Pharmacological Treatment of the Overweight Patient

34 Pages·2007·0.64 MB·English

0031-6997/07/5902-151–184$20.00
PHARMACOLOGICALREVIEWS Vol.59,No.2
Copyright©2007byTheAmericanSocietyforPharmacologyandExperimentalTherapeutics 50441/3199591
PharmacolRev59:151–184,2007 PrintedinU.S.A
Pharmacological Treatment of the Overweight Patient
GEORGEA.BRAYANDFRANKL.GREENWAY
PenningtonBiomedicalResearchCenter,LouisianaStateUniversitySystem,BatonRouge,Louisiana
I. Introduction........................................................................... 153
II. Using the currently available drugs...................................................... 155
III. Drugs approved by the U.S. Food and Drug Administration or the European Medicinal
Evaluation Agency for treatment of overweight patients ................................... 157
A. Drugs approved for long-term use .................................................... 157
1. Orlistat......................................................................... 157
a. Mechanism of action .......................................................... 157
b. Long-term studies............................................................. 157
c. Studies in special populations.................................................. 158
d. Meta-analysis of orlistat studies................................................ 159
e. Safety considerations.......................................................... 159
2. Sibutramine..................................................................... 160
a. Mechanism of action .......................................................... 160
b. Long-term studies............................................................. 160
c. Studies in special populations.................................................. 161
d. Meta-analysis of sibutramine studies............................................ 163
e. Combining sibutramine and orlistat............................................. 163
f. Dosage and safety considerations............................................... 164
3. Rimonabant..................................................................... 164
a. Mechanism of action .......................................................... 164
b. Long-term studies............................................................. 164
c. Studies in special populations.................................................. 166
d. Safety considerations.......................................................... 166
e. Other cannabinoid antagonists ................................................. 166
B. Drugs approved by the U.S. Food and Drug Administration for short-term treatment of
overweight patients................................................................. 166
1. Sympathomimetic drugs.......................................................... 166
a. Mechanism of action .......................................................... 166
b. Clinical studies ............................................................... 166
IV. Antidepressant and antiepileptic drugs that produce weight loss but are not approved by the
U.S. Food and Drug Administration for weight loss........................................ 167
A. Fluoxetine and Sertraline ........................................................... 167
1. Mechanism of action ............................................................. 167
2. Clinical studies.................................................................. 167
B. Bupropion ......................................................................... 167
1. Mechanism of action ............................................................. 167
2. Clinical studies for weight loss.................................................... 167
C. Topiramate ........................................................................ 168
1. Mechanism of action ............................................................. 168
2. Clinical studies for weight loss.................................................... 168
3. Special situations................................................................ 168
D. Zonisamide......................................................................... 169
1. Mechanism of action ............................................................. 169
2. Clinical studies for weight loss.................................................... 169
Address correspondence to: Dr. George A. Bray, Pennington Center, 6400 Perkins Road, Baton Rouge, LA 70808. E-mail: brayga@
pbrc.edu
Thisarticleisavailableonlineathttp://pharmrev.aspetjournals.org.
doi:10.1124/pr.59.2.2.
151
152 BRAY AND GREENWAY
E. Lamotrigine........................................................................ 169
1. Mechanism of action ............................................................. 169
2. Clinical studies.................................................................. 169
V. Drugs approved by the U.S. Food and Drug Administration for uses other than overweight ... 169
A. Metformin ......................................................................... 169
1. Mechanism of action ............................................................. 169
2. Clinical studies.................................................................. 169
B. Pramlintide........................................................................ 170
1. Mechanism of action ............................................................. 170
2. Clinical studies.................................................................. 170
C. Exenatide.......................................................................... 170
1. Mechanism of action ............................................................. 170
2. Clinical studies with weight loss as a component.................................... 170
D. Somatostatin....................................................................... 171
1. Mechanism of action ............................................................. 171
2. Clinical studies for weight loss.................................................... 171
E. Atomoxetine........................................................................ 171
1. Mechanism of action ............................................................. 171
2. Clinical study for weight loss...................................................... 171
F. Growth hormone and growth hormone fragment....................................... 171
1. Mechanism of action ............................................................. 171
2. Clinical studies on body composition............................................... 171
VI. Drugs with clinical data or in clinical studies............................................. 172
A. Leptin............................................................................. 172
1. Mechanism of action ............................................................. 172
2. Clinical studies.................................................................. 172
B. Neuropeptide Y receptor antagonists ................................................. 172
1. Mechanism of action ............................................................. 172
2. Clinical studies.................................................................. 173
C. Serotonin 2C receptor agonists....................................................... 173
1. Mechanism of action ............................................................. 173
2. Clinical studies.................................................................. 173
D. Peptide YY ...................................................................... 173
3-36
1. Mechanism of action ............................................................. 173
2. Clinical studies.................................................................. 173
E. Oxyntomodulin..................................................................... 173
1. Mechanism of action ............................................................. 173
2. Clinical studies.................................................................. 173
F. Pancreatic lipase inhibitor........................................................... 174
1. Mechanism of action ............................................................. 174
2. Clinical studies.................................................................. 174
G. Cholecystokinin .................................................................... 174
H. Combination of bupropion and naltrexone (Contrave)................................... 174
I. Combination of bupropion and zonisamide (Empatic)................................... 174
J. Combination of topiramate and phentermine (Qnexa) .................................. 174
VII. Drugs in the early phases of development ................................................ 174
A. Melanin-concentrating hormone receptor-1 antagonist.................................. 174
B. Histamine-3 receptor antagonists..................................................... 175
C. Ghrelin antagonists................................................................. 175
D. Angiogenesis antagonists and fat cell antibodies....................................... 175
VIII. Drugs and herbal medications no longer under investigation or withdrawn .................. 175
A. Ephedra ........................................................................... 175
B. (cid:1)-Adrenergic agonists .............................................................. 176
3
C. Bromocriptine...................................................................... 176
D. Ecopipam.......................................................................... 176
E. Axokine............................................................................ 176
IX. Over-the-counter medications ........................................................... 177
DRUG TREATMENT OF OBESITY 153
A. Orlistat............................................................................ 177
B. Phenylpropanolamine............................................................... 177
X. Herbal products, functional foods, and nutriceuticals ...................................... 177
A. Interventions requiring special training............................................... 177
1. Acupuncture/acupressure......................................................... 177
2. Homeopathy..................................................................... 177
3. Hypnotherapy ................................................................... 177
B. Minerals and metabolites............................................................ 177
1. Chromium picolinate............................................................. 177
2. Hydroxymethyl butyrate.......................................................... 177
3. Pyruvate........................................................................ 177
4. Conjugated linoleic acid .......................................................... 177
5. Calcium......................................................................... 178
C. Herbal dietary supplements ......................................................... 178
1. Ephedra sinica .................................................................. 178
2. Green tea extract ................................................................ 178
3. Garcinia cambogia............................................................... 179
4. Yohimbine from Pausinystalia yohimbe ............................................ 179
5. Hoodia.......................................................................... 179
6. Citrus aurantium (bitter orange) .................................................. 179
7. Ayurvedic preparations........................................................... 179
D. Fibers ............................................................................. 179
1. Chitosan........................................................................ 179
2. Glucomannan ................................................................... 179
3. Guar gum....................................................................... 179
4. Plantago psyllium................................................................ 180
XI. Conclusions ........................................................................... 180
References ............................................................................ 180
I. Introduction drugs are stopped weight regain is the expected
outcome.
