Obesity: A Growing Pharmacologic Challenge

Obesity has increased in epidemicproportions in the United Statesover the last decade and is fastbecoming an urgent health problem. Thepercentage of obese individuals in thiscountry was reported to be nearly 31% inthe year 2000?which translates to 60 millionpeople.^1-4

Obesity is associated with prematuremortality² and multiple comorbidities,including stroke, heart disease, sleep disorders,and the triad of disease states?hypertension, diabetes, and hyperlipidemia?often referred to as metabolicsyndrome.^5-7

Obesity, as defined by the WorldHealth Organization, in adults is determinedby the body mass index (BMI). BMIis defined as weight in kilograms dividedby height in meters squared. A value of25 to 29.9 indicates that an individual isoverweight, whereas a value of 30 orhigher defines obesity. In children andadolescents, obesity has not yet beendefined.^2-4

Nonpharmacologic Treatment

Treatment of obesity may be successfulwith nonpharmacologic interventions,primarily focusing on dietaryinterventions and changing behaviors.Total therapeutic lifestyle changes thatfocus on behavioral therapy, education,and structured meal planning may benecessary for success.^8-11 Patients withmetabolic syndrome require proper diseasemanagement, dietary modification,and exercise programs to controltheir obesity.^5,12-18

Surgical options for obesity, includingbariatric surgery procedures, usually arereserved for the morbidly obese, definedas having a BMI of >40 kg/m².^19-21

Pharmacologic Treatment

Although nonpharmacologic interventionsmay be successful, in somepatients may need adjunct pharmacologicmanagement.²² Whereas numerousmedications have been studied and evaluatedfor weight loss, at the present timeonly 3 classes of drugs (Table) are usedfor the treatment of obesity. Theseagents include sibutramine (Meridia), orlistat(Xenical), and the older anorexigenic,central-acting amphetamine congeners,which have a high risk of rebound weightgain and abuse.^23-25

Sibutramine (Meridia)

Sibutramine is a central-acting noradrenergicdrug that increases theamount of serotonin (5HT) and norepinephrineand, to a smaller extent,dopamine through reuptake inhibition.Through its action on these neurotransmitters,sibutramine reduces food intakeby causing satiety after eating and providingdose-dependent weight loss.²⁵

Studies have reported weight loss inpatients ranging from 5% to 10%, versuspatients receiving diet and exercisealone.^26-31 Maintaining initial weight lossat 2 years was reported to be greaterwith sibutramine, compared with exerciseand diet regimens.^32-33

Because of the drug's potential toincrease blood pressure and heart rate,careful monitoring and/or considerationof the risk-benefit ratio is necessary inpatients with a history of hypertension orcardiac disease.³⁰ Other potential sideeffects include insomnia, headache, anddry mouth.^25,34

Orlistat (Xenical)

Orlistat is an intestinal lipase inhibitor;it blocks the enzyme pancreatic lipase.This activity results in decreased fatabsorption in the intestines. It has anindirect effect on appetite by encouragingcompliance with a low-fat diet.^34,35

Studies with orlistat for the treatmentof weight loss over 1 to 2 years havereported weight-loss percentages rangingfrom 4% to 10%, versus placebo.^36-40Weight loss with orlistat appears to peakat 6 months and is maintained for up to2 years.^37-40 Combination therapy with orlistatand metformin in patients with diabetesproduced additive benefits andresulted in improved blood glucose controland cardiovascular factors.^37-39

Adverse effects include gastrointestinalproblems in patients noncompliantwith low-fat diets, in addition toconcerns about malabsorption of fatsolublevitamins (A, D, E, and K), necessitatingconcurrent multivitamin supplementation.^36,41,42

When comparing sibutramine and orlistatin combination therapy, the limiteddata available showed no additive benefits.⁴³ Both of these agents may have arole in the treatment of obesity in type 2diabetes.⁴⁴

Other Anorexigenic Agents

Central-acting amphetamine congenersinclude phentermine (Adipex-P)and diethylpropion (Tenuate)?both ofwhich are Federal Controlled SubstancesSchedule IV (C-IV) drugs?and benzphetamine(Didrex) and phendimetrazine(Bontril)?both of which are C-III drugs.These drugs are used as an adjunct tocaloric restriction in the short-term (afew weeks) management of obesity.²⁴

Phentermine was marketed a fewyears ago with fenfluramine in a combinationproduct that was associated withvalvulopathy and was withdrawn from themarket.^45-47 Phentermine in monotherapydoes not appear to be associated withvalvulopathy.^47,48

Although weight-loss benefits arereported with these agents, toleranceof their anorexigenic effect can developin as little as 2 weeks, so short-termuse is recommended. Adverse effectsinclude insomnia, nervousness, psychosis,depression, rash, dry mouth,constipation, palpitations, and increasedblood pressure.^49-55

