Original Investigation. management of type 2 diabetes mellitus.

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1 Reserch Originl Investigtion Roux-en-Y Gstric Bypss Surgery or Lifestyle With Intensive Medicl Mngement in Ptients With Type 2 Dibetes Fesibility nd 1-Yer Results of Rndomized Clinicl Tril Florenci Hlperin, MD; Su-Ann Ding, MD; Donld C. Simonson, MD, MPH, ScD; Jennifer Pnosin, BA; Ann Goebel-Fbbri, PhD; Mrlene Wewlk, MD; Osm Hmdy, MD, PhD; Mrtin Abrhmson, MD; Kerri Clncy, RN; Kthleen Foster, RN; Dvid Lutz, MD; Ashley Vernon, MD; Allison B. Goldfine, MD IMPORTANCE Emerging dt support britric surgery s therpeutic strtegy for mngement of type 2 dibetes mellitus. Supplementl content t jmsurgery.com OBJECTIVE To test the fesibility of methods to conduct lrger multisite tril to determine the long-term effect of Roux-en-Y gstric bypss () surgery compred with n intensive dibetes medicl nd weight mngement (Weight Achievement nd Intensive Tretment []) progrm for type 2 dibetes. DESIGN, SETTING, AND PARTICIPANTS A 1-yer prgmtic rndomized clinicl tril ws conducted in n cdemic medicl institution. Prticipnts included persons ged 21 to 65 yers with type 2 dibetes dignosed more thn 1 yer before the study; their body mss index ws 3 to 42 (clculted s weight in kilogrms divided by height in meters squred) nd hemoglobin A 1c (HbA 1c ) ws greter thn or equl to 6.5%. All prticipnts were receiving ntihyperglycemic medictions. INTERVENTIONS (n = 19) or (n = 19) including 12 weekly multidisciplinry group lifestyle, medicl, nd eductionl sessions with monthly follow-up therefter. MAIN OUTCOMES AND MEASURES Proportion of ptients with fsting plsm glucose levels less thn 126 mg/dl nd HbA 1c less thn 6.5%, mesures of crdiometbolic helth, nd ptient-reported outcomes. RESULTS At 1 yer, the proportion of ptients chieving HbA 1c below 6.5% nd fsting glucose below 126 mg/dl ws higher following thn (58% vs 16%, respectively; P =.3). Other outcomes, including HbA 1c, weight, wist circumference, ft mss, len mss, blood pressure, nd triglyceride levels, decresed nd high-density lipoprotein cholesterol incresed more fter compred with. Improvement in crdiovsculr risk scores ws greter in the surgicl group. At bseline the prticipnts exhibited modertely low self-reported qulity-of-life scores reflected by Short Form-36 totl, physicl helth, nd mentl helth, s well s high Impct of Weight on Qulity of Life Lite nd Problem Ares in Dibetes helth sttus scores. At 1 yer, improvements in Short Form-36 physicl nd mentl helth scores nd Problem Ares in Dibetes scores did not differ significntly between groups. The Impct of Weight on Qulity of Life Lite score improved more with nd correlted with greter weight loss compred with. CONCLUSIONS AND RELEVANCE In obese ptients with type 2 dibetes, produces greter weight loss nd sustined improvements in HbA 1c nd crdiometbolic risk fctors compred with medicl mngement, with emergent differences over 1 yer. Both tretments improve generl qulity-of-life mesures, but provides greter improvement in the effect of weight on qulity of life. These differences my help inform therpeutic decisions for dibetes nd weight loss strtegies in obese ptients with type 2 dibetes until lrger rndomized trils re performed. TRIAL REGISTRATION clinicltrils.gov Identifier: NCT1732 JAMA Surg. 214;149(7): doi:1.11/jmsurg Published online June 4, 214. Author Affilitions: Division of Endocrinology, Dibetes, nd Hypertension, Brighm nd Women s Hospitl, Hrvrd Medicl School, Boston, Msschusetts (Hlperin, Simonson); Reserch Division, Joslin Dibetes Center, Hrvrd Medicl School, Boston, Msschusetts (Ding, Pnosin, Goebel-Fbbri, Wewlk, Hmdy, Abrhmson, Foster, Goldfine); Center for Metbolic nd Britric Surgery, Brighm nd Women s Hospitl, Hrvrd Medicl School, Boston, Msschusetts (Clncy, Lutz, Vernon). Corresponding Author: Allison B. Goldfine, MD, Reserch Division, Joslin Dibetes Center, Hrvrd Medicl School, One Joslin Plce, Boston, MA jmsurgery.com Copyright 214 Americn Medicl Assocition. All rights reserved. Downloded From: on 1/3/218