Tousemedicationsproperlyfortreatmentoftheover- • Weight loss plateaus during continued treatment
weightpatient,itisimportanttostartwithaframework when compensatory mechanisms come into play to
based on the realities associated with this treatment. counterbalance the effect of the drug.
These are briefly summarized below: • Monotherapy usually produces weight loss in the
range of 10% (5% better than placebo).
• Overweightisduetoanimbalancebetweenenergy • Frustrationwiththefailuretocontinuetoloseweight
intake and energy expenditure. oftenleadstodiscontinuationoftherapyandthento
• Drugs can either reduce food intake or increase weightregainwithlabelingofthedrugasafailure.
energy expenditure.
• Drugtreatmentdoesnotcuretheoverweightpatient. Physicianshaveseveralstrategiesforconfrontingthe
• The therapeutic armamentarium of physicians is problems of the overweight patient. The physician can
limited to only a few drugs. counselthepatientthatheorsheisconcernedaboutthe
• The use of drugs labors under the negative halo of patient’s current level of body weight and can initiate
treatment mishaps. treatmentifthepatientisinterested.Alternatively,ifa
• Drugs do not work when they are not taken; when physician feels uncomfortable with addressing over-
weightinpatients,heorshecanignoretheproblemand
hopethatthepatientwillnotraisetheissue.Or,finally
1Abbreviations: DPP, Diabetes Prevention Program; BMI, body
the physician can wait until the complications of excess
massindex;GLP-1,glucagon-likepeptide-1;CI,confidenceinterval;
HDL, high-density lipoprotein; LDL, low-density lipoprotein; GI, weight manifest themselves as diabetes, dyslipidemia,
gastrointestinal;NPY,neuropeptideY;POMC,proopiomelanocortin; hypertension, or other disorders and then institute ap-
VLCD,verylow-caloriediet;FDA,U.S.FoodandDrugAdministra- propriate therapy for each of these medical problems.
tion;PYY,peptideYY;5-HT,5-hydroxytryptamine(serotonin);TNP-
With the current high-quality therapies available to
470, O-(chloroacetyl-carbamoyl); L-796568, (R)-N-[4-[2-[[2-hydroxy-
treatdiabetesmellitus,dyslipidemia,andhypertension,
2-(3-pyridinyl)ethyl]amino]ethyl]-phenyl]-4-[4-[4-(trifluoromethyl)-
phenyl]thiazol-2-yl]-benzenesulfonamide,dihydrochloride. many physicians would prefer this latter strategy.
154 BRAY AND GREENWAY
However,ifmedicaltreatmentoftheoverweightpatient occur together. For example, a 10% weight loss, which
were more effective, physicians might prefer to treat the would be clinically significant for a 300-pound (145-kg)
excess weight and thus delay the onset of the problems person, would only reduce body weight by 30 to 270
related to overweight. This strategy was the basis for the pounds, a weight change that many people might not
long-term Diabetes Prevention Program (DPP)1 and the notice and would not be considered a cosmetic success.
Swedish Obese Subjects Study. In the DPP, the onset of Attheotherextreme,a10%weightlossforanindividual
new cases of diabetes among individuals with impaired weighing 150 pounds would lower his or her weight to
glucosetolerancewasreduced55%duringanaveragefol- 135pounds,whichwouldhaveaverypositiveimpacton
low-upof3.2yearsinthegroupwholostweightcompared self-image. We also know that cosmetically significant
withthecontrolgroupwhodidnotloseweight(Knowleret weight losses may not produce clinically significant ef-
al.,2002).IntheSwedishObeseSubjectsStudy,theinci- fects. After liposuction that removed (cid:2)7% of body
denceofnewcasesofdiabeteswasreducedtozeroover2 weight, there were no improvements in health-related
yearsinpatientswholostweightandmaintainedaweight risk factors. These distinctions are shown in Table 1.
lossof(cid:2)12%,comparedwithanincidenceof8.5%fornew Three other issues aggravate the problem of treating
casesofdiabetesinthosewhodidnotloseweight(Sjostrom overweightpatients.Thefirstisthe“negativehalo”that
et al., 2004). Thus, effective treatment of the overweight surroundstheuseofappetitesuppressantsbecauseam-
patientatriskfordiabetesorhypertensioncanreducethe phetamine is addictive. There was never any evidence
riskofdevelopingtheseseriousdiseasesinthefuture. that dexfenfluramine was addictive. Nonetheless, the
One reason most physicians are reluctant to treat drug was scheduled by the U.S. Drug Enforcement
overweightpatientsisthatthetreatmentsarelimitedin AgencyasaScheduleIVdrugbecause,onpaper,ithad
number and effectiveness. At the time this article was chemical similarities to amphetamine.