Other Agents

Anticonvulsants

Various anticonvulsants continue to beevaluated for the treatment of obesityand weight loss. Topiramate, in dosesranging from 100 to 1400 mg daily, hasbeen studied in both retrospective andclinical trials for up to 30 months in thetreatment of weight loss and binge-eatingdisorders.^56-62 Although efficacy hasbeen reported, potential concerns aboutcentral nervous system side effects?including difficulty with concentrating,language problems, and memory problems?have limited its use in clinicalpractice.^63-64

Zonisamide (Zonegran), a more recentlyapproved anticonvulsant, also hasbeen reported to be effective and well-toleratedfor weight loss in short-termstudies in obese patients.^65,66 Adverseeffects reported with zonisamide rangedfrom fatigue to nephrolithiasis, and morestudies are needed.^66,67

Small trials with levetiracetam(Keppra), another newer anticonvulsant,reported no significant effects on weightloss.⁶⁸ Although the potential mechanismof action of weight reduction with anticonvulsantsis not completely understood,multiple modes of action havebeen considered.^58,65

Antidepressants

Numerous selective serotonin reuptakeinhibitors have been studied inshort-and long-term trials in the treatmentof obesity, including fluoxetine,sertraline, citalopram, and fluvoxamine.^69-75 Using higher than standardantidepressant doses, many of thesetrials reported initial weight loss andbinge-eating reduction, although theyoften were followed by rebound weightgain.^73-77 Presently, these agents are notrecommended for the management ofobesity, although their future roles in certain populations may need further study.⁷⁷

Bupropion, a norepinephrine and dopaminereuptake inhibitor, was evaluatedin short-and long-term trials, whichreported significant weight-loss effects.^78-82One long-term trial reported a lack ofrebound weight gain with this agent indepressed patients.⁸¹ Venla-faxine, a serotonin-norepinephrine reuptake inhibitor,was evaluated in a case series study andwas reported to cause weight loss andreduced binge eating.⁸³

Herbals and Other Products

Numerous supplements containing avariety of herbals and other substancesused alone and in combination continueto be promoted for their potentialweight-loss benefits. Many of these productsare unregulated and have limited orno data to support their utility for weightloss.^84-87 Products containing ephedrineand ephedra (ma huang; an herbal formof the same) were banned by the FDA in2004, because of concerns about cardiacand psychiatric problems.^84-90

Other herbals and substances promotedand/or used for weight loss mayinclude chromium picolinate, greentea, hydroxycitrate, garcinia, guarana,germander, bitter orange, biotin, barley,flaxseed oil, country mallow, chaparral,bladderwort, chitosan, pyruvate, andcitrus aurantium. Some of these productshave been found to contain fenfluramineand thyroid gland extracts,which have the potential for causingharm to patients. Because of the limitedevidence supporting their efficacyand their often unknown safety profiles,these agents are not recommendedfor weight loss.^91-93

Investigational Agents

Research and drug development forthe treatment of obesity include a varietyof agents and targets. Two new diabetestreatments, exenatide and pramlintide,have been reported to causeweight loss in patients with diabetes.^94,95Other investigational therapies includethe 5HT 2C modulators,⁹⁶ the cannabinoidblockers (eg, rimonabant),⁹⁷ andleptin supplements.⁹⁸

Obesity and its management continueto be a growing challenge for health careproviders in the United States. Preventionand nonpharmacologic interventions arekey to the management of obesity.Although the present pharmacotherapiesoffer some benefits, more effective andtolerable agents are needed.

Dr. DeMaagd is an associate professorof pharmacy practice at Ferris StateUniversity, At the time of assisting inwriting this article, Dr. Chipperi was aPharmD candidate at Ferris StateUniversity.

For a list of references, send a stamped,self-addressed envelope to: ReferencesDepartment, Attn. A. Rybovic, PharmacyTimes, Ascend Media Healthcare, 103 CollegeRoad East, Princeton, NJ 08540; or send an emailrequest to: arybovic@ascendmedia.com

DIIABETES and OBESIITY FACTOIIDS:

• An estimated 80% of those who develop type 2 diabetes are obese.
• A number of controlled clinical trials show strong evidence thatweight loss reduces blood glucose levels and HbA1C levels in somepatients with type 2 diabetes.
• If a person tends to have an "apple-shaped" body in which fat isstored around the abdomen, he or she is more at risk for type 2 diabetes.
• Although type 2 diabetes usually develops after age 40, about halfof all people diagnosed with the disease are older than 55. It is suggestedthat, as people age, they tend to become more sedentary andtherefore heavier, putting them at greater risk for the disease.
• Obesity is the only risk factor for diabetes that can be self-controlled.
• Obese children and adolescents have shown an alarming increasein the incidence of type 2 diabetes, which usually only occurs inadults.
• A National Institutes of Health study involving people who wereoverweight and who had high, but not yet diabetic, blood sugarlevels found that a combination of diet and exercise cut their riskof developing diabetes by 58%.