2 Roux-en-Y Bypss vs Lifestyle Chnges in Dibetes Originl Investigtion Reserch Despite substntil improvements in phrmcotherpy for dults with type 2 dibetes mellitus, fewer thn hlf ttin the recommended gols for hemoglobin A 1c (HbA 1c ) concentrtion, blood pressure, or cholesterol levels. 1 These findings, s well s the considerble individul nd public helth burden of dibetes-relted microvsculr nd mcrovsculr complictions, demonstrte the continued need for new pproches to tret hyperglycemi nd crdiovsculr risk fctors in ptients with dibetes. Emerging dt support substntil improvement in the mngement of dibetes, hypertension, nd dyslipidemi for dults with dibetes following britric surgery. Few dt re vilble for persons with lower-mgnitude obesity, nd very few rndomized studies hve mesured ptient-reported outcomes in this popultion. We conducted the Surgery or Lifestyle With Intensive Medicl Mngement in the Tretment of Type 2 Dibetes (SLIMM- T2D) tril, rndomized, controlled, prgmtic, singlecdemic center study responding to n Americn Recovery nd Reinvestment Act 2 request for pplictions (5-DK-12) to ssess the fesibility of methods to conduct lrger multisite tril compring the long-term effect of britric surgery with tht of medicl mngement to improve glycemic control nd crdiometbolic risk in obese ptients with type 2 dibetes. We compred Roux-en-Y gstric bypss () surgery with the intensive multidisciplinry medicl dibetes nd weight mngement progrm Weight Achievement nd Intensive Tretment (), designed for ppliction in rel-world clinicl prctice. s cognitive behviorl support is bsed on the Dibetes Prevention Progrm 3 nd Look AHEAD (Action for Helth in Dibetes) study 4,5 but the progrm differs importntly in mediction djustment pln, mount of cloric reduction nd dietry composition, exercise type nd durtion, nd dibetes eduction sessions, nd is performed only in group sessions. A prgmtic design ws selected to compre the effectiveness of using ongoing clinicl cre progrms. Methods Tril Design The study ws rndomized, prllel-group, prgmtic tril strtified for body mss index (BMI) bove or equl to 35 nd below 35 (clculted s weight in kilogrms divided by height in meters squred) with blnced rndomiztion (1:1) (Figure 1). The study ws conducted t n outptient clinic nd hospitl with shred cdemic ffilitions to Hrvrd Medicl School. Setting nd Prticipnts Prticipnts were recruited from hospitls nd clinics using electronic medicl record review for identifiction or by dvertisements. Eligible prticipnts were ged 21 to 65 yers with t lest 1 yer of type 2 dibetes, BMI 3 to 42, strong desire for substntil weight loss, nd commitment to life-long medicl nd nutritionl follow-up. They were free from ctive crdiovsculr or other diseses prohibiting them from exercising sfely or undergoing britric surgicl procedure. Additionlly, potentil prticipnts hd HbA 1c levels bove 7% (to convert to proportion of totl Hb, multiply by.1), regrdless of ongoing tretment, or 6.5% or greter while receiving either 2 orl ntihyperglycemic gents t greter thn or equl to hlf-mximl dose or insulin, nd with stble-dose tretment for more thn 8 weeks. Individuls were excluded if they hd detectble levels of ntiglutmic cid