written,therewereonlytwodrugsapprovedbytheU.S. The second issue is the concern about the plateau of
Food and Drug Administration for long-term use. As body weight that is reached when homeostatic mecha-
monotherapy, these agents can produce an overall nismsinthebodycomeintoplayandstopfurtherweight
weight loss of 8 to 10% among patients who continue to loss. There is an analogy with treatment of hyperten-
takethemedicationfor(cid:1)6months.However,toachieve sion. When an antihypertensive drug is given, blood
theeliminationofnewcasesofdiabetesasnotedabove, pressuredropsandthenstopsfallingwithinafewweeks
the weight loss needs to exceed 12%, a goal that is not to reach a plateau at a new lower level. The antihyper-
usuallyachievedwithcurrentmonotherapy.Thus,there tensive drug has not lost its effect when the plateau
isagreatneedfornewdrugstobeusedasmonotherapy occurs,butitseffectisbeingcounteractedbyphysiolog-
and probably in combinations when prevention fails. icalmechanismsdesignedtomaintainbloodpressure.In
Bothphysiciansandpatientsknowthatoverweightis the treatment of overweight patients, a similar plateau
a stigmatized disease (Puhl and Brownell, 2003). One in body weight is often viewed as a therapeutic failure
commonly held view is that overweight people are lazy for the weight loss drug. This is particularly so when
and weak-willed. If fat people just had willpower, they weightisregainedafterthedrugisstopped.Theseatti-
would push themselves away from the table and not be tudesandbiasesneedtochangebeforeanyeffectivenew
overweight.Thiswidelyheldviewissharedbythepub- therapy will become widely accepted.
lic and by health professionals alike. The clamoring of The final issue is the toxicity associated with many
women to be lean and well proportioned supports this antiobesitydrugs.Thedisasterthatoccurredforsomeof
view.Thedecliningrelativeweightofcenterfoldmodels the patients who took the combination of fenfluramine
in Playboy magazine and of women who are winners of and phentermine is one example (others are listed in
the Miss America contest in the latter part of the 20th Table 2). Aortic regurgitation occurred in up to 25% of
centuryalsosupportsthisview.Manyphysiciansjustdo thepatientstreatedwiththiscombinationofdrugsand
not like to see overweight patients come into their of- led many physicians to say, “I told you so” and “I’m
fices.Thisattitudeposesamajorchallengetoanyefforts certainly glad I didn’t use those drugs.” This issue has
to improve the lot of people who are overweight. largelysubsidedwithtime,buttherewillalwaysremain
There can be both medical and cosmetic (self-image) aresidueofconcernamongsomephysiciansandamong
benefitstoweightloss.However,theydonotnecessarily regulatorsaboutthepotentialproblemsthatmightsur-
TABLE1
Cosmeticallysignificantversusclinicallysignificantweightloss
TypeofProcedure WeightLoss ClinicallySignificant CosmeticallySignificant
Diet/exercise 10%;from300to270lb Yes No
10%;from200to180lb Yes Probablynot
10%;from150to135lb Yes Yes
Liposuction 7%;from220to200lb No Probablynot
7%;from160to149lb No Yes
Surgery(gastricbypass) 40%;from264to165lb Yes Yes
DRUG TREATMENT OF OBESITY 155
TABLE2 Lung, and Blood Institute. The first step in this algo-
Unintendedconsequencesofsometreatmentsforobesity
rithm is to measure height, weight, and waist circum-
Year Drug Consequence ference to establish the body mass index (BMI) and the
1893 Thyroid Hyperthyroidism degree of central adiposity. If the BMI, ([weight in kilo-
1932 Dinitrophenol Cataracts/neuropathy
grams divided by the square of the height in meters] or
1937 Amphetamine Addiction
1968 Rainbowpills Deaths:arrhythmias [weight in pounds divided by square of the height
1985 Gelatindiets Cardiacdeaths (inches)](cid:3)703]is(cid:1)30kg/m2thepatientisbydefinition
1997 Phentermine/fenfluramine Valvulopathy
1998 Phenylpropanolamine Strokes obese and can be considered for medications. Over-
2003 Mahuang Heartattacks/strokes weightindividualswithaBMIbetween27and30kg/m2
may also be considered if they have diabetes, hyperten-
sion, sleep apnea, or another medical condition that
face when new treatments for overweight are made
would benefit from weight loss.
available to the public. Although the drug treatment of
Waist circumference is also an important indicator of
overweight patients has at least a century-long history
risk from excess fat. The currently recommended upper
(Colman, 2005), progress in drug discovery was given a
limit for waist circumference in the United States is 102
newimpetusbythediscoveryofleptinin1994(Zhanget
cm (40 inches) for a man and 88 cm (35 inches) for a
al., 1994). This peptide demonstrated that overweight
woman.ArecentproposalfromtheInternationalDiabetes
can be caused by a hormone deficiency and be reversed
Federation requires the presence of central adiposity to
by replacement of that hormone (Halaas et al., 1995;
diagnosethemetabolicsyndromeandusesvaluesforwaist
Maffeietal.,1995;Farooqietal.,2002).Evenbeforethe
circumference(cid:1)80cmforfemalesand(cid:1)94cmformales.
discoveryofleptin,overweighthadbeendeclaredtobea
Another important initial step in evaluating the over-
chronic disease by a National Institutes of Health Con-
weightpatientistoassessassociated(comorbid)conditions
sensus Conference in 1985 (Bray, 2004). In the 20th
by measuring blood pressure, glucose, lipids and, when
century, bad eating habits were considered a primary
indicated,byperformingothertests.Withresultsfromthis
cause for overweight. Because some bad habits can be
laboratory panel and waist circumference, the metabolic
behaviorallyextinguishedovera12-weekperiodoftime,
syndrome can be diagnosed. This is best done with the
overweight medications approved before 1985 were ap-
criteria from the National Cholesterol Education Panel
proved for periods up to 12 weeks as an adjunct to a
AdultTreatmentIIIGuidelines(Table4).
lifestylechangeprogram.Equatingoverweightwithbad
Oncethepatienthasbeenestablishedasanappropriate
habits and the stigmatization of obesity slowed the use
candidatetoloseweightandheorsheismotivatedtodoso,
of overweight medications chronically, as is done with
the next step is to set a weight loss goal. Most patients
medications for other chronic diseases (Puhl and
haveanunrealisticviewofhowmuchweighttheycanlose.
