advances in the science, treatment, and prevention of the ... · the medical costs of obesity in...

Advances in the ScienceTreatment and Prevention of theDisease of Obesity Ref lectionsFrom a Diabetes Care EditorsrsquoExpert ForumDiabetes Care 2015381567ndash1582 | DOI 102337dc15-1081

As obesity rates increase so too do the risks of type 2 diabetes cardiovasculardisease and numerous other detrimental conditions The prevalence of obesity inUS adults more than doubled between 1980 and 2010 from 150 to 361Although this trend may be leveling off obesity and its individual societal andeconomic costs remain of grave concern In June 2014 a Diabetes Care EditorsrsquoExpert Forum convened to review the state of obesity research and discuss thelatest prevention initiatives and behavioral medical and surgical therapies Thisarticle an outgrowth of the forum offers an expansive view of the obesity epi-demic beginning with a discussion of its root causes Recent insights into thegenetic and physiological factors that influence body weight are reviewed asare the pathophysiology of obesity-relatedmetabolic dysfunction and the conceptofmetabolically healthy obesity The authors address the crucial question of howmuch weight loss is necessary to yield meaningful benefits They describe thechallenges of behavioral modification and predictors of its success The effectsof diabetes pharmacotherapies on body weight are reviewed including poten-tial weight-neutral combination therapies The authors also summarize theevidence for safety and efficacy of pharmacotherapeutic and surgical obesitytreatments The article concludes with an impassioned call for researchersclinicians governmental agencies health policymakers and health-related in-dustries to collectively embrace the urgent mandate to improve prevention andtreatment and for society at large to acknowledge and manage obesity as aserious disease

Obesity is a crucial public health concern given its contribution to the risk of di-abetes cardiovascular disease (CVD) and other comorbidities The prevalence ofobesity (BMI $300 kgm2) in US adults more than doubled between 1980 and2010 from 150 to 361 (12) More than two-thirds (687) of all American adultsare overweight or obese (BMI $250 kgm2) (1) Although recent data suggest aleveling off in this trend persistently high obesity rates remain of grave concern (3)Obesity rates are now also climbing in developing countries worldwide obesity hasnearly doubled since 1980 affecting 500 million adults (4)As obesity rates increase so too do the risks of type 2 diabetes CVD hyperten-

sion arthritis cognitive impairment and some cancers (5) In the US diagnoseddiabetes increased from 78 million in 1993 to 21 million in 20128 million peopleremain undiagnosed and an estimated 86 million adults have prediabetes (67)

1Pennington Biomedical Research Center Louisi-ana State University Baton Rouge LA2Newcastle University Newcastle upon TyneUK3Department of Nutrition Sciences University ofAlabama at Birmingham and Birmingham Veter-ans Affairs Medical Center Birmingham AL4Center for Human Nutrition Washington Uni-versity School of Medicine St Louis MO5Obesity Research Center Department of Medi-cine Columbia University New York NY6Departments of Nutrition and EpidemiologyHarvard TH Chan School of Public Health Bos-ton MA7Department of Internal Medicine DiabetesUnit Hadassah Hebrew University HospitalJerusalem Israel8Department of Endocrinology Diabetology andMetabolismAntwerpUniversityHospital AntwerpBelgium9Department of Surgery Oregon Health and Sci-ence University Portland OR

Corresponding authorWilliamT Cefalu williamcefalupbrcedu

copy 2015 by the American Diabetes AssociationReaders may use this article as long as the workis properly cited the use is educational and notfor profit and the work is not altered

William T Cefalu1 George A Bray1

Philip D Home2 W Timothy Garvey3

Samuel Klein4 F Xavier Pi-Sunyer5

Frank B Hu6 Itamar Raz7 Luc Van Gaal8

Bruce M Wolfe9 and Donna H Ryan1

Diabetes Care Volume 38 August 2015 1567

DIABETES

CAREEX

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TFO

RUM

Population-based studies have suggestedthat 75 of hypertension is attribut-able to obesity (8) and approximatelyone-third of cancer deaths are linkedto poor nutrition excess weight andsedentary lifestyle (9) Worldwide44 of the diabetes burden 23 of is-chemic heart disease and 7ndash41 ofcertain cancers are attributable to ex-cess weight (4) Obesity also decreasesboth health-related quality of life (10)and life expectancy (11)The medical costs of obesity in the

US were estimated at $190 billion in2012 (12) A recent systematic reviewfound that worldwide obesity-relatedmedical costs accounted for 07ndash28of a countryrsquos total health care expendi-ture and that people with obesity hadmedical costs 30 higher than theirnormal-weight peers (13)With these alarming statistics in

mind a Diabetes Care Editorsrsquo ExpertForum convened in June 2014 to reviewthe state of obesity research and discussprevention and treatment initiativesThis article summarizes the proceedingsof that forum

OBESITY IN CONTEXT

What explains the sharp uptick in obe-sity rates that occurred after 1980Hindsight suggests that a combinationof technological advances certain agri-cultural and economic policies and a de-cline in physical activity all contributedIn the 1970s the US enacted agricul-tural subsidies aimed at lowering foodprices by encouraging increased produc-tion of crops such as corn and soybeansSuch subsidies in concert with large-scaleindustrialized farming practices resultedin an overabundance of inexpensive foodIn addition to lowering the price of grainssubsidies reduced the cost of meat (fromlivestock fed on less expensive crops) andallowed the food manufacturing industryto produce a wide range of inexpensiveand convenientdbut also energy-denseand nutrient-poordproducts (14)It has been suggested that chronic ex-

posure to easily obtainable highly palat-able foods can cause the hedonic orreward-based neuronal pathway tooverride the homeostatic pathway thatordinarily controls energy balance (15)Average daily calorie consumption inthe US increased by 245 or530 cal-ories between 1970 and 2000 (Fig 1)(16) Meanwhile as dietary intake was

observed to increase both occupationaland leisure-time energy expendituresdeclined (1718) Similar patterns havebecome apparent elsewhere in theworld (19)

The complex issues of grain overpro-duction fruit and vegetable underavail-ability detrimental food processing andmarketing practices and consumerknowledge deficits are beyond thescope of this article but have been elo-quently elucidated elsewhere (520)

Much Learned More Still to LearnIn recent decades there has been animpressive expansion in our knowl-edge base regarding obesity We havelearned that the genetic componentsof obesity are key contributors to indi-vidual risk Studies involving familiestwins and adoption have shown thatadiposity is highly heritable (21)Genome-wide association studies havedemonstrated that numerous genesare associated with weight gain (22)and that the presence of risk allelesfor multiple small-effect genes can re-sult in marked cumulative effects onBMI (23) Genetics can also informthe selection of obesity interventionsone example is the Preventing Over-weight Using Novel Dietary Strategies(POUNDS LOST) trial (24) in which car-riers of the FTO variant risk allele lostweight more successfully on a high-protein than on a low-protein diet Epi-genetic factors can modify weight gainand aid in identifying individuals athigher risk for obesity (2526) In addi-tion social factors appear to influenceits occurrence (27)

The physiological milieu promotingobesity involves complex and interrelatedmetabolic factors Once considered sim-ple storage depots for body energy adi-pocytes are now recognized as active

endocrine cells that have many roles in-cluding the regulation of metabolism en-ergy intake and fat storage (2829) Smalladipocytes found in normal-weight indi-viduals release adipokines that do not up-set metabolic homeostasis whereasenlarged adipocytes found in peoplewith obesity release adipokines in largeramounts which can promote inflamma-tion and insulin resistance More than 50adipokines have been identified perhapsthe best known of which are leptin andadiponectin (29)

Research is similarly elucidating theneural pathways involved in regulatingfood intake and energy control and theways in which genetic and early environ-mental factors can modulate the func-tioning of these pathways (30) Guthormones such as ghrelin cholecystoki-nin peptide YY and glucagon-like peptide1 (GLP-1) appear to have key roles Addi-tionally insulin resistance inflammationand the gut microbiome all affect weight(3132)

OBESITY-RELATED METABOLICDYSFUNCTION

Obesity is associated with a constella-tion of metabolic abnormalities includ-ing insulin resistance b-cell failureatherogenic dyslipidemia (ie high tri-glycerides low HDL cholesterol and in-creased small dense LDL particles) andnonalcoholic fatty liver disease (NAFLD)However not all people with obesity ex-hibit these abnormalities and ametabol-ically healthy obese (MHO) phenotype(ie BMI$300 kgm2 with normal fast-ing blood glucose insulin sensitivity lipidprofile and intrahepatic triglyceride[IHTG] content levels) has been de-scribed (33)

The MHO phenotype is more commonin younger than in older people and oc-curs more often in women than in menThe proportion of the population withobesity considered to be MHO dependson the criteria used to define ldquometaboli-cally healthyrdquoOne study that applied fiveexisting definitions of MHO to the samegroup of adults found prevalence ratesranging from 68 to 366 (34) whereasdata from the 1999ndash2004National Healthand Nutrition Examination Surveys (35)which defined metabolic health as thepresence of no more than one compo-nent of the metabolic syndrome foundthat 292 of men and 354 of womenwith obesity were metabolically healthy

Figure 1mdashFood available for consumption1900ndash2000 Reprinted from ref 16

1568 Update on Obesity Treatment and Prevention Diabetes Care Volume 38 August 2015

The most clinically relevant questionhowever is whether there is somethinginherently different and protective inMHO individuals or whether givenmore time or additional weight gain theirmetabolic function will deteriorate intometabolically unhealthy obesity (MUO)(36) Accumulating evidence suggeststhat the MHO phenotype represents adistinct subset of the obese populationand that people identified as MHO whileat higher risk for future diabetes andheart disease than their lean metaboli-cally normal counterparts have lowerrisks than both people with obesity andlean people who aremetabolically abnor-mal (37ndash41) Other studies have also sup-ported the concept that individuals withthe MHO phenotype are more resistantto the adverse metabolic effects of mod-erate weight gain (42)Several organs including the liver ad-

ipose tissue skeletal muscle and intes-tine are involved in the pathophysiologyand pathogenesis of obesity-relatedmetabolic dysfunction (Fig 2) For ex-ample the liver is an important markerof metabolic health and an increase inIHTG content is associated with multi-organ metabolic dysfunction Triglycer-ides accumulate in hepatocytes if theirrate of production (from fatty acids de-livered from plasma or produced denovo) exceeds their rate of removal(via triglyceride lipolysis and fatty acidoxidation or secretion as VLDL par-ticles) IHTG content is negatively cor-related with insulin sensitivity in the

liver (ability to suppress glucose pro-duction) skeletal muscle (ability tostimulate glucose uptake) and adiposetissue (ability to suppress lipolysis) (43)People with NAFLD also have an in-crease in hepatic de novo lipogenesis(44) and in VLDL-triglyceride secretionrate compared with people with obesityand normal IHTG content (45)

Adipose tissue is also a key organ inthe development of metabolic dysfunc-tion Excessive circulating fatty acidsreleased from lipolysis of subcutaneousand visceral adipose tissue triglycer-ides can cause hepatic and skeletalmuscle insulin resistance (4647) Com-pared with MHO individuals peoplewithMUO exhibit alterations in adiposetissue metabolic and immune functionincluding decreased expression of adi-pose tissue genes involved in fatty acidand glucose metabolism (48ndash51) in-creased collagen production (52) andincreased markers of adipose tissue in-flammation (53)

Recently data from both preclinicaland clinical studies have shown that in-testinal microbiota are another poten-tially important regulator of metabolichealth (54) People with insulin resis-tance and impaired glucose controlhave decreased microbial diversity(55) and transferring microbiota frommetabolically healthy or metabolicallyunhealthy donors can transfer the do-norrsquos metabolic phenotype to the recipi-ent (56) Finally the brain also modulatesperipheral metabolism (57)

HOW MUCH WEIGHT LOSS ISENOUGHAlthough no current therapeutic ap-proaches offer an obesity cure losingweight significantly ameliorates obesity-associated morbidity and reduces its re-lated costs Even without reaching a BMIin the normal range (250 kgm2) peo-ple with obesity can accrue meaningfulhealth benefits from weight loss (58) Onthe basis of evidence available at the timethe 1998 National Heart Lung and BloodInstitute (NHLBI) obesity guidelines de-fined an initial goal of weight-loss therapyas 10 of body weight (59) More re-cent guidelines (60) noted that ldquoalthoughsustainedweight loss of as little as 3ndash5of body weight may lead to clinicallymeaningful reductions in some cardiovas-cular risk factors larger weight losses pro-duce greater benefitsrdquo and set an initialgoal of 5ndash10 In addition to links be-tween obesity and cardiovascular risk ex-cess weight may play an independent rolein the development of microvascular dis-eases including kidney disease (microal-buminuria) (61) and retinopathy (62)

