverse effects. In pursuit of an indication for weight loss, the manufacturer launched 2 phase-3 studies (the SCALE studies-1 for patients with T2DM and 1 for nondiabetic patients), which are expected to be completed by mid-2013.

FORMULARY CONSIDERATIONS

Obesity, a complex metabolic and behavioral disorder, is undeniably a leading cause of morbidity and mortality. Along with lifestyle interventions, long-term pharmacologic adjunctive therapy is to be expected in battling obesity. Prior to the approval of lorcaserin and phentermine/topiramate ER, there had been no new drugs approved for the treatment of obesity for 13 years, since orlistat. This void was not because of a lack of pursuit of the next best pharmacologic treatment, but because of a tighter regulatory emphasis on metabolic indices, long-term cardiovascular benefits, and safety profile owing to the lessons learned through the withdrawal of effective agents due to adverse outcomes. While all 3 currently approved agents produce modest amounts of weight loss after 1 year of treatment, clinical outcome studies demonstrating the long-term effects of these anti-obesity agents on morbidity and mortality have not been performed.¹¹ Treatments that reduce weight but do not improve cardiovascular outcomes are thought to be a cosmetic benefit and may not be covered by managed care organizations. 

While there have been no direct comparative trials between the long-term obesity agents, each agent has its own advantages and would benefit a specific subpopulation of obese and overweight patients with 1 or more chronic comorbidities. Orlistat works in the GI tract and is not systemically absorbed, resulting in minimal drug interactions. Therefore, patients who are receiving multiple medications to treat other disease states may be appropriate candidates for orlistat. Orlistat is also the only approved anti-obesity agent for use in patients ages 12 to 16 years, allowing for treatment of a younger population having no other pharmacologic options.¹⁹ The LDL-lowering effects of orlistat also may benefit patients with an elevated LDL. Lorcaserin may have more drug and disease state interactions in comparison to orlistat, but it also significantly improves lipid profiles and reduces blood pressure and reduces HbA_1c. Despite being classified as a controlled substance, it is expected to be readily available through community pharmacies. The phentermine/topiramate ER combination resulted in overall improvements in lipids, blood pressure, and HbA_1c that were consistent with increased weight loss when indirectly compared to lorcaserin, but the additional restricted distribution through certified mail-order pharmacies and the REMS program may limit its accessibility and hamper its market uptake. Without consideration of comparative drug cost, the selection of an agent should be patient-specific, based upon concomitant disease states, interacting medications, and adverse-effect profile. The authors propose that these anti-obesity medications should require prior authorization for individuals with a BMI ≥30 kg/m² or BMI ≥25 kg/m² with 2 comorbidities and who have received lifestyle modification counseling. In addition, attainment of at least 3% weight loss in 12 weeks should be required for continuation. Periodic confirmation of maintenance of weight loss should also be considered.

CONCLUSION

There is an enormous unmet need for more effective and safer treatments for obesity. Emerging therapies that target the central nervous system as well as the gut pathway have produced some exciting preliminary data. Agents that can meet or exceed the raised expectations and regulatory requirements will be most welcomed to enhance our armamentarium in the obesity war. However, it cannot be overemphasized that the most effective interventions involve both high-intensity multicomponent behavioral interventions and pharmacologic agents.

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