decrboxylse ntibody, history of dibetic ketocidosis, uncontrolled type 2 dibetes (HbA 1c >12%), gstrointestinl disese, mlignnt disese within 5 yers, significnt crdiopulmonry or renl dis- Figure 1. Enrollment, Rndomiztion, nd Retention of the Study Prticipnts 22 Assigned to 3 Lost to follow-up before intervention 1 Withdrew consent 1 New brest cncer dignosis 1 New psychitric illness 19 Anlyzed 822 Telephone inquiries 148 Attended clinicl tril orienttion session 93 Screening visits 43 Rndomized 21 Assigned to Why WAIT 2 Lost to follow-up before intervention 2 Withdrew consent 19 Anlyzed 674 Uninterested or ineligible 55 Did not pursue screening visit 5 Excluded fter screening 14 Surgicl preference LAGB 7 HbA 1c out of rnge 5 Physicin-deemed inpproprite 5 Renl function/lbuminuri 4 BMI out of rnge 4 No follow-up/moved 3 GAD positive 3 Desired only surgery 2 Smoker 3 Other (eg, ge, crdic stent, cirrhosis) BMI indictes body mss index; GAD, ntiglutmic cid decrboxylse ntibody positive; HbA 1c, hemoglobin A 1c ; LAGB, lproscopic djustble gstric bnd;, Roux-en-Y gstric bypss; nd WAIT, Weight Achievement nd Intensive Tretment. jmsurgery.com JAMA Surgery July 214 Volume 149, Number Copyright 214 Americn Medicl Assocition. All rights reserved. Downloded From: on 1/3/218

3 Reserch Originl Investigtion Roux-en-Y Bypss vs Lifestyle Chnges in Dibetes ese, ctive eting disorder, drug nd/or lcohol buse, impired mentl sttus, weight loss greter thn 3% within the previous 3 months, prticiption in nother weightreduction progrm, or were using weight-reduction medictions nd/or supplements. Prticipnts hd to be nonsmoking for more thn 2 months. Additionl informtion on the full exclusion criteri re presented in the Supplement (emethods). Rndomiztion nd Interventions The protocol ws pproved by Prtner s Helthcre humn subject institutionl review bord nd the US Food nd Drug Administrtion. An independent dt monitoring committee reviewed ptient sfety. The study ws described by telephone to the respondents. Potentilly interested individuls ttended in-person orienttions, during which study design nd medicl nd surgicl interventions were reviewed. People with preference for britric procedure other thn were not enrolled. Those interested in the tril were screened for ppropriteness for the surgicl nd medicl interventions. Rndomiztion ws computer-generted in centrlly llocted blocks of 4, strtified by BMI bove or equl to 35 nd below 35. The procedure ws performed t Brighm nd Women s Hospitl. All surgicl ptients were given routine ntibiotic nd venous thromboembolism prophylxis nd stndrdized nesthesi per routine hospitl protocols. The procedure involved 75-cm ntecolic, ntegstric Roux limb creted with 5-cm biliopncretic limb. A 15- to 2-mL gstric pouch ws creted long the lesser curve of the stomch, nd the lesser omentum ws divided t tht level. A gstrojejunostomy ws constructed using liner cutter stpler, nd the gstroenterotomy ws closed using running polyglctin 91 suture (Vicryl 2.; Ethicon Inc). Provoctive lek tests were performed, including blue dye nd bubble tests. Prticipnts rndomized to the medicl rm of the study enrolled in the progrm, which is designed for clinicl prctice 6 nd run qurterly t the Joslin Dibetes Center for groups of 1 to 15 ptients. s multidisciplinry pproch includes n endocrinologist (O.H.), registered dieticin, exercise physiologist, mentl helth provider (A.G.