Brownell, 2003). With the recognition that longer-term
For them, a weight loss of (cid:4)15% is often viewed as a
therapy was needed, clinical trials have been extended
failure. In contrast, weight loss using monotherapy with
inlength.Since1990,onlythreemedicationshavebeen
thedrugsthatarecurrentlyavailableisnotusually(cid:1)10%.
approved for the chronic treatment of overweight, and
Itis,thus,importantforphysicianandpatientaliketoset
one of them, dexfenfluramine, was withdrawn 2 years
aweightlossgoalforinitialtherapythatisnot(cid:1)10%and
later (Anonymous, 1996).
to set a lower limit for weight loss of (cid:4)5%, which will
suggestthatanalternativestrategyisneeded.
II. Using the Currently Available Drugs
The next step is to be certain that the patient is
Inthisarticle,wereviewthefieldofdrugtherapyfor “ready”toloseweight.Withuseofideasfrompsychol-
the overweight patient. Table 3 lists the drugs that are ogy, the patient must be ready to work on weight loss
available and whether they are approved for long-term as opposed to not yet thinking about the problem.
use by the U.S. Food and Drug Administration or are Once the weight goal is established and patients are
restricted (scheduled) by the U.S. Drug Enforcement prepared to take charge of their weight loss program,
Agency on the basis of the belief that there is risk of the next steps are to help them develop lifestyle
abuse from the drug. For individuals desiring more de- changes that will benefit their program. The most
tail or additional guidance in the use of medications to importantoftheseismonitoringwhattheyeat,where
treat overweight, information can be found in a variety they eat it, and under what circumstances they eat. A
of sources (Bray and Greenway, 1999; National Heart, second element is to provide advice on diet and phys-
Lung, and Blood Institute and North American Associ- ical activity. Replacing voluntary choices with “por-
ation for the Study of Obesity, 2000; Haddock et al., tion-controlled” choices at one or more meals can be
2002; Yanovski and Yanovski, 2002; Kim et al., 2003; helpful. There are frozen foods, ready-to-make food
Padwaletal.,2004,2005;Colman,2005;Lietal.,2005; items,andcannedmealreplacementsthatcanbeused
Snow et al., 2005; Vettor et al., 2005). for this purpose. Patients also need more exercise.
As a guide for the use of medications, we will use an One strategy is to have them get a step-counter and
algorithm that was described by the National Heart, record the number of steps they take with the goal of
156 BRAY AND GREENWAY
TABLE3
DrugsproducingweightlossthatareapprovedbytheU.S.FoodandDrugAdministration
U.S.Drug
Enforcement
DrugName TradeName(s) Dosage SideEffectsandComments
Agency
Schedule
Cannabinoidreceptorantagonist
Rimonabant Accomplia 20mg/day N.A. Depressivesymptoms,nausea,
diarrhea;approvedbytheCenterfor
ProprietaryMedicinalProductsin
Europe—approvalbyFDApending
Pancreaticlipaseinhibitor
Orlistat Xenical 120mgt.i.d.before None Dailyvitaminpillintheevening;may
meals interactwithcyclosporine
Norepinephrine-serotoninreuptakeinhibitor
Sibutramine Meridia 5–15mg/day IV Raisesbloodpressureslightly;donot
Reductil usewithmonoamineoxidase
inhibitors,selectiveserotonin
reuptakeinhibitors,sumatriptan,
dihydroergotamine,meperidine,
methadone,pentazocine,fentanyl,
lithium,ortryptophan
Sympathomimeticdrugs
Diethylpropion Tenuate 25mgt.i.d. IV Allsympathomimeticdrugsare
Tepanil 25mgt.i.d. similar;donotusewithmonoamine
Tenuate 75mginA.M. oxidaseinhibitors,guanethidine,
Dospan alcohol,sibutramine,ortricyclic
antidepressants
Phentermine Standardrelease: 18.75–37.5mgt.i.d. IV
Adipex-P
Fastin
Obenix
Oby-Cap
Oby-Trim
Zantryl
Slowrelease: 15–30mg/dayinA.M.
Ionamin
Benzphetamine Didrex 25–50mg1–3times/day III Allsympathomimeticdrugsare
similar;donotusewithmonoamine
oxidaseinhibitors,guanethidine,
alcohol,sibutramine,ortricyclic
antidepressants
Phendimetrazine Standardrelease: 35mgt.i.d.beforemeals III Allsympathomimeticdrugsare
BontrilPDM similar;donotusewithmonoamine
Plegine oxidaseinhibitors,guanethidine,
X-Trozine alcohol,sibutramine,ortricyclic
antidepressants
Slowrelease: 105mg/dayinA.M.