Although the precise ldquodose-responserdquorelationships between weight loss andobesity-related complications vary prog-ress has been made in this area (Table 1)(63ndash80) If the objective of weight-losstherapy is to derive health benefits asso-ciated with the amelioration of complica-tions then the weight-loss goal should beestablished based on this evidence

Intuitively in improving metabolic riskfactors weight loss should also have apositive impact on mortality Howeverthis has been more difficult to show inpart because the extent and nature ofthe excess weight-mortality associationremains a matter of debate (58) Somestudies have suggested that this rela-tionship resembles a U- or J-shapedcurve with its lowest point at a BMI of23 kgm2 after taking into accountconfounding by smoking and reversecausation (ie low BMI caused by pre-existing or subclinical chronic diseases)(8182) Obesity has been found tolower life expectancy (1183) and CVDhas been identified as the major causeof excess mortality among people withobesity (8485)

Conversely studies in overweightindividuals (BMI 250 to 300 kgm2)have found little or no increasedmortal-ity risk and some have shown re-duced mortality rates compared with

Figure 2mdashPutative factors involved in the pathogenesis and pathophysiology of metabolicdysfunction associated with obesity CHO carbohydrate ChREBP carbohydrate response ele-mentndashbinding protein FAS fatty acid synthase FFA free fatty acid Glut 4 glucose transporter4 PPARg peroxisome proliferatorndashactivated receptor g TG triglyceride

carediabetesjournalsorg Cefalu and Associates 1569

normal-weight individuals (8586) How-ever interpretation of this phenomenonis complicated by methodological prob-lems in BMI-mortality analysis especiallywith regard to reverse causation and theuse of a broad BMI category as the refer-ence group (87) In addition it seemslikely that improved detection and treat-ment of conditions such as diabetes hy-pertension dyslipidemia and sleepapnea have blunted the relative risk ofobesity-related mortality over timeA 2013 meta-analysis of 97 studies (88)found that relative to individuals of nor-mal weight there was no increased mor-tality risk even in individuals with grade1 obesity (BMI 300 to 350 kgm2 HR095 [95CI 088ndash101]) although individ-uals with obesity grades 2 and 3 combined(BMI$350 kgm2) did have a significantlyhigher mortality rate (HR 129 [95CI 118ndash141]) Because this meta-analysiswas based on published literature withoutanalyzing individual-level data it could notfully address confounding by smokingbehavior or the problem of reverse causa-tion (89)To date bariatric surgery has most

effectively demonstrated a reductionin mortality (90) Analysis of long-termfollow-up data from the Swedish ObeseSubjects (SOS) study found that bariatricsurgery reduced cardiovascular deaths

and first-time (fatal and nonfatal) car-diovascular events after a mean follow-up of 147 years (91)

Until recently nonsurgical lifestyle in-terventions have failed to show a signifi-cant reduction in cardiovascular eventseven after one to two decades of follow-up (9293) However the latest reportfrom the Da Qing Diabetes PreventionStudy of adults with impaired glucose tol-erance demonstrated a reduction in CVDmortality mainly in women that beganto emerge after 12 years but did not be-come statistically significant until 23 yearsafter the initial 6-year intervention (94)The ongoing Action for Health in Diabetes(Look AHEAD) lifestyle intervention studyhas reported no significant reductions incardiovascular morbidity and mortalityover nearly 10 years in people with type2 diabetes who are overweight or obeseand who lost an average 6 of theirbaseline body weight (95) For nowthe questions of whether and howmuch weight loss will reduce mortalityremain unanswered

LIFESTYLE INTERVENTION ANDBEHAVIORAL MODIFICATION

Lifestyle interventions emphasizing re-duced caloric intake and increased phys-ical activity and incorporating behavioralmodification techniques are considered

first-line therapy for overweight and obe-sity (60) Because obesity arises fromcomplex interactions between geneticsand environmental factors such inter-ventionsmust focus not solely on the eat-ing and exercise habits of people withobesity but rather on those habits in thecontext of the environment in which peo-ple live Thus lifestyle interventions mustbe tailored to the needs preferences andcircumstances of individuals and adaptedto the settings and populations in whichthey are provided (96)

Two lifestyle intervention studiesdtheDiabetes Prevention Program (DPP) (97)and Look AHEAD (9899)dhave yieldedthe most valuable information on thepotential of such interventions to bringabout significant long-term weightreduction In the DPP 3234 adultswith glucose tolerance test results in-dicative of prediabetes and a mean BMIof 34 kgm2 were randomly assigned toplacebo metformin therapy or a life-style intervention with the goal ofachieving a weight loss $7 of initialbody weight After a mean follow-up of28 years weight loss in the lifestylegroup averaged 55 and the incidenceof diabetes was reduced by 58 in thelifestyle group and 31 in the metfor-min group compared with placebo (97)Look AHEAD was designed to assess the

Table 1mdashEvidence regarding therapeutic weight loss for complications of obesity

Obesity complicationWeight loss required fortherapeutic benefit () Notes References

Diabetes (prevention) 3ndash10 Maximum benefit at 10 DPP Research Group 2009 (63)Garvey et al 2014 (64)

Hypertension 5 to 15 Blood pressure still decreasingat 15

Wing et al 2011 (65)

Dyslipidemia 3 to 15 Triglycerides still decreasing at 15 Wing et al 2011 (65)

Hyperglycemia (elevated A1C) 3 to 15 A1C still decreasing at 15 Wing et al 2011 (65)

NAFLD 10 Improves steatosis inflammation andmild fibrosis

Assy et al 2007 (66)Dixon et al 2004 (67)Patel et al 2009 (68)

Sleep apnea 10 Little benefit at 5 Foster et al 2009 (69)Winslow et al 2012 (70)

Osteoarthritis 5ndash10 Improves symptoms and joint stressmechanics

Christensen et al 2007 (71)Felson et al 1992 (72)Aaboe et al 2011 (73)

Stress incontinence 5ndash10 Burgio et al 2007 (74)Subak et al 2009 (75)

Gastroesophageal reflex disease 5ndash10 in women 10 in men Singh et al 2013 (76)Tutuian 2011 (77)

Polycystic ovary syndrome 5ndash15 (10 optimal) Lowers androgens improves ovulationand increases insulin sensitivity

Panidis et al 2008 (78)Norman et al 2002 (79)Moran et al 2013 (80)


long-term effects on cardiovascularmorbidity and mortality of an intensiveweight-loss program delivered over4 years to adults with type 2 diabeteswho were overweight or obese Thestudy included 5145 participants as-signed to either usual care (diabetessupport and education) or the interven-tion which aimed at reducing bodyweight by$10 (98) This interventionwas found to have no significant effecton CVD mortality but did improve someCVD risk factors after a mean follow-upof 96 years and reduced mean weightby $8 by year 1 and 5 by year 8(99100)

Highly Variable SuccessParticipants in the DPP and Look AHEADhad similar rates of initial success In theDPP 49 of intervention participantsmet their weight-loss goal and 74met their physical activity goal byweek 24 37 and 67 respectivelymet these goals by the final interven-tion visit (101) After 1 year in theLook AHEAD intervention 378 of par-ticipants met their individual weight-loss goal ($10 of initial weight) and552 met the group average goal($7) (100)Although these average losses may

seem modest it is important to remem-ber that success rates with lifestyle in-tervention are highly variable and asignificant proportion of individualsachieve success far exceeding themean results Figure 3 which showsweight changes after 1 year for a seriesof 245 participants in the New York Obe-sity Nutrition Research Center (NYORC)weight-loss program illustrates thispoint Although 94 of these individualsexperienced weight gain the remainderlost weight withmore than one-third los-ing 10 and several losing 25 oftheir initial body weight

Real-World ChallengesMost intensive lifestyle programs (egthe DPP and Look AHEAD) have beencarried out with highly structured inter-ventions employing protocols that maybe difficult to implement in real-worldsettings (9798102103) Despite thepotential difficulties in replicating suchprograms numerous promising effortsare underway to implement DPP-styleinterventions in creative and cost-effectiveways in communities across the US(104105)

Predictors of Long-term SuccessIn general lifestyle interventions appearto be moderately successful in inducinginitial weight loss however weight re-gain often begins to occur after 6months as noted in both the DPP andLook AHEAD (99106)

In the DPP the likelihood of meetingweight- loss and activity goals in-creased with participantsrsquo age (101)even after 10 years of follow-up par-ticipants who were 45 years of age atrandomization had less sustainedweight loss than those $45 years ofage (63) Those who performed moredietary self-monitoring and those whomet the activity goal were more likelyto meet their weight-loss goal Impor-tantly initial success atweek24predictedlonger-term success at 32 years withthose achieving initial goals 15ndash3 timesmore likely to achieve the longer-termgoals (101)

In Look AHEAD lifestyle participantswho lost $5 or $10 of body weightby year 1 were more likely to have thesesame losses by year 4 Those whomaintained a loss of $10 for 4 yearsattended more treatment sessions andreported getting more physical activityand consuming fewer calories thanthose who did not As in the DPP olderparticipants lost significantlymoreweightthan younger participants throughout thestudy (107)

The ongoing National Weight ControlRegistry has yielded additional importantinsights into the factors that contribute tosuccessful long-term weight manage-ment Registry participants who have

maintained an intentional weight lossof $30 lb for an average of 57 yearsreport regularly self-monitoring includ-ing recording their food intake andweighing themselves at least onceweekly eating a low-calorie low-fatdiet (1300ndash1400 kcalday with 25of calories from fat) eating breakfastdaily maintaining a consistent eatingpattern across weekdays and weekendsand engaging in high levels of physicalactivity (expending 2500 kcalweekfor women and 3200 kcalweek formen) Successful weight-loss main-tainers also report continuing to ad-here to the diet and exercise strategiesthey employed to lose weight havinglow levels of depression and dietarydisinhibition and having had a medicaltrigger for their initial weight loss(108)

Of these factors a high level of phys-ical activity appears to be particularlyimportant A study by Jakicic et al(109) demonstrated a dose-responserelationship between the amount of exer-cise performed per week and long-termweight loss and maintenance in over-weight adult women Individuals whoexercised $200 minweek had greater18-month weight losses than thosewho were active either 150 or 151ndash199 minweek (ndash131 ndash35 and ndash85 kgrespectively)

Nonresponders The Importance ofEarly IdentificationAlthough quite a bit is known about suc-cessful weight losers less is known aboutthose who fail to respond to lifestyle

Figure 3mdashPercentage of weight change by subject (n = 245) at week 52 of the NYORCweight-lossprogram Courtesy of RichardWeilMEd CDE (Columbia University New York NY) Betty KovacsMS RD (Columbia University New York NY) and FXP-S


interventions In the NYORC program forexample some participants not onlyfailed to lose weight but actually gainedweight over 1 year even though theywere highly invested in the programhad paid to participate regularly at-tended sessions and contributed ac-tively One can only surmise that somecombination of genetic and environmen-tal determinants is responsible for mak-ing weight loss more difficult for somepeople than for others Until such factorsare better understood the finding thatearly success predicts long-term successbecomes even more important individu-als who fail lifestyle intervention early onmay be better served by pursuing alter-natives such as pharmacotherapy or bari-atric surgery than by continuing in abehavioral program in which they maybe destined to fail

DIABETES PHARMACOTHERAPIESWEIGHT CONSIDERATIONS

Associations between improved glyce-mic control and weight gain with tradi-tional pharmacotherapies such asinsulin sulfonylureas and thiazolidine-diones are well documented (110ndash112)Weight gain is of less concern with mod-ern analog insulin formulations as seenin the Outcome Reduction With InitialGlargine Intervention (ORIGIN) trial(113) Weight gain with thiazolidine-diones appears to be continuous andmostly subcutaneous whereas thatwith sulfonylureas is central and oc-curs mostly in the first year (112)Numerous factors have been found to

predict weight responses to traditionaldiabetes pharmacotherapies In the Ac-tion in Diabetes and Vascular DiseasePreterax and Diamicron MR ControlledEvaluation (ADVANCE) trial (114) olderage female sex and current smoker sta-tus predictedweight loss whereas higherA1C levelsmore oral medications Cauca-sian ethnicity and to a lesser extent lon-ger diabetes duration and higher systolicblood pressure were associated withweight gain The noninterventional Car-diovascular Risk Evaluation in PeopleWith Type 2 Diabetes on Insulin Therapy(CREDIT) study (115) of insulin startedin routine care identified higher base-line A1C higher insulin requirementsand lower baseline BMI as independentpredictors of insulin-associated weightgain These findings suggest that therapy-related weight gain may be attenuated

by starting insulin earlier before pa-tients have a very poor A1C and havelost significant weight through poorglycemic control