-F.), nd certified dibetes nurse eductor. Two-hour weekly group sessions re conducted during 12-week initition phse. Ptients receive individul mediction djustments nd prticipte in supervised group exercise nd support/didctic sessions. Key spects of include (1) weekly mediction djustments; (2) structured modified dietry intervention with hypocloric (15-18 kcl) diet with crbohydrtes (4%- 45%), protein (2%-3%), nd sturted ft intke reduced to less thn 7%, 7 with the 6 initil weeks including brekfst nd lunch mel replcement (Boost Glucose Control; Nestle Helth Science; nutrient content per 237 ml [8 fl oz] including clories, 19; protein, 16 g; crbohydrte, 16 g; fiber, 3 g; nd ft, 7g), 2 sncks, nd structured dinner menus; (3) up to 3 minutes per week of grded, blnced, nd individulized exercise, with emphsis on strength trining; (4) cognitive behviorl intervention; nd (5) group eduction. A mintennce phse of individul monthly counseling follows for the reminder of the yer. Additionl informtion describing the Why WAIT progrm is provided in the Supplement, including the progression of exercise (etble 1) nd the didctic core curriculum (etble 2). Prticipnts provided written informed consent first for screening for eligibility nd gin prior to rndomiztion. Prticipnts received compenstion for the time nd inconvenience ssocited with in-person study visits nd locl trnsporttion or prking vouchers. Prticipnts in the progrm lso receive mel replcement nutritionl drinks (Boost Glucose Control) for use during the 6 initil weeks of the progrm nd s needed during the first yer. Prticipnts pid their copyments nd insurnce deductibles for nd interventions. Surgicl costs were covered by n investigtor-initited wrd from Covidien for prticipnts with BMI less thn 35 becuse insurnce does not cover these procedures. Follow-up nd Outcome Assessments Metbolic ssessments were performed t bseline nd repeted t 1% of initil body weight loss to obtin ssessments t comprble level of weight lost in both cohorts. If 1% weight loss did not occur, metbolic ssessments were performed t 3 months. Finl ssessments were repeted t 12 months, providing time-bsed comprison. Metbolic ssessments included medictions nd dosing, weight (model 51 electronic scle; ACME), height (wll-mounted stdiometer), wist circumference (Gulk tpe mesure ccording to the Ntionl Hert, Lung, nd Blood Institute Clinicl Guidelines 8 ), nd seted blood pressure using n utomted device (BP742, Omron Helthcre). Body composition nd bsl metbolic rte were ssessed by bioelectricl impednce (TBF- 215; Tnit Corportion). A 6-minute wlk test ws performed. 9 Ptient-reported outcomes were systemticlly ssessed using surveys including the 36-item Short-Form (SF-36), version 2 1 ; Brriers to Being Physiclly Active 11 ; EuroQol 5 Dimensions (EQ- 5D) (EuroQol Group) 12 ; Problem Ares In Dibetes (PAID) 13,14 ; nd Impct of Weight on Qulity of Life Lite (IWQOL) (which ssesses weight-relted physicl function, self-esteem, sexul life, public distress, nd work-relted stress). 15 The United Kingdom Prospective Dibetes Study (UKPDS) Risk Engine ws used to clculte crdiovsculr risk. 16 Lbortory Tests Clinicl lbortory evlutions were performed by Quest Dignostics. Quest Lbortories is certified by both the Clinicl Lbortory Improvement Amendment nd the College of Americn Pthologists. Sttisticl Anlysis The primry outcome ws ttining glycemic control (fsting plsm glucose levels below 126 mg/dl [to convert to millimoles per liter, multiply by.555] nd HbA 1c below 6.5%) t 1 yer of follow-up, regrdless of whether ptients were using phrmceuticl interventions. We estimted the smple size ssuming tht would result in resolution of hyperglycemi in 8% of the ptients nd medicl mngement in 2%. Twenty prticipnts per group provided 97% power to detect significnt difference 718 JAMA Surgery July 214 Volume 149, Number 7 jmsurgery.com Copyright 214 Americn Medicl Assocition. All rights reserved. Downloded From: on 1/3/218