Bontril
Prelu-2
X-Trozine
TABLE4
TheNationalCholesterolEducationProgramAdultTreatmentPanelIIIandtheInternationalDiabetesFederationcriteria
fordiagnosisofthemetabolicsyndrome
Criterion ATP-IIIModifiedCriteria InternationalDiabetesFederation
Waistcircumference
Female (cid:1)35inches (cid:1)88cm (cid:2)31inches (cid:2)80cm
Male (cid:1)40inches (cid:1)102cm (cid:2)37inches (cid:2)94cm
HDLcholesterol
Female (cid:4)50mg/dl (cid:4)1.29mmol/l (cid:4)50mg/dl (cid:4)1.29mmol/l
Male (cid:4)40mg/dl (cid:4)1.03mmol/l (cid:4)40mg/dl (cid:4)1.03mmol/l
Glucose (cid:2)110mg/dl (cid:2)6.2mmol/l (cid:2)100mg/dl (cid:2)5.6mmol/l
Bloodpressure (cid:2)130/85mmHg (cid:2)130/85mmHg
gradually increasing this number to 10,000 steps/day. whetherheorshehasmetthegoals.Ifso,thepatient
In a review of lifestyle treatment used with pharma- continues as is, but if after 3 months he or she fails to
cotherapy in randomized clinical trials Poston et al. meet the goals, then medications may be considered.
(2001) found that balanced-deficit diets were used in The next step is to discuss the pros and cons of med-
40.7%, low-calorie diets in 25% and self-monitoring ication with the patient. An algorithm from the
behavioral strategies in 23.1% of patients (Poston et American College of Physicians (Snow et al., 2005)
al., 2001). When a patient returns to you, establish recommends six medications: orlistat, sibutramine,
DRUG TREATMENT OF OBESITY 157
phentermine, diethylpropion, fluoxetine, and bupro-
pion. The first four have been approved by the U.S.
Food and Drug Administration for treatment of over-
weight patients, but fluoxetine and bupropion have
not, and they should not be used primarily for this
purpose.Inourview,fluoxetineandbupropionshould
only be used for weight loss in special situations.
Fluoxetine is appropriate for the overweight patient
who is depressed. Bupropion may also be helpful in
reducingorpreventingweightgainwhenpeopletryto
stop smoking and when they are depressed.
III. Drugs Approved by the U.S. Food and Drug
Administration or the European Medicinal
Evaluation Agency for Treatment of Overweight
Patients
A. Drugs Approved for Long-Term Use
FIG. 1. Double-blind,randomizedclinicaltrialoforlistatversuspla-
1. Orlistat. cebowitharerandomizationofparticipantsafterthe1styear.Reprinted
from The Lancet, vol. 352, Sjostrom et al., “Randomized Placebo-Con-
a. Mechanism of action. Orlistat is a lipase inhibi- trolledTrialofOrlistatforWeightLossandPreventionofWeightRegain
tor. In pharmacological studies, it was shown to be a inObesePatients:EuropeanMulticenterOrlistatStudyGroup,”pp167–
172,copyright1998,withpermissionfromElsevier.
potentselectiveinhibitorofpancreaticlipaseandtothus
reduce the intestinal digestion of fat. The drug has a
dose-dependent effect on fecal fat loss, increasing it to year was changed to 60 mg three times per day (102 pa-
(cid:2)30%. Thus, orlistat is recommended to be used with a tients), and the others were switched to placebo (95 pa-
dietthathas30%ofitsenergyasfat.Orlistathaslittle tients)(Davidsonetal.,1999).After1year,theweightloss
effect in subjects eating a low-fat diet, as might be an- was(cid:5)8.67kgintheorlistat-treatedgroupand(cid:5)5.81kgin
ticipated from its mechanism of action. In single-dose theplacebogroup(P(cid:4)0.001).Duringthe2ndyear,those
randomized and placebo-controlled studies, 120 mg of switchedtoplaceboafter1yearreachedthesameweight
orlistat was shown to increase glucagon-like peptide-1 as those treated with placebo for 2 years ((cid:5)4.5% in those
(GLP-1)andC-peptidemorethanplacebo(Damcietal., treated with placebo for 2 years and (cid:5)4.2% in those
2004), to increase fecal fat loss but decrease the acute switchedtoplaceboduringyear2).
increaseincholecystokinin(O’Donovanetal.,2003),but In a third 2-year study, 783 patients remained in
not to influence the behavioral measures of satiety the placebo or orlistat-treated groups at 60 or 120 mg
(Goedecke et al., 2003). three times per day for the entire 2 years (Rossner et
b. Long-term studies. Results of a number of 1- to al., 2000). After 1 year with a weight-loss diet, the
2-yearlong-termclinicaltrialswithorlistathavebeenpub- placebo group lost (cid:5)7 kg, which was significantly less
lished. The results of a 2-year trial are shown in Fig. 1 than the (cid:5)9.6 kg lost by the group treated with orl-
(Sjostrometal.,1998).Thetrialconsistedoftwoparts.In istat60mgthreetimesdailyorthe(cid:5)9.8kglostbythe
the1styear,patientsreceivedahypocaloricdietcalculated group treated with 120 mg of orlistat three times
to be 500 kcal/day less than the patient’s requirements. daily. During the 2nd year, when the diet was liber-
During the 2nd year, the diet was calculated to maintain alizedtoa“weightmaintenance”diet,allthreegroups
body weight. By the end of year 1, the placebo-treated regained some weight. At the end of 2 years, the
patients lost (cid:5)6.1% of their initial body weight and the patients in the placebo group were (cid:5)4.3 kg below
drug-treatedpatientslost(cid:5)10.2%.Thepatientswereran- baseline, the patients treated with 60 mg of orlistat
domized again at the end of year 1. Those switched from three times per day were (cid:5)6.8 kg below baseline, and
orlistattoplacebogainedweightfrom(cid:5)10to(cid:5)6%below the patients who took 120 mg of orlistat three times
baseline. Those switched from placebo to orlistat lost per day were (cid:5)7.6 kg below baseline.