Weight-Adding Effects of OtherCommon MedicationsSome nonndashglucose-lowering medica-tions commonly prescribed to peoplewith diabetes have been linked toweight gain including hormones suchas corticosteroids (116) drugs affectingenergy metabolism such as b-blockers(117) and antiepileptic medicationsthat are more often used for diabeticneuropathy (eg gabapentin andpregabalin) (118) second-generationantipsychotics (119) and protease in-hibitors (120)

Weight-Neutral or Weight-LoweringEffects of Newer Glucose-LoweringMedicationsMetformin is the most widely usedfirst-line agent for type 2 diabetes andis generally described as weight neu-tral Dipeptidyl peptidase 4 (DPP-4) in-hibitors which enhance circulatingGLP-1 and glucose-dependent insulino-tropic polypeptide and thereby regu-late insulin and glucagon secretionhave demonstrated weight neutrality(121ndash124) GLP-1 receptor agonistswhich additionally slow gastric empty-ing and decrease appetite cause mod-erate to significant weight loss whilereducing glycemia (125ndash127) Sodiumndash

glucose cotransporter 2 (SGLT2) inhibi-tors which block glucose reabsorptionin the kidney improve glycemic controland result in moderate weight loss withreductions in visceral and subcutaneousadipose tissue (22128129)

Potentially Weight-NeutralCombination TherapiesGiven the differing weight effects of ex-isting glucose-lowering pharmacothera-pies consideration of combinationtherapies appears warranted One suchcombination involves a GLP-1 receptoragonist and long-acting insulin This hasbeen tested in insulin-naive people whoare starting basal insulin and in peoplealready on basal insul in therapyadding a GLP-1 receptor agonist insteadof mealtime insulin (130ndash133) Resultsinclude amelioration of weight gain orweight loss with improved glycemic con-trol and reduction in the incidence ofhypoglycemia compared with insulin

alone Although continuing metforminwith all other agents is standard othercombination strategies involving incretin-based therapies and SGLT2 inhibitorsmight help to overcome compensatoryeating and other mechanisms that appearto limit the weight-loss potential of indi-vidual drug classes while further improv-ing glycemic control (124134)

OBESITY PHARMACOTHERAPIESTROUBLED PAST PROMISINGFUTURE

Although the history of obesity pharma-cotherapy has been fraught with set-backs several viable agents are nowavailable and expanding clinical experi-ence is beginning to elucidate their mostefficacious use (135) From the 1940sthrough the 1980s pharmacological op-tions for obesity were limited to phen-termine and other appetite-suppressingsympathomimetics approved only forshort-term use because of concernsabout potential abuse Later other cen-trally acting agents were marketed in theUSdthe amphetamine serotonergic-like drugs fenfluramine (1972) anddexfenfluramine (1996) and the serotonin-norepinephrine reuptake inhibitor si-butramine (1997) However the firsttwo of these (often used in the combina-tion known as ldquofen-phenrdquo) were with-drawn because of suspected heartvalve damage and the third because ofincreased risk of cardiovascular events(136137) Likewise rimonabant a canna-binoid receptor antagonist was intro-duced in Europe in 2006 but laterwithdrawn because of links to severemood disorders (138) Introduced in1999 orlistat a gastrointestinal (GI) li-pase inhibitor was until recently theonly obesity medication approved forlong-term use in the US (139) Howeverfour newer agents have since becomeavailable 1) phenterminetopiramate ex-tended release (ER) combining a sympa-thomimetic and an anticonvulsant in2012 2) the 5-HT2c serotonin receptor ag-onist lorcaserin in 2012 3) naltrexonebupropion ER combining a dopaminenoradrenaline reuptake inhibitor and anopioid receptor antagonist in 2014 and4) a high-dose (3-mg) preparation of theGLP-1 receptor agonist liraglutide in 2015(140ndash143)

Although concerns about the safetyof weight-loss medications remain therationale for their use in appropriate


candidates is sound When used as anadjunct to lifestyle intervention theseagents can help people who are strug-gling to achieve health benefits throughweight loss by enhancing their abilityto comply with a reduced-calorie dietNumerous studies have shown thatadding a weight-loss medication canyield greater weight loss than lifestyleintervention alone and allows peopleto sustain any loss for a longer periodof time (144ndash154)

Recommendations for UseSeveral principles guide the incorpora-tion of weight-loss medications intothe management of obesity Impor-tantly current guidelines advise theiruse only for people with health risksand not merely for cosmetic reasons(6155) In addition prescribing infor-mation for phenterminetopiramateER lorcaserin and naltrexonebupropionER calls for discontinuation after 12weeks if weight loss is5 on the max-imal dose (156ndash158) liraglutide 3 mgshould be discontinued if weight lossis 4 after 16 weeks (159) Obesitymedications have some degree of pri-mary failure but the availability of mul-tiple options means that should onedrug fail to yield significant weightloss another drug can be tried Finallyobesity should be considered a life-longdisease requiring long-term treatmentand follow-up

Evidence for EfficacyHead-to-head trials comparing the effi-cacy of obesity medications have notbeen published However one can pre-dict relative effectiveness by comparingthe placebo-subtracted weight lossesresulting from their use in separatestudies In the study design of these clin-ical trials all patients were placed onlifestyle interventions and then random-ized to placebo versus weight-loss med-ication Because the intensity of thelifestyle intervention was variableplacebo-subtracted weight loss can beused to compare weight loss attribut-able to the medications alone Figure 4shows such a comparison of intention-to-treat data usually after 1 year on themaximum dose (144ndash154160ndash162) Inthis analysis phenterminetopiramateappears most efficacious with a placebo-subtracted loss of 9 followed bynaltrexonebupropion (6) liraglutide(6) lorcaserin (4) and orlistat

(3ndash5) As with other chronic diseaseswhen medications are discontinued theeffect of medication on weight loss is notsustained when the medication is discon-tinued patients generally regain weightto a level determined by the intensity ofthe lifestyle intervention upon cessationof the medication Still each of thesepharmacological options has the poten-tial to achieve enough weight loss tohave therapeutic benefit on at leastsome of the associated complicationslisted in Table 1

The effects of these medications inprediabetes and diabetesdarguablythe most common and troublesomeobesity complicationsdprovide fur-ther support for their use In a recentphenterminetopiramate ER study inpeople with prediabetes (64) drug-assistedweight loss reduced the incidenceof progression to type 2 diabetes over108weeks by 79comparedwith placebo

Efficacy data are also strong in peoplewho already have diabetes Table 2 sum-marizes data from various studies on theeffects ofweight-loss drugs versus placeboon weight A1C and the need for oralglucose-lowering agents (150163ndash167)For all drug-assisted weight loss yieldsbetter glycemic control while reducingthenumber anddosesof glucose-loweringmedications and generally lowering bloodpressure and improving lipids This sug-gests that weight-loss therapy should beconsidered in any newly diagnosed personwith type 2 diabetes or whenever intensi-fication of therapy is indicated to achieveA1C targets as an adjunct or alternative tothe addition of a conventional glucose-lowering agent

Unanswered QuestionsThemost pressing unanswered questionwith regard to obesity pharmacothera-pies is howwell they perform in the longterm For the newest medications weonly have 2-year data More must belearned about the optimal managementof obesity over a lifetime and whethercombination therapy may be a viableoption Clarification is needed on theefficacy of weight loss as a primary in-tervention for specific complicationsand the dose-response relationships be-tween weight loss and meaningful im-provements in those complicationsBecause obesity medications are ad-junctive to lifestyle intervention wemust also refine our understanding ofbest practices for such interventionsThis will give people with obesity healthcare providers and third-party payers aclearer idea of what can be expectedfrom lifestyle programs We also lackdata and experience regarding lifestyleand pharmacological intervention in therapidly growing population of elderlypeople with obesity Answers to thesequestions will be needed to build ahealth-economic case for the medicaltreatment of obesity

Finally there remain numerous head-winds against the widespread uptake ofavailable weight-lossmedications Peoplewith obesity face the prevailing attitudethat their condition is a lifestyle choicerather than a disease This attitude per-vades not only the general public but alsothe health care professions in part be-cause of the lack of obesity training inmedical schools and other health care ac-ademic programs In addition the history

Figure 4mdashComparative efficacy of weight-loss medications All data are placebo-subtractedmaximal dose 1-year results in intention-to-treat populations using last-observation-carried-forward method unless otherwise indicated (144ndash154160ndash162)


of failed obesity drugs has left many pa-tients and providers reluctant to initiateeven newer therapies The need for life-style intervention also makes adoption ofthese therapies less appealing both toprimary care providers who often haveno local intervention programs availableand to patients who may have to absorbthe time and financial costs of participat-ing in these programs Insurance cover-age for obesity medications and lifestyleinterventions continues to be problem-atic In addition health care providersand their patientswith obesitywhooftenare already taking multiple medicationsmay be reluctant to add to existing out-of-pocket costs and psychological ldquotabletburdenrdquo with yet another prescriptionOne final key factor hindering the ac-

ceptance of obesity drugs is the lack of awidely accepted medically meaningfulactionable diagnosis of obesity Towardthis end an American Association of Clin-ical Endocrinologists (AACE) consensusdevelopment panel on obesity recentlyproposed an advanced framework for anew diagnosis of obesity as a chronic dis-ease (168169) This proposed strategyoffers a guide to diagnosis based onboth an anthropometric measure of adi-posity (BMI) and a clinical componentthat indicates the degree to which excessadiposity is adversely affecting the pa-tientrsquos health (presence and severity ofweight-related complications)

BARIATRIC SURGERY OPTIONSAND OUTCOMES

The rationale for bariatric surgery isstraightforward it is for now the most

effective means of producing short- andlong-term weight losses of$15 and assuch has themost successful track recordin inducing remission in comorbiditiesand improving survival rates quality oflife and social functioning (170) How-ever surgery is invasive carries risk andinitial cost and is currently reserved forpeople with severe obesity who havefailed to respond adequately to all otheravailable treatments A 1991 National In-stitutes of Health consensus conferencerecommended criteria for selection ofsurgical candidates that included age18ndash65 years BMI 400 kgm2 or350 kgm2with obesity-related comor-bidity understanding of the lifelong con-sequences of surgery abstinence fromdrugs and alcohol and agreement tolong-term follow-up (171) These criteriahave persisted with some modificationsincluding their expansion to younger andolder people and inclusion of some pa-tients with a BMI 350 kgm2 particu-larly those with type 2 diabetes (60)

The four most common bariatric pro-cedures are shown in Fig 5 and havebeen described in detail elsewhere(170) All are now routinely performedlaparoscopically Adjustable gastricbanding (AGB) is the simplest procedureand restricts intake by producing a verysmall gastric pouch above a band Itsprimary benefits include low periopera-tive risk and adjustability which enablesboth individual alteration of band tight-ness and reversibility (172) The Roux-en-Y gastric bypass (RYGB) produces apouch similar in size to that of AGBand adds bypass of the stomach

duodenum and proximal jejunumThis causes cessation of nutrient expo-sure to the mucosa of the bypassed up-per GI tract resulting in rapid entry ofnutrients into the jejunum and a distalshifting of the site of digestion and nu-trient absorption Themechanism of ac-tion of RYGB is complex involvingmultiple changes in gut hormone secre-tion and signaling including a reductionin the release of ghrelin a hormone thatstimulates appetite and increased foodintake malabsorption of ingested energy-containing macronutrients may not be afactor (170) The vertical sleeve gastrec-tomy (VSG) reduces the size of the stom-ach by85 and results in a reduction inghrelin release (173) Its mechanism of ac-tion appears to involve altered GI gut hor-mone signaling as gastric emptyingincreases after this procedure VSG has be-come the most common bariatric surgicalprocedure in the US because of its sim-plicity and lower perioperative incidenceof complications compared with RYGB Fi-nally the biliopancreatic diversion withaduodenal switch (BPD-DS) is amore com-plex higher-risk procedure combiningboth restrictive (VSG) and malabsorptive(partial intestinal bypass) components(174) Although it may be superior toRYGB in long-termweight loss direct com-parative studies have been difficult toperform and its associated short- andlong-term complication rates have limitedits acceptance in clinical practice (170174)

Evidence for Efficacy TheLongitudinal Assessment of BariatricSurgery StudyOnly a few studies have reported out-comes for2 years after surgery Thosethat have were limited in generalizabil-ity had generally poor retention or in-cluded outdated procedures (175ndash180)To address this lack of long-term data inthe US the National Institute of Diabe-tes and Digestive and Kidney Diseases in