4 Roux-en-Y Bypss vs Lifestyle Chnges in Dibetes Originl Investigtion Reserch between groups, with α =.5. Dichotomous nd continuous vribles were nlyzed using logistic regression nd generl liner mixed model, respectively, to test the null hypotheses of equl resolution of hyperglycemi nd other mjor outcomes t 1 yer while controlling for covrites. Ech mesure s outcome nlysis during the 1-yer study ws djusted for bseline, unless noted otherwise. The primry nlysis ws intention-to-tret nd involved ll rndomly ssigned ptients who received t lest 1 postrndomiztion ssessment (modified per-protocol nlysis). Sensitivity nlysis included ll rndomized prticipnts (Supplement [etble 3]). Bseline chrcteristics re presented s men (SD) nd outcome dt re men (95% CI) or medin (interqurtile rnge [IQR]). No interim nlyses for superiority or futility were performed. All prticipnts completed the visits before dt nlysis. Results Prticipnts During recruitment (Mrch 12, 21, to September 7, 211), 822 potentil prticipnts underwent telephone screening, nd 148 subsequently ttended n orienttion session (Figure 1). Additionl informtion on recruitment pproches nd reported resons for not pursuing tril involvement re provided in the Supplement (etble 4 nd etble 5). Of those individuls, 93 underwent full medicl screening. The most common resons for screening filure were preference for n lterntive surgicl procedure, out-of-rnge HbA 1c, poor surgicl cndidcy, inbility to prticipte in n unsupervised exercise progrm, nd renl dysfunction. Forty-three prticipnts were rndomized to surgicl (, 22) or medicl (Why WAIT, 21) interventions. Before ny intervention, 3 prticipnts withdrew consent, 1 received dignosis of brest cncer, nd 1 received dignosis of severe depression; these individuls were not included further in summry dt (primry end-point nlysis including ll rndomized prticipnts is provided in the Supplement [etble 3]). Nineteen ptients were included in ech group for the finl nlysis. Bseline demogrphics of the ptients undergoing intervention re provided in Tble 1 nd include 6 prticipnts (32%) with BMI under 35 in the surgicl group nd 7 (37%) in the nonsurgicl group. Estblished microvsculr complictions were mild nd infrequent. Primry End Point Eleven prticipnts (58%) in the group reched the trget HbA 1c level of less thn 6.5% nd the fsting plsm glucose level below 126 mg/dl t nths, compred with 3 (16%) in the medicl therpy group (P =.3). The odds of resolution of hyperglycemi, s defined bove, were 6.9 times greter in the surgicl group t 1 yer. All ptients in the surgicl group who chieved trget glycemi were no longer receiving dibetes medictions t 1 yer. Weight nd Glycemi Erly ssessment ws performed when prticipnts lost 1% of their body weight or t 3 months if 1% loss ws not chieved by then. All prticipnts chieved 1% weight loss before 3 months, t medin of 39 dys (rnge, dys). In comprison, 37% (7 of 19) of prticipnts in the group chieved this 1% weight loss gol. Of prticipnts who did not lose 1% of their body weight by 3 months, men weight loss ws 5.4% (rnge, +.3% to 9.2%) t 3 months, with men group weight lost 7.7% (.8%) t 3 months. Thus, both groups were successful in weight loss, but there were greter reductions in weight following thn, nd differences emerged over time (Figure 2). Reductions in wist circumference, nd ft nd len mss by bioelectricl impednce were lso greter following compred with (Tble 2). At the erly ssessment, HbA 1c reduction did not differ significntly between groups, nd both groups chieved significnt reductions from