weight from (cid:5)6 to (cid:5)8.1% below baseline, which was es- The final 2-year trial evaluated 796 subjects in a
sentiallyidenticaltothe(cid:5)7.9%weightlossinthepatients general-practice setting (Hauptman, 2000). After 1
treatedwithorlistatforthefull2years. year of treatment with 120 mg of orlistat three times
Inasecond2-yearstudy,892patientswererandomized per day, the orlistat-treated patients (n (cid:6) 117) lost
to orlistat or placebo (Davidson et al., 1999). One group (cid:5)8.8 kg, compared with (cid:5)4.3 kg in the placebo group
receivedplacebothroughoutthe2years(97patients),and (n (cid:6) 91). During the 2nd year, when the diet was
a second group received orlistat (120 mg three times per liberalized to “maintain body weight,” both groups
day) for 2 years (109 patients). At the end of 1 year, the regained some weight. At the end of 2 years, the
dosefortwo-thirdsofthegrouptreatedwithorlistatfor1 orlistatgroupwas(cid:5)5.2kgbelowtheirbaselineweight
158 BRAY AND GREENWAY
compared with (cid:5)1.5 kg below baseline for the group
treated with placebo.
The pooled 2-year data from these four studies are
showninFig.2.Thisfigurecontainsinformationonboth
the 120- and 60-mg-three-times-a-day doses. It is clear
that there is a dose response. The maximal weight loss
was achieved between 6 and 9 months, and then there
wasaslowregaininallofthegroupsduringtherestof
the study.
Theresultsofa4-yeardouble-blind,randomized,place-
bo-controlled trial with orlistat have also been reported
(Torgerson et al., 2004). A total of 3304 overweight pa-
tients,21%ofwhomhadimpairedglucosetolerance,were
included in this Swedish trial (Fig. 3). The lowest body
weight was achieved during the 1st year: (cid:1)(cid:5)11% below FIG. 3. Effectoforlistatonbodyweightina4-yearrandomized,pla-
cebo-controlledclinicaltrial.
baseline in the orlistat-treated group and 6% below base-
line in the placebo-treated group. Over the remaining 3
yearsofthetrial,therewasasmallregaininweight,such more weight than the placebo-treated group (Hollander
that by the end of 4 years, the orlistat-treated patients et al., 1998; Kelley et al., 2002; Miles et al., 2002). The
were(cid:5)6.9%belowbaselinecomparedwith(cid:5)4.1%forthose subjects with diabetes also showed a significantly
receivingplacebo.Thetrialalsoshoweda37%reductionin greater decrease in hemoglobin A levels. In another
1c
theconversionofpatientsfromimpairedglucosetolerance study of orlistat and weight loss, investigators pooled
to diabetes; essentially all of this benefit occurred in the data on 675 subjects from three of the 2-year studies
patients with impaired glucose tolerance when they were described previously in which glucose tolerance tests
enrolledintothetrial. were available (Heymsfield et al., 2000). During treat-
Weight maintenance with orlistat was evaluated in ment,6.6%ofthepatientstakingorlistatconvertedfrom
a 1-year study (Hill et al., 1999). Patients were en- a normal to an impaired glucose tolerance test, com-
rollediftheyhadlost(cid:1)8%oftheirbodyweightover6 pared with 10.8% in the placebo-treated group. None of
months while eating a 1000 kcal/day (4180 kJ/day) the orlistat-treated patients who originally had normal
diet. The 729 patients were randomized to receive glucose tolerance developed diabetes, compared with
placeboororlistatat30,60,or120mgthreetimesper 1.2%intheplacebo-treatedgroup.Ofthosewhoinitially
dayfor12months.Attheendofthistime,theplacebo- hadnormalglucosetolerance,7.6%intheplacebogroup
treated patients regained 56% of their body weight, but only 3% in the orlistat-treated group developed
compared with 32.4% in the group treated with 120 diabetes.
mgoforlistatthreetimesperday.Theothertwodoses The effect of orlistat in preventing diabetes has been
of orlistat were no different from placebo in prevent- assessed in a 4-year study (Torgerson et al., 2004). In
ing the regain of weight. thistrialweightwasreducedby2.8kg(95%CI1.1–4.5
c. Studies in special populations. kg) compared with placebo, and the conversion rate to
i. Diabetic patients. Patients with diabetes treated diabetes was reduced from 9 to 6% for a relative risk
with orlistat, 120 mg three times daily for 1 year, lost reduction of 0.63 (95% CI 0.46–0.86) (Padwal et al.,
2005).
ii.Metabolicsyndromeandlipids. Inafurtheranal-
ysis, patients who participated in the studies described
aboveweredividedintothehighestandlowestquintiles
for triglycerides and HDL cholesterol levels (Reaven et
al., 2001). Those with high triglyceride and low HDL
cholesterol levels were labeled “syndrome X,” and those
with the lowest triglyceride levels and highest HDL
cholesterol levels were the “nonsyndrome X” controls.
Withthisclassification,therewerealmostnomeninthe
nonsyndrome X group, compared with an equal sex
breakdown in the syndrome X group. In addition, the
syndrome X group had slightly higher systolic and dia-
stolic blood pressure levels and a nearly 2-fold higher
level of fasting insulin. Besides weight loss, the only
FIG. 2. Two-yearpooleddatacomparingorlistatand120and60mg difference between the placebo and orlistat-treated pa-
three times a day and placebo. From Hoffmann-LaRoche data, with
permissionfromDr.JonathanHauptman. tients was the decrease in LDL cholesterol levels in the
DRUG TREATMENT OF OBESITY 159
patientstreatedwithorlistat.However,thesyndromeX betweenorlistatandplaceboafter12monthsoftherapy
subgroupshowedasignificantlygreaterdecreaseintri- in22studieswas(cid:5)2.70kg(95%CI(cid:5)3.79to(cid:5)1.61kg).
glyceride and insulin levels than those without syn- Becausethisanalysisincludeddiabeticandnondiabetic
drome X. Levels of HDL cholesterol increased more in subjects, we have summarized the data from the five
the syndrome X group, but LDL cholesterol levels 2-year studies in Table 5.