Table 2mdashEffects of weight-loss medications on glycemic control and the need fororal antidiabetes agents in people with type 2 diabetes

Orlistat(163)

Lorcaserin(149)

Phenterminetopiramate(164165)

Naltrexonebupropion

(166)Liraglutide3 mg (167)

Weight loss ()DrugPlacebo

62 45 96 50 6043 15 26 18 20

Initial A1C () 81 81 86 80 80

A1C change ()DrugPlacebo

203 209 216 206 +02 204 212 201

Patients reaching anA1C 7 ()

DrugPlacebo

504 53 44 69 263 40 26 27

Need for oralantidiabetes agents darr darr darr darr

Figure 5mdashBariatric surgical options Imagecourtesy of Walter Pories MD (East CarolinaUniversity Greenville NC)


2003 formed the Longitudinal Assess-ment of Bariatric Surgery (LABS) Consor-tium to carry out a coordinated bariatricsurgery research program (181) TheLABS initiative aimed to assess the risksand benefits of bariatric surgery andidentify predictors of optimal outcomesIt was divided into three phases LABS-1included all adults who had bariatricsurgery performed by a certified sur-geon at one of the six participating cen-ters and evaluated short-term safetyissues LABS-2 is ongoing and evaluatesthe longer-term safety and efficacy ofbariatric surgery and LABS-3 also ongo-ing focuses on the psychosocial aspectsof obesity quality of life and possiblemechanisms of surgery-induced diabe-tes remission (181)Because of its detailed protocols and

rigorous follow-up the LABS initiativeprovides high-quality evidence regard-ing the efficacy of bariatric surgery andits effects on diabetes and other compli-cations Three-year weight-loss resultsfrom LABS-2 (182) (n = 2458) showed amedian loss of 41 kg for RYGB corre-sponding to 315 of baseline weightFor AGB these figures were 20 kg and159 Although weight loss was fairlyuniform for 6 months five distinctweight-loss trajectories later became ap-parent for each procedure and continuedthrough 3 years This phenomenon is inkeeping with the highly variable weightloss reported with other treatments andemphasizes the importance of being ableto stratify possible candidates by factorsother than BMISeveral observational studies have re-

ported on weight loss $10 years afterbariatric surgery (176179183) AfterRYGB weight loss is rapid to a nadirexceeding a mean 30 by 18ndash24monthsLimited regain to a mean loss of30 isfollowed by relatively stable weight overseveral years Two randomized clinicaltrials have reported that weight loss afterVSG is similar to or somewhat less thanthat after RYGB and superior to that afterAGB (184185) Weight loss after BPD-DSmay be superior to that after RYGB al-though the benefit of slightly greaterweight loss with a greater risk for compli-cations is uncertainJust as weight loss from RYGB was

about twice that from AGB so toowere 3-year remission rates for obesitycomorbidities including diabetes hy-pertension and dyslipidemia (Table 3)

Likewise incidence rates of new comor-bidities were all lower after RYGB thanafter AGB (182)

The mechanisms explaining postsur-gical remission of diabetes are not fullyunderstood although it does not ap-pear to be caused by weight loss alonein most cases remission begins di-rectly after surgery and before signifi-cant weight loss has occurred (186)Instead this effect appears to be re-lated to the degree to which food is ex-cluded from the proximal gut (187188)Gastric bypass has been shown to in-duce remission even in people with di-abetes but not obesity (189) RecentLABS data for RYGB and AGB indicatethat the incidence of remission progres-sively increases with increasing weightloss (190) The remission rate afterRYGB was found to be superior to thatafter AGB after controlling for weightloss Thus both use of RYGB and pro-gressive weight loss are predictors of di-abetes remission

Safety EvidenceConcerns about the safety of bariatricsurgery have become more widespreadas these procedures have become morecommon However data from LABS-1suggest that bariatric surgery is muchsafer now than it was 8ndash10 years ago(191) Longer-term complications andpotential nutritional deficiencies associ-ated with bariatric surgery have beenrecently reviewed elsewhere (60)

As with other obesity treatment mo-dalities unresolved issues related to bari-atric surgery remain Foremost is theneed for improvedmethods of identifyingappropriate surgery candidates The abil-ity to identify candidates on the basis oftheir physiological and personal charac-teristics rather than BMI alone wouldimprove medical and quality-of-life out-comes by targeting surgical interventionto those most likely to accrue maximumbenefit (192) Better understanding isneeded of the variation in success ratesand of the specific relationships be-tween weight loss and changes in co-morbidities Strong evidence regardingpreoperative predictors of success isalso lacking

OBESITYMANAGEMENTGUIDELINES

Recent decades have brought improve-ments in all three therapeutic modalitiesfor obesity management lifestyle inter-ventions medications and bariatric

surgery The current challenge is to de-termine how best to use these toolsalone or in combination balancing effi-cacy safety and costs Toward that endseveral organizations have developedrecommendations to guide obesitytreatment Although all emphasize thehealth benefits of losing excess weightthese guidelines can be viewed as fallingalong a continuum from a more BMI-centric approach with a goal of losing agiven amount of weight to a complica-tions-centric model focused on preventingand treating complications (Fig 6) (160)

The BMI-centric approach is best illus-trated by the 1998 NHLBI guidelines(59) in which appropriate treatment isdefined by baseline BMI with patientshaving a BMI of 250ndash269 kgm2 receiv-ing dietary physical activity and behav-ior interventions and pharmacotherapyand surgery being added for those withprogressively higher BMIs Although thisapproach makes some allowances forcomorbidities it depends largely onBMI as the major determinant of appro-priate treatment

Two sets of guidelinesdone from TheObesity Society (TOS) the AmericanHeart Association (AHA) and the Amer-ican College of Cardiology (ACC) (60) andthe other from the American Society ofBariatric Physicians (ASBP) (193)dfall inthe middle of the continuum The TOSAHAACC guidelines call for treatmentfor anyone with a BMI $25 kgm2 butadvise that treatment of complicationsshould occur from the outset regardlessof patientsrsquo weight-loss efforts TheASBP obesity algorithm offers a hybridapproach that includes not only BMIpercentage of body fat and waist cir-cumference but also assessment of andtreatment goals aimed at amelioratingthe adverse health consequences of ex-cess body fat

Table 3mdashThree-year comorbidityresponses in LABS-2 (182)

Comorbidity RYGB () AGB ()

DiabetesRemissionIncidence

619 37109 32

HypertensionRemissionIncidence

382 174126 180

DyslipidemiaRemissionIncidence

619 27132 160


Finally there is the 2013 complications-centric approach developed by the AACE(155) In this model weight lossbecomes a therapeutic tool for the treat-ment of obesity-related complicationsto a large extent independent of thedegree of general adiposity or BMIThis approach targets more aggres-sive therapies to those who will derivethe greatest benefits from weightlossdnamely those with weight-related complicationsdthereby opti-mizing benefitrisk outcomes andcost-effectiveness (160)

TREATING OBESITY AS A DISEASEPOLICY IMPLICATIONS ANDFUTURE DIRECTIONS

The past half-century has seen muchprogress in scientific discovery relatedto obesity and to a lesser extent thetranslation of this into advancements inmanagement and prevention Still theobesity puzzle is far from complete Wehave a mandate to fill in the gaps in ourunderstanding of obesity and there issome urgency to this mission given thehigh individual and societal costs involvedSuccessfully managing and prevent-

ing obesity requires acknowledging obe-sity as a disease as opposed to viewingit as the result of poor personal choicesAdvances in our knowledge of homeo-static regulation of body weight factorsthat impose obesity risk biological re-sistance to weight loss in the presenceof excess body weight and the mecha-nisms by which excess weight drives

metabolic mechanical and other co-morbidities support a more modernview of people with obesity Fifty yearsago it was widely assumed that prevent-ing and reversing obesity would be amat-ter of education once individuals knewwhat to eat and how to be physically ac-tive they would lose weight and becured Clearly this is not the case

Although society as a whole does notyet universally acknowledge obesity as adisease progress has beenmade amongmedical societies and policymakersChief among the medical societies isthe American Medical Association whichpassed a resolution in 2013 recognizingobesity and overweight as a chronic med-ical condition (de facto disease state) andurgent public health problem (194) Theconcept was also endorsed in a joint po-sition statement of the medical profes-sional societies most concerned withcaring for patients with obesity (195)Obesity is also acknowledged as a chronicdisease by theWorld Health Organization(196) and the US Food and Drug Admin-istration (FDA) (197)

The clinical practice guidelines dis-cussed above will help to define bestpractices and an approach to obesitythat is both more unified and more per-sonalized to the needs of individual pa-tients In addition the American Boardof Obesity Medicine established in2011 now conducts annual credential-ing examinations for physicians seekingcertification of excellence in the practiceof obesity medicine (198)

Several recent health policy initiativesare also encouraging Among these are a2012 Centers for Medicare amp MedicaidServices decision to reimburse the costsof intensive behavioral intervention forobesity delivered by primary care pro-viders (199) and a recent announcementthat the Patient-Centered Outcomes Re-search Institute will provide substantialfunding for research furthering obesitytreatment in primary care settings(200) The FDArsquos recent approval offour new medications to treat obesityhas expanded therapeutic options andcoverage of these medications is nowprovided by more insurance payers in-cluding the Federal Employees HealthBenefits Program (201) Problems re-main in terms of limitations on theamount of reimbursement allowed andthe types of professionals who can pro-vide them In many cases patientsrsquo co-payments remain prohibitive Stillthese are early positive developmentsthat can and should be refined and im-proved over time

Progress also has been made in ad-dressing fraudulent claims by the man-ufacturers of commercial weight-lossproducts Weight-loss products accountfor 13 of all Federal Trade Commission(FTC) fraud claimsdmore than twicethat of any other category (202) Thepervasive peddling of such spuriousproducts minimizes the seriousness ofobesity and undermines legitimate ef-forts of researchers to better under-stand and treat this disease The FTCdemonstrated commitment to the issuein imposing several fines in 2014including a $465 million penalty onthe makers of Sensa products (202)

Moving forward we must better dif-ferentiate the therapies and initiativesaimed at obesity prevention from thosetargeting weight loss and those focusedon weight-loss maintenance becausethe physiology behavioral issues andtreatment goals of each are uniqueFor prevention environmental defaultsthat promote a healthy lifestyle are im-portant Prevention must begin in theprenatal neonatal and early childhoodperiods when nutritional programmingcan affect chronic disease risk through-out life Indeed the origins of severeobesity in adulthood can be found inchildhood For weight-loss treatmentwe will require better more pragmaticmodels for delivering care in the primary

Figure 6mdashSpectrum of obesity guidelines


care setting Much more needs to belearned about the biology and psychol-ogy of weight-loss maintenance to de-velop more effective approachesFinally more intensive public health

campaigns and training opportunitiesare needed to better inform providersindustry representatives insurers regu-lators policymakers and the generalpublic about the health impact of obe-sity and the need for medical manage-ment Perpetuating the outdated viewthat obesity is simply a matter to be ad-dressed by individuals choosing to eatless and exercise more does a disservicenot only to the health care providers andresearchers working to expand the evi-dence base for obesity treatment butalso to people with obesity whosevery lives may depend on our collectiveresolve to take obesity seriouslySuccessfully combating the obesity

epidemic will involve not only researchto address remaining questions regard-ing mechanisms prevention and treat-ment but also the concerted efforts ofgovernmental agencies and publichealth policymakers contributionsfrom the pharmaceutical medical de-vice and insurance industries and per-haps most important and most difficultto achieve a shift in prevailing attitudesabout obesity throughout society In thetwenty-first century we all have an im-perative we must do this because ourfuture health demands it

Acknowledgments Writing and editing sup-port services for this article were provided byDebbie Kendall of Kendall Editorial in RichmondVA The Editorial Committee recognizes that thework of the journal and contributions such asthis Expert Forum would not be possiblewithout the dedicated work and continuedsupport from many individuals Specificallythe planning logistics and funding of themeeting and the incredible editorial supportwould not have been possible without thetireless effort of Chris Kohler and his staff atthe American Diabetes Association (ADA) pub-lications office In addition the Editorial Com-mittee thanks Lyn Reynolds and her staff in theADA editorial office for support and Anne Goochat the Pennington Biomedical Research Centerfor her valuable assistance in helping to organizethe Expert Forum