bseline (Figure 2), lthough there ws shorter time intervl to the erly ssessment in the surgicl compred with the medicl group. At 1 yer, the chnge from bseline for HbA 1c ws significntly greter fter thn, nd significnt reduction from bseline ws sustined only in the surgicl group. The pttern for fsting glucose levels ws similr (Figure 2). Blood Pressure nd Lipid Levels Systolic nd distolic blood pressure nd triglycerides were lower t 1 yer nd high-density lipoprotein cholesterol ws incresed only in the group. The difference between the groups ws significnt (Tble 3) nd ws observed despite greter reductions in ntihypertensive nd lipid-lowering mediction use following (Supplement [efigure A nd B]). Crdiometbolic Risk At rndomiztion, prticipnts were free from ctive crdiovsculr or other diseses prohibiting them from exercising sfely, including unsupervised exercise. However, fitness ssessed by the 6-minute wlk test improved in those rndomized to the structured progrm, but hert rte recovery from exercise ws better following surgery. Nonsignificnt improvement in fitness tended to occur in the group by 1 yer such tht the difference between the groups ws not significnt. Crdiometbolic risk scores for coronry hert disese, ftl coronry hert disese, stroke, nd ftl stroke, estimted using the UKPDS Risk Engine, were ll reduced more t 1 yer following thn (Figure 2). In ddition, cretinine, white blood cell count, nd hemtocrit were lower, but the vitmin D level ws greter following thn. Ptient-Reported Outcomes At bseline prticipnts exhibited modertely low SF-36 totl, physicl helth, nd mentl helth scores, nd high IWQOL nd PAID helth sttus scores, consistent with moderte distress cross ll xes (Figure 3 nd Supplement [etble 6]). At erly ssessment, prticipnts reported greter improvements compred with prticipnts in qulity of life, ssessed by SF-36 totl, physicl helth, nd mentl helth scores. Differences between the groups did not persist t 1 yer. PAID cptured reductions in emotionl distress, eting behviors, jmsurgery.com JAMA Surgery July 214 Volume 149, Number Copyright 214 Americn Medicl Assocition. All rights reserved. Downloded From: on 1/3/218

5 Reserch Originl Investigtion Roux-en-Y Bypss vs Lifestyle Chnges in Dibetes Tble 1. Bseline Chrcteristics by Study Group Chrcteristic Roux-en-Y Gstric Bypss Age, men (SD), y 5.7 (7.6) 52.6 (4.3) Sex, No. (%) Mle 6 (32) 9 (47) Femle 13 (68) 1 (53) Rce/ethnicity, No. (%) White 14 (74) 1 (53) Africn Americn 3 (16) 8 (42) Asin 1 (5) Hispnic 1(5) 1(5) BMI, men (SD) 36. (3.5) 36.5 (3.4) BMI <35, No. (%) 6 (32) 7 (37) Weight, men (SD), kg 14.6 (15.5) 12.7 (17.) Blood pressure, men (SD), mm Hg Systolic (1.5) (14.7) Distolic 81.7 (7.4) 76.6 (8.8) Dibetes mellitus Yers since dignosis, men (SD) 1.6 (6.6) 1.2 (6.1) Complictions, No. (%) Retinopthy 1 (5) 6 (32) Neuropthy 3 (16) 5 (26) Nephropthy 1 (5) Medictions, No. (%) Insulin 15 (79) 8 (42) Metformin hydrochloride 17 (89) 15 (79) GLP-1 gonist 5 (26) 2 (11) Prmlintide cette 1 (5) Other glycemic mediction 7 (37) 12 (63) Sttin 15 (79) 16 (84) Other lipid-lowering mediction 3 (16) 2 (11) ACE inhibitor/arb 17 (89) 14 (74) Other ntihypertensive mediction 14 (74) 12 (63) Lbortory vlues, men (SD) b HbA 1c, % 8.24 (1.42) 8.83 (1.1) Glucose, mg/dl (49.7) (53.8) Totl cholesterol, mg/dl (34.) (38.6) Triglycerides, mg/dl (65.7) (75.7) HDL-C, mg/dl 43.6 (9.7) 39.1 (9.9) LDL-C, mg/dl c 88.1 (27.7) 98.9 (29.3) UKPDS risk scores, men (SD) CHD 9.8 (9.6) 1.9 (6.9) Ftl CHD 6.5 (7.7) 6.9 (4.9) Stroke 4. (4.1) 4. (2.3) Ftl stroke.6 (.6).5 (.3) Abbrevitions: ACE, ngiotensin-converting enzyme; ARB, ngiotensin receptor blocker; BMI, body