showed a smaller decrease than that in the nonsyn- Inanothermeta-analysisoforlistat,8-year-longstud-
drome X group. All of the clinical studies with orlistat ies,onlyoneofwhichwasindiabeticsubjects,examined
have shown significant decreases in serum cholesterol the effects of weight loss at 1 and 2 years and on the
andLDLcholesterollevelsthatusuallyaregreaterthan various laboratory and clinical responses. The overall
decreasesthatcanbeaccountedforbyweightlossalone effect of orlistat on weight loss at 12 months using the
(Bray and Greenway, 1999). One study showed that weighted mean difference was (cid:5)3.01 kg (95% CI (cid:5)3.48
orlistatreducestheabsorptionofcholesterolfromtheGI to(cid:5)2.54kg)(Table6).After24months,theoveralleffect
tract,thusprovidingamechanismfortheclinicalobser- oforlistatonweightlosswas(cid:5)3.26kg(95%CI(cid:5)4.15to
vations (Mittendorfer et al., 2001). (cid:5)2.37 kg). In terms of weight maintenance, the overall
iii. Studies in children. A multicenter trial tested effect of orlistat after 12 months was (cid:5)0.85 kg (95% CI
the effect of orlistat in 539 obese adolescents (Chanoine (cid:5)1.50 to (cid:5)0.19 kg) (Davidson et al., 1999; Hill et al.,
etal.,2005).Subjectswererandomizedtoplaceboor120 1999;Hauptman,2000;Rossneretal.,2000).Thepooled
mgoforlistatthreetimesadayandamildlyhypocaloric datashowsignificantoveralleffectsafter1yearoftreat-
diet containing 30% fat. By the end of the study BMI ment on the change in cholesterol [(cid:5)0.34 mM (95% CI
decreased (cid:5)0.55 kg/m2 in the drug-treated group but (cid:5)0.41 to (cid:5)0.027)] (n (cid:6) 7 studies), the change in LDL
increased(cid:7)0.31kg/m2intheplacebogroup.Bytheend cholesterol[(cid:5)0.29mM(95%CI (cid:5)0.34to(cid:5)0.24)](n(cid:6)7
of the study, weight increased by only (cid:7)0.51 kg in the studies),thechangeinHDLcholesterol[(cid:5)0.03mM(95%
orlistat-treated group, compared with (cid:7)3.14 kg in the CI (cid:5)0.05 to (cid:5)0.01)] (n (cid:6) 6 studies), the change in tri-
placebo-treatedgroup(Fig.4).Thisdifferencewasdueto glycerides [0.03 mM (95% CI (cid:5)0.04 to 0.10)] (n (cid:6) 6
differences in body fat. The side effects were gastroin- studies),thechangeinhemoglobinA1c[(cid:5)0.17%(95%CI
testinalinorigin,asexpectedfromthemodeofactionof (cid:5)0.24 to (cid:5)0.10] (n (cid:6) 3 studies) (Hollander et al., 1998;
orlistat. A second small 6-month randomized clinical Lindgarde, 2000; Broom et al., 2002), the change in
trialfromasinglesitefailedtoshowadifferenceresult- systolicbloodpressure[(cid:5)2.02mmHg(95%CI(cid:5)2.87to
ing from treatment with orlistat in a population of 40 (cid:5)1.17)](n(cid:6)7studies),andthechangeindiastolicblood
adolescents (Maahs et al., 2006). pressure [(cid:5)1.64 mm Hg (95% CI (cid:5)2.20 to (cid:5)1.09)] (n (cid:6)
d. Meta-analysis of orlistat studies. Several meta- 7 studies)]. In a meta-analysis focused on the use of
analysesoforlistathavebeenpublished(Haddocketal., orlistat in diabetics Norris et al. (2004) reported a
2002;Avenelletal.,2004;Lietal.,2005).Bypoolingsix weighted mean difference in favor of orlistat of (cid:5)2.6 kg
studies Haddock et al. (2002) estimated the weight loss (95%CI(cid:5)3.2to(cid:5)2.1)after52to57weeksoftreatment.
in patients treated with orlistat to be (cid:5)7.1 kg (range e. Safety considerations. Orlistat is not absorbed to
(cid:5)4.0 to (cid:5)10.3 kg) compared with (cid:5)5.02 kg (range (cid:5)3.0 any significant degree from the gastrointestinal tract,
to (cid:5)6.1 kg) for the placebo-treated groups. In the meta- and its side effects are thus related to the blockade of
analysis of Li et al. (2005), the overall mean difference triglyceride digestion in the intestine (Zhi et al., 1999).
Fecal fat loss and related GI symptoms are common
initially, but they subside as patients learn to use the
drug (Bray and Greenway, 1999). The quality of life in
patients treated with orlistat may improve despite con-
cerns about GI symptoms. Orlistat can cause small but
significantdecreasesinfat-solublevitamins.Levelsusu-
allyremainwithinthenormalrange,butafewpatients
mayneedvitaminsupplementation.Becauseitisimpos-
sible to tell which patients need vitamins, it is wise to
TABLE5
Meta-analysisofstudieswithlong-termuseoforlistat
AdaptedfromLietal.(2005).
Reference Mean
95%CI
Davidsonetal.(1999) (cid:5)2.95((cid:5)4.45to(cid:5)1.45)
Hauptman(2000) (cid:5)3.80((cid:5)5.37to(cid:5)2.23)
FIG. 4. Effectoforlistatonbodymassindexinarandomized,placebo- Rossneretal.(2000) (cid:5)3.00((cid:5)4.17to(cid:5)1.83)
controlled clinical trial of orlistat in adolescents. Reproduced from The Sjostrometal.(1998) (cid:5)4.20((cid:5)5.26to(cid:5)3.14)
JournaloftheAmericanMedicalAssociation,volume293,pp2873–2883. Torgersonetal.(2004) (cid:5)4.17((cid:5)4.60to(cid:5)3.74)
Copyright©2005AmericanMedicalAssociation.