WTC is supported in part by grant number1-U54-GM-104940 from the National Institute ofGeneral Medical Sciences of the National Insti-tutes of HealthDuality of Interest WTC has served as aprincipal investigator on clinical studies awarded tohis institution from AstraZeneca GlaxoSmithKlineJanssen Lexicon and Sanofi He has served

as a consultant to Intarcia Therapeutics andSanofi GAB is a speakersrsquo bureau member forEisai Novo Nordisk and TakedaVIVUS and is aconsultant to Herbalife and Medifast PDH orinstitutions with which he is associated receivefunding for his advisory speaking and researchactivities fromAstraZeneca Eli Lilly and CompanyJanssen Novo Nordisk Sanofi and companieswith undeclared products in development inthis area WTG is a stockholder in Bristol-MyersSquibb Eli Lilly and Company Isis Pharmaceuti-cals Merck Novartis and Pfizer He has servedon advisory boards for AstraZeneca BoehringerIngelheim Daiichi-Sankyo Eisai JanssenLipoScience Novo Nordisk Takeda and VIVUSHe has research support from AstraZenecaEisai Lexicon Merck Pfizer Sanofi and WeightWatchers SK is a stock shareholder in AspireBariatrics Human Longevity and MetroMidwestBiotech and sits on advisory boards for or servesas a consultant to Aspire Bariatrics Danone-Yakult Novo Nordisk NuSi and Takeda FXP-Sserves on advisory panels for Eli Lilly and Com-pany McNeil Specialty Products Novo Nordiskand Zafgen FBH has received research supportfrom the California Walnut Commission andMetagenics IR serves on advisory boards forAstraZenecaBristol-Myers Squibb Eli Lilly andCompany LabStyle Innovations MedscapeMerck Sharp amp Dohme Novo Nordisk OrgenesisSanofi and SmartZyme Innovation He is a con-sultant to AstraZenecaBristol-Myers SquibbFutuRx GiliMedical InsulineMedical andKamadaHe is on the speakersrsquo bureau of AstraZenecaBristol-Myers Squibb Eli Lilly and CompanyJohnson amp Johnson Merck Sharp amp DohmeNovartis Novo Nordisk Sanofi and Teva He is astock shareholder in GlucoMe Insuline MedicalLabStyle Innovations Orgenesis and SmartZymeInnovation LVG has served on advisory boardsor as a speaker for AstraZeneca BoehringerIngelheim Eli Lilly and Company Janssen Johnsonamp Johnson MerckMerck Sharp amp Dohme NovoNordisk and Sanofi He has received research sup-port from the European Union (HEPADIP and Re-solveConsortium) and from theNational ResearchFunds of Belgium BMW serves as a consultantto EnteroMedics DHR has served on advisorypanels or as a speaker for Medscape NovoNordisk Pfizer Real Appeal Takeda and VIVUSand as a consultant to Novo Nordisk and ScientificIntake She is a stock shareholder in Scientific In-take and Tulip Medical No other potential con-flicts of interest relevant to this article werereported

References1 Fryar CD Carroll MD Ogden CL Prevalence

of overweight obesity and extreme obesity

among adults United States trends 1960ndash

1962 through 2009ndash2010 [Internet] 2012 Na-

tional Center for Health Statistics Available

from httpwwwcdcgovnchsdatahestat

obesity_adult_09_10obesity_adult_09_10htm

Accessed 24 September 20142 Flegal KM Carroll MD Kuczmarski RJ Johnson

CL Overweight and obesity in the United States

prevalence and trends 1960-1994 Int J Obes Re-

lat Metab Disord 19982239ndash473 Ogden CL Carroll MD Kit BK Flegal KM

Prevalence of childhood and adult obesity in

the United States 2011-2012 JAMA 2014311806ndash8144 World Health Organization Global HealthRisks [Internet] 2009 Available from httpwwwwhointhealthinfoglobal_burden_diseaseglobal_health_risksen Accessed 24 September20145 Trust for Americarsquos Health and Robert WoodJohnson Foundation F as in Fat How ObesityThreatens Americarsquos Future Washington DCTrust for Americarsquos Health 20126 Centers for Disease Control and PreventionLong-term trends in diabetes [Internet] 2014Available from httpwwwcdcgovdiabetesstatisticsslideslong_term_trendspdf Ac-cessed 24 September 20147 Centers for Disease Control and PreventionNational diabetes statistics report estimates ofdiabetes and its burden in the United States2014 [Internet] 2014 Available from httpwwwcdcgovdiabetespubsstatsreport14national-diabetes-report-webpdf Accessed 24September 20148 Garrison RJ Kannel WB Stokes J 3rd CastelliWP Incidence and precursors of hypertensionin young adults the Framingham OffspringStudy Prev Med 198716235ndash2519 American Cancer Society Cancer facts amp fig-ures 2012 [Internet] 2012 Available from httpwwwcancerorgresearchcancerfactsstatisticscancerfactsfigures2012 Accessed 24 September201410 Fontaine KR Barofsky I Obesity and health-related quality of life Obes Rev 20012173ndash18211 Peeters A Barendregt JJ Willekens FMackenbach JP Al Mamun A Bonneux LNEDCOM the Netherlands Epidemiology andDemography Compression of Morbidity Re-search Group Obesity in adulthood and its con-sequences for life expectancy a life-tableanalysis Ann Intern Med 200313824ndash3212 Cawley J Meyerhoefer C The medical carecosts of obesity an instrumental variables ap-proach J Health Econ 201231219ndash23013 Withrow D Alter DA The economic burdenof obesityworldwide a systematic review of thedirect costs of obesity Obes Rev 201112131ndash14114 Rudd Center for Food Policy amp ObesityCommodity policy and agricultural subsidies [In-ternet] Available from httpyaleruddcenterorgwhat_we_doaspxid=81 Accessed 29September 201415 Lutter M Nestler EJ Homeostatic and he-donic signals interact in the regulation of foodintake J Nutr 2009139629ndash63216 Putnam J Allshouse J Kantor LS US percapita food supply trends more calories re-fined carbohydrates and fats FoodReview2002252ndash1517 Church TS Thomas DM Tudor-Locke C et alTrends over 5 decades in US occupation-relatedphysical activity and their associations with obe-sity PLoS ONE 20116e1965718 Ladabaum U Mannalithara A Myer PASingh G Obesity abdominal obesity physicalactivity and caloric intake in US adults 1988to 2010 Am J Med 2014127717ndash727e1219 World Health OrganizationFood and Agri-culture Organization of the United NationsGlobal and regional food consumption patternsand trends In Diet Nutrition and the Prevention


of Chronic Diseases Report of the Joint WHOFAO Expert Consultation Geneva World HealthOrganization 2003 (Tech Rep Ser no 916)p 13ndash2920 Bray GA From farm to fat cell why arenrsquotwe all fat Metabolism 201564349ndash35321 Maes HH Neale MC Eaves LJ Genetic andenvironmental factors in relative body weightand human adiposity Behav Genet 199727325ndash35122 Fall T Ingelsson E Genome-wide associa-tion studies of obesity andmetabolic syndromeMol Cell Endocrinol 2014382740ndash75723 Speliotes EK Willer CJ Berndt SI et alMAGIC Procardis Consortium Association anal-yses of 249796 individuals reveal 18 new lociassociated with body mass index Nat Genet201042937ndash94824 Zhang X Qi Q Zhang C et al FTO genotypeand 2-year change in body composition and fatdistribution in response to weight-loss diets thePOUNDS LOST Trial Diabetes 2012613005ndash301125 Herrera BM Keildson S Lindgren CM Ge-netics and epigenetics of obesity Maturitas20116941ndash4926 Godfrey KM Sheppard A Gluckman PDet al Epigenetic gene promoter methylation atbirth is associated with childrsquos later adiposityDiabetes 2011601528ndash153427 Christakis NA Fowler JH The spread of obe-sity in a large social network over 32 years NEngl J Med 2007357370ndash37928 Halberg N Wernstedt-Asterholm I SchererPE The adipocyte as an endocrine cell Endocri-nol Metab Clin North Am 200837753ndash76829 Greenberg AS Obin MS Obesity and therole of adipose tissue in inflammation and me-tabolism Am J Clin Nutr 200683(Suppl)461Sndash465S30 Lenard NR Berthoud H-R Central and pe-ripheral regulation of food intake and physicalactivity pathways and genes Obesity (SilverSpring) 200816(Suppl 3)S11ndashS2231 Hardy OT Czech MP Corvera S Whatcauses the insulin resistance underlying obe-sity Curr Opin Endocrinol Diabetes Obes20121981ndash8732 Sweeney TE Morton JM The human gutmicrobiome a review of the effect of obesityand surgically induced weight loss JAMA Surg2013148563ndash56933 Phillips CM Metabolically healthy obesitydefinitions determinants and clinical implica-tions Rev EndocrMetabDisord 201314219ndash22734 Phillips CM Dillon C Harrington JM et alDefining metabolically healthy obesity role ofdietary and lifestyle factors PLoS ONE 20138e7618835 Wildman RP Muntner P Reynolds K et alThe obese without cardiometabolic risk factorclustering and the normal weight with cardio-metabolic risk factor clustering prevalence andcorrelates of 2 phenotypes among the US pop-ulation (NHANES 1999-2004) Arch Intern Med20081681617ndash162436 Kramer CK ZinmanB RetnakaranR Aremet-abolically healthy overweight and obesity benignconditions A systematic review andmeta-analysisAnn Intern Med 2013159758ndash76937 Garrison RJ Castelli WP Weight and thirty-year mortality of men in the Framingham StudyAnn Intern Med 19851031006ndash1009

38 HamerM Stamatakis EMetabolically healthyobesity and risk of all-cause and cardiovasculardisease mortality J Clin Endocrinol Metab 2012972482ndash248839 Hwang L-C Bai C-H Sun C-A Chen C-J Prev-alence of metabolically healthy obesity and itsimpacts on incidences of hypertension diabetesand the metabolic syndrome in Taiwan Asia PacJ Clin Nutr 201221227ndash23340 Chang Y KimB-K Yun KE et alMetabolically-healthy obesity and coronary artery calcificationJ Am Coll Cardiol 2014632679ndash268641 Appleton SL Seaborn CJ Visvanathan Ret al North West Adelaide Health StudyTeam Diabetes and cardiovascular disease out-comes in the metabolically healthy obese phe-notype a cohort study Diabetes Care 2013362388ndash239442 Fabbrini E Yoshino J Yoshino M et al Met-abolically normal obese people are protectedfrom adverse effects following weight gain JClin Invest 2015125787ndash79543 Korenblat KM Fabbrini E Mohammed BSKlein S Liver muscle and adipose tissue insulinaction is directly related to intrahepatic triglyc-eride content in obese subjects Gastroenterol-ogy 20081341369ndash137544 Lambert JE Ramos-Roman MA BrowningJD Parks EJ Increased de novo lipogenesis is adistinct characteristic of individuals with nonal-coholic fatty liver disease Gastroenterology2014146726ndash73545 Fabbrini E Mohammed BS Magkos FKorenblat KM Patterson BW Klein S Altera-tions in adipose tissue and hepatic lipid kineticsin obese men and women with nonalcoholicfatty liver disease Gastroenterology 2008134424ndash43146 Boden G Fatty acid-induced inflammationand insulin resistance in skeletal muscle andliver Curr Diab Rep 20066177ndash18147 Boden G Chen X Ruiz J White JV RossettiL Mechanisms of fatty acid-induced inhibitionof glucose uptake J Clin Invest 1994932438ndash244648 Fabbrini E Magkos F Mohammed BS et alIntrahepatic fat not visceral fat is linked withmetabolic complications of obesity Proc NatlAcad Sci USA 200910615430ndash1543549 Herman MA Peroni OD Villoria J et al Anovel ChREBP isoform in adipose tissue regu-lates systemic glucose metabolism Nature2012484333ndash33850 Graham TE Kahn BB Tissue-specific alter-ations of glucose transport and molecularmechanisms of intertissue communication inobesity and type 2 diabetes Horm Metab Res200739717ndash72151 Kursawe R EszlingerM Narayan D et al Cel-lularity and adipogenic profile of the abdominalsubcutaneous adipose tissue from obese adoles-cents association with insulin resistance and he-patic steatosis Diabetes 2010592288ndash229652 Sun K Kusminski CM Scherer PE Adiposetissue remodeling and obesity J Clin Invest20111212094ndash210153 Lumeng CN Saltiel AR Inflammatory linksbetween obesity and metabolic disease J ClinInvest 20111212111ndash211754 Khan MT Nieuwdorp M Backhed F Micro-bial modulation of insulin sensitivity Cell Metab201420753ndash760