mss index (clculted s weight in kilogrms divided by height in meters squred); CHD, coronry hert disese; GLP-1, glucgonlike peptide 1; HbA 1c, hemoglobin A 1c ; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; UKPDS, United Kingdom Prospective Dibetes Study; WAIT, Weight Achievement nd Intensive Tretment. SI conversion fctors: To convert glucose to millimoles per liter, multiply by.555; HbA 1c to proportion of totl Hb,.1; HDL-C, LDL-C, nd totl cholesterol to millimoles per liter,.259; nd triglycerides to millimoles per liter,.113. Hispnic prticipnts my be ny rce. b Lbortory ssessments were mde fter ptients fsted overnight. c Direct mesurement ws performed. nd difficulty with dibetes self-mngement fter both interventions nd were similr in mgnitude between the groups. The number of brriers to being ctive ws reduced, nd the mgnitude of improvement ws similr between the groups. The visul nlog scle score of the EQ-5D lso improved similrly between groups, with no significnt chnge within or between groups for the EQ-5D index score (dt not shown). The IWQOL score lso improved significntly following nd, nd the mgnitude of improvement ws significntly greter in the group t 1 yer. In the groups combined, improvement in IWQOL scores correlted with greter weight loss (r =.7;P <.1). Adverse Events No prticipnt experienced severe hypoglycemi (requiring ssistnce). Surgicl rm postintervention serious dverse events included ischemic hert disese with coronry rtery bypss surgery, new brest cncer dignosis, nephrolithisis, excerbted depression with suicide ttempt, nd hip rthroplsty. Notbly, hip pin preceded enrollment nd did not improve following weight loss; thus, hip rthroplsty following ws not the result of improved surgicl cndidcy. Three different prticipnts in the nonsurgicl rm hd presyncope serious dverse events. Discussion Risks nd benefits of britric surgery compred with nonsurgicl medicl mngement for obese ptients with type 2 dibetes, prticulrly for those with lesser-mgnitude obesity, re of incresing interest. The present study nd others 17,18 confirm tht rndomized tril of britric surgery compred with medicl nd lifestyle intervention for dibetes is fesible in the US popultion consistent with reported trils in other countries 18-2 nd with studies compring surgery with medicl pproches for coronry disese mngement. 21 Ptients often hve strong preference for the type of surgery, nd if lrger trils to directly ddress mortlity or crdiovsculr outcomes re conducted, prgmtic or innovtive designs to ccommodte ptients surgicl preference my be needed. We found tht obese ptients with type 2 dibetes re more likely to chieve the trget HbA 1c level of less thn 6.5% nd fsting plsm glucose less thn 126 mg/dl 1 yer fter rndomiztion to compred with intensive medicl dibetes nd weight mngement. Other glycemic thresholds often used to quntify chieving dibetes gols were lso higher following. Notbly, ll ptients in the surgicl group chieved glycemic control without using dibetes medictions. Likewise, the surgicl group experienced improved blood pressure nd lipid levels with reduction or elimintion of concomitnt medictions in mny ptients (Supplement). Our study lso dds to the reltively sprse dt vilble on ptients with lower-mgnitude obesity. 22 To our knowledge, our tril ws the first to use prgmtic, cliniclly vilble intensive dibetes weight mngement progrm designed specificlly for ppliction in rel-world clinicl prctice 6 modeled off clinicl tril prctices with demonstrted effectiveness, such 72 JAMA Surgery July 214 Volume 149, Number 7 jmsurgery.com Copyright 214 Americn Medicl Assocition. All rights reserved. Downloded From: on 1/3/218