160 BRAY AND GREENWAY
TABLE6
Meta-analysisofthestudiesusingorlistat
AdaptedfromAvenelletal.(2004).
Treatment Placebo
Reference Weight WeightedMeanDifference
n Mean(cid:8)S.D. n Mean(cid:8)S.D.
% 95%CI
Sjostrometal.(1998) 343 (cid:5)8.10(cid:8)8.21 340 (cid:5)3.90(cid:8)7.02 11.1 (cid:5)4.20((cid:5)5.35to(cid:5)3.05)
Hollanderetal.(1998) 156 (cid:5)3.84(cid:8)5.00 151 (cid:5)1.43(cid:8)5.10 11.4 (cid:5)2.41((cid:5)3.54to(cid:5)1.29)
Davidsonetal.(1999) 657 (cid:5)8.76(cid:8)9.48 223 (cid:5)5.81(cid:8)10.01 6.5 (cid:5)2.95((cid:5)4.45to(cid:5)1.45)
Rossneretal.(2000) 241 (cid:5)8.13(cid:8)8.22 236 (cid:5)5.23(cid:8)7.40 7.4 (cid:5)2.90((cid:5)4.30to(cid:5)1.50)
Hauptman(2000) 210 (cid:5)5.40(cid:8)7.44 212 (cid:5)1.41(cid:8)6.31 8.4 (cid:5)3.99((cid:5)5.31to(cid:5)2.67)
Lindegarde(2000) 190 (cid:5)4.20(cid:8)7.03 186 (cid:5)2.90(cid:8)6.74 7.5 (cid:5)1.30((cid:5)2.69to0.09)
Fineretal.(2000) 110 (cid:5)3.29(cid:8)6.85 108 (cid:5)1.31(cid:8)6.29 4.8 (cid:5)1.98((cid:5)3.73to(cid:5)0.23)
Broometal.(2002) 259 (cid:5)5.80(cid:8)8.50 163 (cid:5)2.30(cid:8)6.40 8.7 (cid:5)3.50((cid:5)4.79to(cid:5)2.21)
provide a multivitamin routinely with instructions to Sibutramine has been evaluated extensively in several
take it before bedtime. Orlistat does not seem to affect multicenter trials lasting 6 to 24 months. In a 6-month
the absorption of other drugs, except cyclosporin. dose-ranging study of 1047 patients, 67% treated with
2. Sibutramine. sibutramine achieved a 5% weight loss from baseline,
a. Mechanism of action. Sibutramine is a highly and 35% lost (cid:2)10% (Bray and Greenway, 1999). There
selective inhibitor for the reuptake at nerve endings of was a clear dose-response effect in this 24-week trial,
norepinephrine and serotonin and, to a lesser degree, and patients regained weight when the drug was
dopamine.Inpreclinicalexperimentalandclinicalstud- stopped, indicating that the drug remained effective
ies, it reduced food intake. In a double-blind placebo- when used. Data from this multicenter trial are shown
controlled2-weektrial,a30-mg/daydoseofsibutramine in Fig. 5 (Bray et al., 1999). In a 1-year trial of 456
reducedfoodintakeby23%onday7and26%onday14 patients who received sibutramine (10 or 15 mg/day) or
relativetoplaceboandalsodecreasedthepercentageof placebo, 56% of those who stayed in the trial for 12
fat eaten. A smaller dose of 10 mg also significantly monthslostatleast5%oftheirinitialbodyweight,and
reduced food intake at 14 days (Rolls et al., 1998). The 30%ofthepatientslost10%oftheirinitialbodyweight
effectofsibutramineonfoodintakehasalsobeenexam- whiletakingthe10-mgdose(SmithandGoulder,2001).
inedoveralongerperiodoftime(Barkelingetal.,2003). Threetrialshaveassessedthevalueofusingsibutra-
The first 2 weeks of this 10-month trial were conducted minetopreventregainofbodyweight(Apfelbaumetal.,
inadouble-blind,randomized,placebo-controlled,cross- 1999; James et al., 2000; Mathus-Vliegen, 2005). In a
overdesign.Participantsthenentereda10-monthopen- multicentertrial,participantswereinitiallygivenavery
labeltrialwithrepeatfoodintakeattheend.Therewas low-caloriediet(VLCD)for6weekstoinduceweightloss
a16%reductioninenergyintakeatthetestlunchinthe (Apfelbaum et al., 1999). Of the initial 181 subjects
firstpartofthestudy(after2weeks).Tenmonthslater, enrolled, 142 were randomized to either 10 mg/day of
there was still a 27% reduction compared with partici- sibutramine or placebo after losing (cid:5)6 kg or more with
pants’ preweight loss placebo-treatment food intake. In theVLCD.Afteranother12months,thosereceivingthe
animals, sibutramine also stimulates thermogenesis,
butthereareconflictingdatainhumans(Hansenetal.,
1998; Seagle et al., 1998). Mechanistic studies have
shownthattheeffectofsibutraminecanbemimickedby
combining a selective serotonin reuptake inhibitor (flu-
oxetine)withaselectivenorepinephrinereuptakeinhib-
itor (nisoxetine). When injected alone these specific re-
uptake inhibitors do not replicate the reduction of food
intake produced by sibutramine (Jackson et al., 1997).
Sibutramine treatment of experimental animals in-
creased the activity of the sympathetic nervous system
andattenuatedtheriseinNPYandfallinPOMCinthe
arcuatenucleusinenergy-restrictedratsindicatingthat
this drug influences both monoamine and peptidergic
pathways involved in food intake (Levin and Dunn-
Meynell, 2000).
b. Long-term studies. Sibutramine has been ap-
proved by the U.S. Food and Drug Administration for FIG. 5. Six-month randomized, placebo-controlled dose-ranging trial
withsibutramineatsixdosesandplacebo.ReproducedfromBrayetal.
long-term use in the treatment of overweight patients. (1999)withpermission.