55 Karlsson FH Tremaroli V Nookaew I et alGut metagenome in European women with nor-mal impaired and diabetic glucose control Na-ture 201349899ndash10356 Vrieze A Van Nood E Holleman F et alTransfer of intestinal microbiota from lean do-nors increases insulin sensitivity in individualswith metabolic syndrome Gastroenterology2012143913ndash91657 Parlevliet ET Coomans CP Rensen PCRomijn JA The brain modulates insulin sensitiv-ity in multiple tissues Front Horm Res 20144250ndash5858 Ogden CL Yanovski SZ Carroll MD FlegalKM The epidemiology of obesity Gastroenter-ology 20071322087ndash210259 National Heart Lung and Blood InstituteObesity Education Initiative Expert Panel onthe Identification Evaluation and Treatmentof Obesity in Adults Clinical guidelines on theidentification evaluation and treatment ofoverweight and obesity in adults the evidencereport National Heart Lung and Blood Insti-tute 1998 (report no 98-4083)60 Jensen MD Ryan DH Apovian CM et al2013 AHAACCTOS guideline for the manage-ment of overweight and obesity in adults a re-port of the American College of CardiologyAmerican Heart Association Task Force on Prac-tice Guidelines and The Obesity Society J AmColl Cardiol 201463(25 Pt B)2985ndash302361 Chang A Van Horn L Jacobs DR Jr et alLifestyle-related factors obesity and incidentmicroalbuminuria the CARDIA (Coronary ArteryRisk Development in Young Adults) study Am JKidney Dis 201362267ndash27562 van Leiden HA Dekker JM Moll AC et alBlood pressure lipids and obesity are associ-ated with retinopathy the Hoorn Study Diabe-tes Care 2002251320ndash132563 Diabetes Prevention Program ResearchGroup 10-year follow-up of diabetes incidenceand weight loss in the Diabetes Prevention Pro-gram Outcomes Study Lancet 20093741677ndash168664 Garvey WT Ryan DH Henry R et al Pre-vention of type 2 diabetes in subjects with pre-diabetes and metabolic syndrome treated withphentermine and topiramate extended releaseDiabetes Care 201437912ndash92165 Wing RR Lang W Wadden TA et al LookAHEAD Research Group Benefits of modestweight loss in improving cardiovascular risk fac-tors in overweight and obese individuals with type2 diabetes Diabetes Care 2011341481ndash148666 Assy N Hussein O Abassi Z Weight lossinduced by orlistat reverses fatty infiltrationand improves hepatic fibrosis in obese patientswith non-alcoholic steatohepatitis Gut 200756443ndash44467 Dixon JB Bhathal PS Hughes NR OrsquoBrienPE Nonalcoholic fatty liver disease improve-ment in liver histological analysis with weightloss Hepatology 2004391647ndash165468 Patel AA Torres DM Harrison SA Effect ofweight loss on nonalcoholic fatty liver disease JClin Gastroenterol 200943970ndash97469 Foster GD Borradaile KE Sanders MHet al Sleep AHEAD Research Group of LookAHEAD Research Group A randomized studyon the effect of weight loss on obstructive sleepapnea among obese patients with type 2


diabetes the Sleep AHEAD study Arch InternMed 20091691619ndash162670 Winslow DH Bowden CH DiDonato KPMcCullough PA A randomized double-blindplacebo-controlled study of an oral extended-release formulation of phenterminetopiramatefor the treatment of obstructive sleep apnea inobese adults Sleep 2012351529ndash153971 Christensen R Bartels EM Astrup A BliddalH Effect of weight reduction in obese patientsdiagnosedwith knee osteoarthritis a systematicreview and meta-analysis Ann Rheum Dis 200766433ndash43972 Felson DT Zhang Y Anthony JM Naimark AAnderson JJWeight loss reduces the risk for symp-tomatic kneeosteoarthritis inwomen theFraming-ham Study Ann Intern Med 1992116535ndash53973 Aaboe J Bliddal H Messier SP Alkjaeligr THenriksen M Effects of an intensive weightloss program on knee joint loading in obeseadults with knee osteoarthritis OsteoarthritisCartilage 201119822ndash82874 Burgio KL Richter HE Clements RH ReddenDT Goode PS Changes in urinary and fecal in-continence symptoms with weight loss surgeryin morbidly obese women Obstet Gynecol20071101034ndash104075 Subak LL Wing R West DS et al PRIDEInvestigators Weight loss to treat urinary in-continence in overweight and obese womenN Engl J Med 2009360481ndash49076 Singh M Lee J Gupta N et al Weight losscan lead to resolution of gastroesophagealreflux disease symptoms a prospective inter-vention trial Obesity (Silver Spring) 201321284ndash29077 Tutuian R Obesity and GERD pathophysi-ology and effect of bariatric surgery Curr Gas-troenterol Rep 201113205ndash21278 Panidis D Farmakiotis D Rousso D KourtisA Katsikis I Krassas G Obesity weight loss andthe polycystic ovary syndrome effect of treat-ment with diet and orlistat for 24 weeks on in-sulin resistance and androgen levels Fertil Steril200889899ndash90679 Norman RJ DaviesMJ Lord J Moran LJ Therole of lifestyle modification in polycystic ovarysyndrome Trends Endocrinol Metab 200213251ndash25780 Moran LJ Ko H Misso M et al Dietarycomposition in the treatment of polycysticovary syndrome a systematic review to informevidence-based guidelines J Acad Nutr Diet2013113520ndash54581 Prospective Studies Collaboration Body-mass index and cause-specific mortality in 900000 adults collaborative analyses of 57 pro-spective studies Lancet 20093731083ndash109682 Berrington de Gonzalez A Hartge P CerhanJR et al Body-mass index and mortality among146 million white adults N Engl J Med 20103632211ndash221983 Fontaine KR Redden DT Wang C WestfallAO Allison DB Years of life lost due to obesityJAMA 2003289187ndash19384 Dorn JM Schisterman EF Winkelstein W JrTrevisan M Body mass index and mortality in ageneral population sample of men and womenThe Buffalo Health Study Am J Epidemiol 1997146919ndash93185 McGee DL Diverse Populations Collabora-tion Body mass index and mortality a meta-

analysis based on person-level data fromtwenty-six observational studies Ann Epidemiol20051587ndash9786 Flegal KM Graubard BI Williamson DF GailMH Excess deaths associated with under-weight overweight and obesity JAMA 20052931861ndash186787 Willett WC Hu FB Thun M Overweightobesity and all-cause mortality JAMA 2013309168188 Flegal KM Kit BK Orpana H Graubard BIAssociation of all-cause mortality with over-weight and obesity using standard body massindex categories a systematic review andmeta-analysis JAMA 201330971ndash8289 Tobias DK Hu FB Does being overweightreally reduce mortality Obesity (Silver Spring)2013211746ndash174990 Sjostrom L Narbro K Sjostrom CD et alSwedish Obese Subjects Study Effects of bari-atric surgery on mortality in Swedish obese sub-jects N Engl J Med 2007357741ndash75291 Sjostrom L Peltonen M Jacobson P et alBariatric surgery and long-term cardiovascularevents JAMA 201230756ndash6592 UusitupaM PeltonenM Lindstrom J et alFinnish Diabetes Prevention Study Group Ten-year mortality and cardiovascular morbidity inthe Finnish Diabetes Prevention Studydsecondaryanalysis of the randomized trial PLoS ONE 20094e565693 Li G Zhang P Wang J et al The long-termeffect of lifestyle interventions to prevent dia-betes in the China Da Qing Diabetes PreventionStudy a 20-year follow-up study Lancet 20083711783ndash178994 Li G Zhang P Wang J et al Cardiovascularmortality all-cause mortality and diabetes in-cidence after lifestyle intervention for peoplewith impaired glucose tolerance in the Da QingDiabetes Prevention Study a 23-year follow-upstudy Lancet Diabetes Endocrinol 20142474ndash48095 Wing RR Bolin P Brancati FL et al LookAHEAD Research Group Cardiovascular effectsof intensive lifestyle intervention in type 2 di-abetes N Engl J Med 2013369145ndash15496 National Heart Lung and Blood InstituteNorth American Association for the Study ofObesity The practical guide identification eval-uation and treatment of overweight and obe-sity in adults National Institutes of Health 2000(NIH publication no 00-4084)97 Knowler WC Barrett-Connor E Fowler SEet al Diabetes Prevention Program ResearchGroup Reduction in the incidence of type 2 di-abetes with lifestyle intervention or metforminN Engl J Med 2002346393ndash40398 Ryan DH Espeland MA Foster GD et alLook AHEAD Research Group Look AHEAD(Action for Health in Diabetes) design andmethods for a clinical trial of weight loss forthe prevention of cardiovascular disease intype 2 diabetes Control Clin Trials 200324610ndash62899 Look AHEAD Research Group Eight-yearweight losses with an intensive lifestyle inter-vention the look AHEAD study Obesity (SilverSpring) 2014225ndash13100 Pi-Sunyer X Blackburn G Brancati FLet al Look AHEAD Research Group Reductionin weight and cardiovascular disease risk factors

in individuals with type 2 diabetes one-yearresults of the look AHEAD trial Diabetes Care2007301374ndash1383101 Wing RR Hamman RF Bray GA et al Di-abetes Prevention Program Research GroupAchieving weight and activity goals among di-abetes prevention program lifestyle partici-pants Obes Res 2004121426ndash1434102 Ackermann RT Finch EA Brizendine EZhou H Marrero DG Translating the DiabetesPrevention Program into the community theDEPLOY pilot study Am J Prev Med 200835357ndash363103 Perri MG Effects of behavioral treatmenton long-term weight loss lessons learned fromthe look AHEAD trial Obesity (Silver Spring)2014223ndash4104 Delahanty LM Nathan DM Implicationsof the diabetes prevention program and LookAHEAD clinical trials for lifestyle interven-tions J Am Diet Assoc 2008108(Suppl 1)S66ndashS72105 Albright AL Gregg EW Preventing type 2diabetes in communities across the US theNational Diabetes Prevention Program Am JPrev Med 201344(Suppl 4)S346ndashS351106 Ratner RE Diabetes Prevention ProgramResearch An update on the Diabetes Preven-tion Program Endocr Pract 200612(Suppl 1)20ndash24107 Wadden TA Neiberg RH Wing RR et alLook AHEAD Research Group Four-year weightlosses in the Look AHEAD study factors associ-ated with long-term success Obesity (SilverSpring) 2011191987ndash1998108 Wing RR Phelan S Long-term weight lossmaintenance Am J Clin Nutr 200582(Suppl)222Sndash225S109 Jakicic JM Winters C Lang W Wing RREffects of intermittent exercise and use of homeexercise equipment on adherence weight lossand fitness in overweight women a randomizedtrial JAMA 19992821554ndash1560110 UK Prospective Diabetes Study (UKPDS)Group Intensive blood-glucose control with sul-phonylureas or insulin compared with conven-tional treatment and risk of complications inpatients with type 2 diabetes (UKPDS 33) Lan-cet 1998352837ndash853111 UK Prospective Diabetes Study (UKPDS)Group Effect of intensive blood-glucose controlwith metformin on complications in overweightpatients with type 2 diabetes (UKPDS 34) Lan-cet 1998352854ndash865112 Kahn SE Haffner SM Heise MA et alADOPT Study Group Glycemic durability of ro-siglitazone metformin or glyburide monother-apy N Engl J Med 20063552427ndash2443113 Gerstein HC Bosch J Dagenais GR et alORIGIN Trial Investigators Basal insulin and car-diovascular and other outcomes in dysglycemiaN Engl J Med 2012367319ndash328114 van Dieren S Czernichow S Chalmers Jet al Weight changes and their predictorsamongst 11 140 patients with type 2 diabetesin the ADVANCE trial Diabetes Obes Metab201214464ndash469115 Balkau B Home PD Vincent M MarreM Freemantle N Factors associated withweight gain in people with type 2 diabetesstarting on insulin Diabetes Care 2014372108ndash2113


116 Stimson RH Walker BR Glucocorticoidsand 11beta-hydroxysteroid dehydrogenasetype 1 in obesity and the metabolic syndromeMinerva Endocrinol 200732141ndash159117 Sharma AM Pischon T Hardt S Kunz I LuftFC Hypothesis b-adrenergic receptor blockersand weight gain a systematic analysis Hyper-tension 200137250ndash254118 DeToledo JC Toledo C DeCerce J RamsayRE Changes in body weight with chronic high-dose gabapentin therapy Ther Drug Monit199719394ndash396119 Tschoner A Engl J Laimer M et al Meta-bolic side effects of antipsychotic medicationInt J Clin Pract 2007611356ndash1370120 Stricker RB Goldberg B Weight gain asso-ciated with protease inhibitor therapy in HIV-infected patients Res Virol 1998149123ndash126121 Inzucchi SE Bergenstal RM Buse JB et alManagement of hyperglycemia in type 2 diabe-tes a patient-centered approach positionstatement of the American Diabetes Associa-tion (ADA) and the European Association forthe Study of Diabetes (EASD) Diabetes Care2012351364ndash1379122 Inzucchi SE Bergenstal RM Buse JB et alManagement of hyperglycemia in type 2 diabe-tes 2015 a patient-centered approach updateto a position statement of the American Diabe-tes Association and the European Associationfor the Study of Diabetes Diabetes Care 201538140ndash149123 Scheen AJ Van Gaal LF Combating thedual burden therapeutic targeting of commonpathways in obesity and type 2 diabetes LancetDiabetes Endocrinol 20142911ndash922124 Cornell S Differentiating among incretintherapies a multiple-target approach to type2 diabetes J Clin Pharm Ther 201237510ndash524125 DeFronzo RA Ratner RE Han J Kim DDFineman MS Baron AD Effects of exenatide(exendin-4) on glycemic control and weightover 30 weeks in metformin-treated patientswith type 2 diabetes Diabetes Care 2005281092ndash1100126 Buse JB Rosenstock J Sesti G et al LEAD-6 Study Group Liraglutide once a day versusexenatide twice a day for type 2 diabetesa 26-week randomised parallel-group multina-tional open-label trial (LEAD-6) Lancet 200937439ndash47127 Van Gaal L Scheen A Weight manage-ment in type 2 diabetes current and emergingapproaches to treatment Diabetes Care 2015381161ndash1172128 Bolinder J Ljunggren O Kullberg J et alEffects of dapagliflozin on body weight total fatmass and regional adipose tissue distribution inpatients with type 2 diabetes mellitus with in-adequate glycemic control on metformin J ClinEndocrinol Metab 2012971020ndash1031129 Bays HE Weinstein R Law G CanovatchelW Canagliflozin effects in overweight andobese subjects without diabetes mellitus Obe-sity (Silver Spring) 2014221042ndash1049130 Buse JB Bergenstal RM Glass LC et al Useof twice-daily exenatide in basal insulin-treatedpatients with type 2 diabetes a randomizedcontrolled trial Ann Intern Med 2011154103ndash112131 Riddle MC Aronson R Home P et al Add-ing once-daily lixisenatide for type 2 diabetes

inadequately controlled by established basal in-sulin a 24-week randomized placebo-controlledcomparison (GetGoal-L) Diabetes Care 2013362489ndash2496132 Rosenstock J Fonseca VA Gross JL et alHarmony 6 Study Group Advancing basal insu-lin replacement in type 2 diabetes inadequatelycontrolled with insulin glargine plus oral agentsa comparison of adding albiglutide a weeklyGLP-1 receptor agonist versus thrice-dailyprandial insulin lispro Diabetes Care 2014372317ndash2325133 Gough SC Bode B Woo V et al NN9068-3697 (DUAL-I) trial investigators Efficacy andsafety of a fixed-ratio combination of insulindegludec and liraglutide (IDegLira) comparedwith its components given alone results of aphase 3 open-label randomised 26-weektreat-to-target trial in insulin-naive patientswith type 2 diabetes Lancet Diabetes Endocri-nol 20142885ndash893134 Wilding JPH Norwood P Trsquojoen C BastienA List JF Fiedorek FT A study of dapagliflozin inpatients with type 2 diabetes receiving highdoses of insulin plus insulin sensitizers applica-bility of a novel insulin-independent treatmentDiabetes Care 2009321656ndash1662135 Kim GW Lin JE Blomain ES Waldman SAAntiobesity pharmacotherapy new drugs andemerging targets Clin Pharmacol Ther 20149553ndash66136 US Food and Drug AdministrationFDA announces withdrawal fenfluramine anddexfenfluramine (fen-phen) [Internet] 15 Sep-tember 1997 Available from httpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm179871htm Accessed 17 December 2014137 US Food and Drug Administration Mer-idia (sibutramine) market withdrawal due torisk of serious cardiovascular events [Internet]8 October 2010 Available from httpwwwfdagovSafetyMedWatchSafetyInformationSafetyAlertsforHumanMedicalProductsucm228830htm Accessed 17 December 2014138 European Medicines Agency Public state-ment on Acomplia (rimonabant) withdrawal ofthe marketing authorisation in the EuropeanUnion [Internet] 30 January 2009 Availablefrom httpwwwemaeuropaeudocsen_GBdocument_libraryPublic_statement200911WC500012189pdf Accessed 17 December2014139 Zhi J Melia AT Guerciolini R et al Retro-spective population-based analysis of the dose-response (fecal fat excretion) relationship oforlistat in normal and obese volunteers ClinPharmacol Ther 19945682ndash85140 US Food and Drug Administration FDAapproves weight-management drug Qsymia[Internet] 17 July 2012 Available fromhttpwwwfdagovNewsEventsNewsroomPressAnnouncementsucm312468htm Accessed17 December 2014141 US Food and Drug Administration FDAapprovesBelviq to treat someoverweightor obeseadults [Internet] 27 June 2012 Available fromhttpwwwfdagovNewsEventsNewsroomPressAnnouncementsucm309993htm Accessed17 December 2014142 US Food and Drug Administration FDAapproves weight-management drug Contrave

[Internet] 10 September 2014 Available fromhttpwwwfdagovNewsEventsNewsroomPressAnnouncementsucm413896htm Ac-cessed 17 December 2014143 US Food and Drug Administration FDAapproves weight-management drug Saxenda[Internet] 23 December 2014 Available fromhttpwwwfdagovNewsEventsNewsroomPressAnnouncementsucm427913htm Ac-cessed 9 February 2015144 Torgerson JS Hauptman J Boldrin MNSjostrom L XENical in the prevention of diabe-tes in obese subjects (XENDOS) study a ran-domized study of orlistat as an adjunct tolifestyle changes for the prevention of type 2diabetes in obese patients Diabetes Care 200427155ndash161145 Allison DB Gadde KM Garvey WT et alControlled-release phenterminetopiramate inseverely obese adults a randomized controlledtrial (EQUIP) Obesity (Silver Spring) 201220330ndash342146 Gadde KM Allison DB Ryan DH et al Ef-fects of low-dose controlled-release phenter-mine plus topiramate combination on weightand associated comorbidities in overweightand obese adults (CONQUER) a randomisedplacebo-controlled phase 3 trial Lancet 20113771341ndash1352147 Garvey WT Ryan DH Look M et al Two-year sustained weight loss and metabolic ben-efits with controlled-release phenterminetopiramate in obese and overweight adults(SEQUEL) a randomized placebo-controlledphase 3 extension study Am J Clin Nutr201295297ndash308148 Fidler MC Sanchez M Raether B et alBLOSSOM Clinical Trial Group A one-year ran-domized trial of lorcaserin for weight loss inobese and overweight adults the BLOSSOM trialJ Clin Endocrinol Metab 2011963067ndash3077149 Smith SR Weissman NJ Anderson CMet al Behavioral Modification and Lorcaserinfor Overweight and Obesity Management(BLOOM) Study Group Multicenter placebo-controlled trial of lorcaserin for weight manage-ment N Engl J Med 2010363245ndash256150 OrsquoNeil PM Smith SR Weissman NJ et alRandomized placebo-controlled clinical trial oflorcaserin for weight loss in type 2 diabetesmel-litus the BLOOM-DM study Obesity (SilverSpring) 2012201426ndash1436151 Greenway FL Fujioka K Plodkowski RAet al COR-I Study Group Effect of naltrexoneplus bupropion on weight loss in overweightand obese adults (COR-I) a multicentre rando-mised double-blind placebo-controlled phase3 trial Lancet 2010376595ndash605152 Apovian CM Aronne L Rubino D et alCOR-II Study Group A randomized phase 3 trialof naltrexone SRbupropion SR on weight andobesity-related risk factors (COR-II) Obesity(Silver Spring) 201321935ndash943153 Wadden TA Hollander P Klein S et alNN8022-1923 Investigators Weight mainte-nance and additional weight loss with liraglu-tide after low-calorie-diet-induced weight lossthe SCALE Maintenance randomized study Int JObes (Lond) 2013371443ndash1451154 Astrup A Carraro R Finer N et alNN8022-1807 Investigators Safety tolerabilityand sustained weight loss over 2 years with the


once-daily human GLP-1 analog liraglutide Int JObes (Lond) 201236843ndash854155 Garber AJ Abrahamson MJ Barzilay JIet al American Association of Clinical Endocri-nologists AACE comprehensive diabetes man-agement algorithm 2013 Endocr Pract 201319327ndash336156 VIVUS Qsymia prescribing information[Internet] 2014 Available from httpswwwqsymiacompdfprescribing-informationpdfAccessed 17 December 2014157 EisaiBelviqprescribing information [Internet]2012 Available from httpswwwbelviqcompdfBelviq_Prescribing_informationpdf Ac-cessed 17 December 2014158 Takeda Pharmaceuticals CONTRAVEprescribing information [Internet] 2014 Avail-able from httpgeneraltakedapharmcomcontentfileaspxfiletypecode=CONTRAVEPIampcacheRandomizer=aaa3d519-2e84-4e5d-bb7a-5759af394a09 Accessed 17 December 2014159 Novo Nordisk Saxenda prescribing infor-mation [Internet] 2014 Available from httpnovo-pinnittestcomsaxendapdf Accessed 9February 2015160 Garvey WT New tools for weight-losstherapy enable a more robust medical model forobesity treatment rationale for a complications-centric approach Endocr Pract 201319864ndash874161 Aronne LJWadden TA Peterson CWinslowD Odeh S Gadde KM Evaluation of phentermineand topiramate versus phenterminetopiramateextended-release in obese adults Obesity (SilverSpring) 2013212163ndash2171162 Munro JF MacCuish AC Wilson EMDuncan LJP Comparison of continuous and in-termittent anorectic therapy in obesity BMJ19681352ndash354163 Hollander PA Elbein SC Hirsch IB et alRole of orlistat in the treatment of obese pa-tients with type 2 diabetes A 1-year random-ized double-blind study Diabetes Care 1998211288ndash1294164 GarveyWT Ryan DH Bohannon NJV et alWeight-loss therapy in type 2 diabetes effectsof phentermine and topiramate extended re-lease Diabetes Care 2014373309ndash3316165 Garvey WT Troupin B Tam P Najarian TPeterson C Day WW One-year treatment withVI-0521 in type 2 diabetes demonstrates contin-ued glycemic improvement and weight loss Di-abetes 200958(Suppl 1)A95166 Hollander P Gupta AK Plodkowski R et alCOR-Diabetes Study Group Effects of naltrexonesustained-releasebupropion sustained-releasecombination therapy on bodyweight and glycemicparameters in overweight and obese patients withtype 2 diabetes Diabetes Care 2013364022ndash4029167 Drugscom People with type 2 diabetesachieve 6 weight loss with liraglutide 3 mg inphase 3a obesity trial [Internet] 2013 Availablefrom httpwwwdrugscomclinical_trialstype-2-diabetes-achieve-6-weight-loss-liraglutide-3-mg-phase-3a-obesity-trial-15264html Ac-cessed 18 December 2014168 GarveyWT Garber AJ Mechanick JI et alon behalf of the AACE Obesity Scientific Commit-tee American Association of Clinical Endocrinol-ogists and American College of Endocrinologyconsensus conference on obesity building an

evidence base for comprehensive action EndocrPract 201420956ndash976169 GarveyWT Garber AJ Mechanick JI et alon behalf of the AACE Obesity Scientific Com-mittee American Association of Clinical Endocri-nologists and American College of Endocrinologyposition statement on the 2014 advancedframework for a new diagnosis of obesityas a chronic disease Endocr Pract 201420977ndash989170 Pories WJ Mehaffey JH Staton KM Thesurgical treatment of type two diabetes melli-tus Surg Clin North Am 201191821ndash836 viii171 Consensus Development ConferencePanel Gastrointestinal surgery for severe obe-sity Ann Intern Med 1991115956ndash961172 Sultan S Parikh M Youn H Kurian MFielding G Ren C Early US outcomes after lap-aroscopic adjustable gastric banding in patientswith a body mass index less than 35 kgm2 SurgEndosc 2009231569ndash1573173 Langer FB Reza Hoda MA Bohdjalian Aet al Sleeve gastrectomy and gastric bandingeffects on plasma ghrelin levels Obes Surg2005151024ndash1029174 Hess DS Hess DW Biliopancreatic diver-sion with a duodenal switch Obes Surg 19988267ndash282175 Buchwald H Avidor Y Braunwald E et alBariatric surgery a systematic review andmeta-analysis JAMA 20042921724ndash1737176 Pories WJ Swanson MS MacDonald KGet al Who would have thought it An operationproves to be the most effective therapy foradult-onset diabetes mellitus Ann Surg 1995222339ndash350 discussion 350ndash352177 Favretti F Segato G Ashton D et al Lap-aroscopic adjustable gastric banding in 1791consecutive obese patients 12-year resultsObes Surg 200717168ndash175178 Higa K Ho T Tercero F Yunus T Boone KBLaparoscopic Roux-en-Y gastric bypass 10-yearfollow-up Surg Obes Relat Dis 20117516ndash525179 Sjostrom L Lindroos A-K Peltonen Met al Swedish Obese Subjects Study ScientificGroup Lifestyle diabetes and cardiovascularrisk factors 10 years after bariatric surgery NEngl J Med 20043512683ndash2693180 Adams TD Davidson LE Litwin SE et alHealth benefits of gastric bypass surgery after6 years JAMA 20123081122ndash1131181 Belle SH Berk PD Courcoulas AP et alLongitudinal Assessment of Bariatric SurgeryConsortium Writing Group Safety and efficacyof bariatric surgery Longitudinal Assessment ofBariatric Surgery Surg Obes Relat Dis 20073116ndash126182 Courcoulas AP Christian NJ Belle SHet al Longitudinal Assessment of Bariatric Sur-gery (LABS) Consortium Weight change andhealth outcomes at 3 years after bariatric sur-gery among individuals with severe obesityJAMA 20133102416ndash2425183 Christou NV Sampalis JS Liberman Met al Surgery decreases long-term mortalitymorbidity and health care use in morbidlyobese patients Ann Surg 2004240416ndash423discussion 423ndash424184 Schauer PR Kashyap SR Wolski K et alBariatric surgery versus intensive medical ther-apy in obese patients with diabetes N Engl JMed 20123661567ndash1576

185 Lee WJ Chong K Ser KH et al Gastricbypass vs sleeve gastrectomy for type 2 diabe-tes mellitus a randomized controlled trial ArchSurg 2011146143ndash148186 Lim EL Hollingsworth KG Aribisala BSChen MJ Mathers JC Taylor R Reversal oftype 2 diabetes normalisation of beta cell func-tion in association with decreased pancreas andliver triacylglycerol Diabetologia 2011542506ndash2514187 Scopinaro N Papadia F Marinari GCamerini G Adami G Long-term control oftype 2 diabetes mellitus and the other majorcomponents of the metabolic syndrome afterbiliopancreatic diversion in patients withBMI 35 kgm2 Obes Surg 200717185ndash192188 Dixon JB OrsquoBrien PE Playfair J et al Ad-justable gastric banding and conventionaltherapy for type 2 diabetes a randomized con-trolled trial JAMA 2008299316ndash323189 Lee WJ Wang W Lee YC Huang MT SerKH Chen JC Effect of laparoscopic mini-gastricbypass for type 2 diabetes mellitus comparisonof BMI35 and35 kgm2 J Gastrointest Surg200812945ndash952190 Purnell J Selzer F Wahed A et al Im-proved probability of diabetes remission 3 yearsafter Roux-en-Y gastric bypass (GBP) comparedto laparoscopic gastric banding (LAGB) control-ling for percentage weight change results fromthe Longitudinal Assessment of Bariatric Sur-gery (LABS) 2 study Poster presented at TheObesity Societyrsquos ObesityWeek 2014 2ndash7 No-vember 2014 Boston Convention and Exhibi-tion Center Boston MA191 Flum DR Belle SH King WC et al Longi-tudinal Assessment of Bariatric Surgery (LABS)Consortium Perioperative safety in the longitu-dinal assessment of bariatric surgery N Engl JMed 2009361445ndash454192 Konttinen H Peltonen M Sjostrom LCarlsson L Karlsson J Psychological aspects ofeating behavior as predictors of 10-y weightchanges after surgical and conventional treat-ment of severe obesity results from the Swed-ish Obese Subjects intervention study Am J ClinNutr 201510116ndash24193 Seger JC Horn DB Westman EC et alObesity algorithm presented by the AmericanSociety of Bariatric Physicians [Internet] Avail-able from wwwobesityalgorithmorg Accessed17 December 2014194 American Medical Association AMA Res-olution No 420 (A-13) [Internet] 2013 Avail-able from httpwwwama-assnorgassetsmeeting2013aa13-addendum-refcomm-dpdfAccessed 7 January 2015195 American Society for Metabolic and Bari-atric Surgery The Obesity Society American So-ciety of Bariatr ic Physic ians AmericanAssociation of Clinical Endocrinologists Obesityis a disease leading obesity groups agree [Inter-net] 2013 Available from httpconnectasmbsorgPDF20DocumentsPress20Releases2013Obesity20is20a20Disease-20Leading20Obesity20Groups20AgreepdfAccessed 21 December 2014196 World Health Organization Obesity Pre-venting and Managing the Global Epidemic Re-port of a WHO Consultation Geneva WorldHealth Organization 2000 (WHO Tech RepSer no 894)


197 US Food and Drug Administration FDArsquosobesity working group report questions andanswers [Internet] Available from httpwwwfdagovFoodFoodScienceResearchConsumerBehaviorResearchucm082094htmgen2211 Accessed 7 January 2015198 American Board of Obesity MedicineHome page [Internet] Available from httpabomorg Accessed 21 December 2014199 Centers for Medicare amp Medicaid ServicesNational coverage determination (NCD) for inten-sive behavioral therapy for obesity (21012) [In-ternet] Available from httpwwwcmsgov

medicare-coverage-databasedetailsncd-detailsaspxNCDId=353ampncdver=1ampCoverageSelection=BothampArticleType=AllampPolicyType=Finalamps=AllampKeyWord=obesityampKeyWordLookUp=TitleampKeyWordSearchType=Andampbc=gAAAABAAAAAAampAccessed 21 December 2014200 Patient-Centered Outcomes Research In-stitute PCORI board approves $102 million insupport for 46 new research projects [Internet]2014 Available from httpwwwpcoriorgcontentpcori-board-approves-102-million-support-46-new-research-projects Accessed 21December 2014

201 The Obesity Society A promising mile-

stone in coverage for obesity treatments [Inter-

net] 2014 Available from httpwwwobesity

orgpublicationsa-promising-milestone-

in-coverage-for-obesity-treatmentshtm Ac-

cessed 21 December 2014202 Wyatt E Weight-loss companies charged

with fraud [Internet] The New York Times 7 Jan-

uary 2014 Available from httpwwwnytimes

com20140108businessus-charges-4-companies-

with-deception-in-weight-loss-productshtml_r=0

Accessed 21 December 2014


Population-based studies have suggestedthat 75 of hypertension is attribut-able to obesity (8) and approximatelyone-third of cancer deaths are linkedto poor nutrition excess weight andsedentary lifestyle (9) Worldwide44 of the diabetes burden 23 of is-chemic heart disease and 7ndash41 ofcertain cancers are attributable to ex-cess weight (4) Obesity also decreasesboth health-related quality of life (10)and life expectancy (11)The medical costs of obesity in the

US were estimated at $190 billion in2012 (12) A recent systematic reviewfound that worldwide obesity-relatedmedical costs accounted for 07ndash28of a countryrsquos total health care expendi-ture and that people with obesity hadmedical costs 30 higher than theirnormal-weight peers (13)With these alarming statistics in

mind a Diabetes Care Editorsrsquo ExpertForum convened in June 2014 to reviewthe state of obesity research and discussprevention and treatment initiativesThis article summarizes the proceedingsof that forum

OBESITY IN CONTEXT

What explains the sharp uptick in obe-sity rates that occurred after 1980Hindsight suggests that a combinationof technological advances certain agri-cultural and economic policies and a de-cline in physical activity all contributedIn the 1970s the US enacted agricul-tural subsidies aimed at lowering foodprices by encouraging increased produc-tion of crops such as corn and soybeansSuch subsidies in concert with large-scaleindustrialized farming practices resultedin an overabundance of inexpensive foodIn addition to lowering the price of grainssubsidies reduced the cost of meat (fromlivestock fed on less expensive crops) andallowed the food manufacturing industryto produce a wide range of inexpensiveand convenientdbut also energy-denseand nutrient-poordproducts (14)It has been suggested that chronic ex-

posure to easily obtainable highly palat-able foods can cause the hedonic orreward-based neuronal pathway tooverride the homeostatic pathway thatordinarily controls energy balance (15)Average daily calorie consumption inthe US increased by 245 or530 cal-ories between 1970 and 2000 (Fig 1)(16) Meanwhile as dietary intake was

observed to increase both occupationaland leisure-time energy expendituresdeclined (1718) Similar patterns havebecome apparent elsewhere in theworld (19)

The complex issues of grain overpro-duction fruit and vegetable underavail-ability detrimental food processing andmarketing practices and consumerknowledge deficits are beyond thescope of this article but have been elo-quently elucidated elsewhere (520)

Much Learned More Still to LearnIn recent decades there has been animpressive expansion in our knowl-edge base regarding obesity We havelearned that the genetic componentsof obesity are key contributors to indi-vidual risk Studies involving familiestwins and adoption have shown thatadiposity is highly heritable (21)Genome-wide association studies havedemonstrated that numerous genesare associated with weight gain (22)and that the presence of risk allelesfor multiple small-effect genes can re-sult in marked cumulative effects onBMI (23) Genetics can also informthe selection of obesity interventionsone example is the Preventing Over-weight Using Novel Dietary Strategies(POUNDS LOST) trial (24) in which car-riers of the FTO variant risk allele lostweight more successfully on a high-protein than on a low-protein diet Epi-genetic factors can modify weight gainand aid in identifying individuals athigher risk for obesity (2526) In addi-tion social factors appear to influenceits occurrence (27)

The physiological milieu promotingobesity involves complex and interrelatedmetabolic factors Once considered sim-ple storage depots for body energy adi-pocytes are now recognized as active

endocrine cells that have many roles in-cluding the regulation of metabolism en-ergy intake and fat storage (2829) Smalladipocytes found in normal-weight indi-viduals release adipokines that do not up-set metabolic homeostasis whereasenlarged adipocytes found in peoplewith obesity release adipokines in largeramounts which can promote inflamma-tion and insulin resistance More than 50adipokines have been identified perhapsthe best known of which are leptin andadiponectin (29)

Research is similarly elucidating theneural pathways involved in regulatingfood intake and energy control and theways in which genetic and early environ-mental factors can modulate the func-tioning of these pathways (30) Guthormones such as ghrelin cholecystoki-nin peptide YY and glucagon-like peptide1 (GLP-1) appear to have key roles Addi-tionally insulin resistance inflammationand the gut microbiome all affect weight(3132)

OBESITY-RELATED METABOLICDYSFUNCTION

Obesity is associated with a constella-tion of metabolic abnormalities includ-ing insulin resistance b-cell failureatherogenic dyslipidemia (ie high tri-glycerides low HDL cholesterol and in-creased small dense LDL particles) andnonalcoholic fatty liver disease (NAFLD)However not all people with obesity ex-hibit these abnormalities and ametabol-ically healthy obese (MHO) phenotype(ie BMI$300 kgm2 with normal fast-ing blood glucose insulin sensitivity lipidprofile and intrahepatic triglyceride[IHTG] content levels) has been de-scribed (33)

The MHO phenotype is more commonin younger than in older people and oc-curs more often in women than in menThe proportion of the population withobesity considered to be MHO dependson the criteria used to define ldquometaboli-cally healthyrdquoOne study that applied fiveexisting definitions of MHO to the samegroup of adults found prevalence ratesranging from 68 to 366 (34) whereasdata from the 1999ndash2004National Healthand Nutrition Examination Surveys (35)which defined metabolic health as thepresence of no more than one compo-nent of the metabolic syndrome foundthat 292 of men and 354 of womenwith obesity were metabolically healthy

Figure 1mdashFood available for consumption1900ndash2000 Reprinted from ref 16




















































































Orlistat(163)

Lorcaserin(149)


Naltrexonebupropion



62 45 96 50 6043 15 26 18 20

Initial A1C () 81 81 86 80 80


203 209 216 206 +02 204 212 201


DrugPlacebo

504 53 44 69 263 40 26 27




















619 37109 32


382 174126 180


619 27132 160


















































































































































Orlistat(163)

Lorcaserin(149)


Naltrexonebupropion



62 45 96 50 6043 15 26 18 20

Initial A1C () 81 81 86 80 80


203 209 216 206 +02 204 212 201


DrugPlacebo

504 53 44 69 263 40 26 27




















619 37109 32


382 174126 180


619 27132 160
















































































619 37109 32


382 174126 180


619 27132 160






























