6 Roux-en-Y Bypss vs Lifestyle Chnges in Dibetes Originl Investigtion Reserch s the Dibetes Prevention Progrm 3 nd Look AHEAD studies. 23 Initilly fvorble glycemic nd weight reduction occurred with medicl nd lifestyle intervention. Although weight loss ws mintined, dysglycemi recidivism rtes were high during the study yer. In generl, prticipnts nd providers ppered hesitnt to dd glycemic mngement phr- Figure 2. Chnges in Crdiometbolic Outcomes Following Britric Surgery nd Medicl Mngement A.5 B 2 Chnge in HbA 1c, % P =.8 Chnge in Fsting Plsm Glucose, mg/dl P < Bseline 1% WL 8 Bseline 1% WL C D 2.5 Chnge in BMI P <.1 Men No. of Dibetes Medictions P <.1 12 Bseline 1% WL E P <.1 P <.1 P =.8 P = CHD Ftl CHD Stroke Ftl Stroke Chnge in UKPDS Risk, % Bseline F Chnge in Weight, kg 1% WL R =.94 P < Chnge in Ft Mss, kg ChngesinhemoglobinA 1c (HbA 1c )(A),fstingplsmglucose(B),ndbodymssindex(BMI)(clcultedsweightinkilogrmsdividedbyheightinmeterssqured)(C) grphed by tretment group nd time s bseline-djusted men, with SE indicted with limit lines. P vlues indicte the significnt difference between groups in liner mixedmodeldjustedforbseline.mennumberofdibetesmedictions(d).chnge from bseline for United Kingdom Prospective Dibetes Study (UKPDS) Risk Scores forcoronryhertdisese(chd),ftlchd,stroke,ndftlstroke.vrinceindicted withthelimitlinesisse(e).thereltionshipbetweentotlweightlost(wl)ndchnge inftbybioelectriclimpednce(f).indictesroux-en-ygstricbypss;wait, Weight Achievement nd Intensive Tretment. jmsurgery.com JAMA Surgery July 214 Volume 149, Number Copyright 214 Americn Medicl Assocition. All rights reserved. Downloded From: on 1/3/218

7 Reserch Originl Investigtion Roux-en-Y Bypss vs Lifestyle Chnges in Dibetes Tble 2. Metbolic Chnges Following nd Dibetes nd Weight Medicl Mngement Bseline-Adjusted Men Chnge (95% CI) Bseline, Men (SD) 1% Weight Lost P End Point Vlue Wist, cm (14.9) (12.2) 9.8 ( 12.9 to 6.6) 5.3 ( 8.4 to 2.1) 26.9 ( 3.4 to 23.5) 6.6 ( 1.3 to 2.9) <.1 b Mss, kg Len 59.2 (14.1) 6.1 (1.8) 1.8 ( 3. to.6) 1.3 ( 2.5 to.1) 5.1 ( 7. to 3.3) 1.4 ( 3.4 to.6).4 b Ft 45.5 (9.4) 42.6 (9.8) 9.4 ( 11.4 to 7.5) 6.1 ( 8. to 4.1) 22.7 ( 25.6 to 19.8) 6.2 ( 9.3 to 3.) <.1 b BP, mm Hg Systolic (1.5) (14.7) 7.3 ( 13.1 to 1.4) 6.3 ( 12.1 to.4) 12.3 ( 18.5 to 6.2) 1. ( 7.2 to 5.3).2 c Distolic 81.7 (7.4) 76.6 (8.8).9 ( 2.3 to 4.1) 4.3 ( 7.5 to 1.1) 5.1 ( 8.3 to 1.9) 2.1 ( 5.3 to 1.2) <.1 c Lbortory vlues Totl cholesterol, mg/dl (34.) (38.6) 18.6 ( 32.3 to 4.9) 3.7 ( 17.4 to 1.) 3.2 ( 17.7 to 11.3) 8.3 ( 7. to 23.5).11 Triglycerides, mg/dl 12 (66) 156 (76) 32 ( 43 to 21) 31 ( 42. to 19) 47 ( 63 to 3) 5 ( 23 to 12).2 b HDL-C, mg/dl 43.6 (9.7) 39.1 (9.9) 5.8 ( 8.5 to 3.2).1 ( 2.5 to 2.8) 1.2 (6.7 to 13.6).4 ( 3.3 to 4.) <.1 c LDL-C, mg/dl d 88.1 (27.7) 98.9 (29.3) 7.4 ( 19. to 4.1) 4.4 ( 16.1 to 7.3) 5.4 ( 17.8 to 6.9) 8.6 ( 4.5 to 21.6).22 ALT, IU/L 32.2 (16.3) 27.7 (12.3) 7.4 ( 1.7 to 4.) 3.8 ( 7.2 to.5) 1.6 ( 15.5 to 5.6) 4.7 ( 1.1 to.6).6 AST, IU/L 3.6 (21.6) 23.3 (13.4) 1.4 ( 5.5 to 2.6).8 ( 4.8 to 3.2) 5.8 ( 1. to 1.6) 3.3 ( 7.6 to 1.1).49 Cretinine, mg/dl.71 (.14).86 (.21).6 (.1 to.2).2 (.2 to.6).7 (.11 to.3) (.5 to.4).1 Urinry lbumin 3(to7) f 3(to1) f ND ND 1. ( 5. to 5.) ( 4.5 to 2.).96 f to cretinine rtio e Vitmin D 3, ng/ml 22.2 (9.) 21. (8.8) 7. (4.3 to 9.7).3 ( 3.1 to 3.7) 4.6 (.5 to 8.6) 1. ( 3.3 to 5.3).1 Hemtocrit, % 36.8 (3.3) 4.2 (4.3) 4.4 ( 5.4 to 3.5). ( 1. to 1.) 2.3 ( 3.6 to 1.1).2 ( 1.2 to1.5) <.1 WBCs, 1 3 /μl 6.8 (2.1) 6.5 (1.8) 1.2 ( 1.7 to.7).4 (.9 to.1).9 ( 1.4 to.4).1 (.4 to.6).1 6-Min wlk, m (65.5) (55.9) 6.4 ( 29.7 to 16.8) 33.2 (1. to 56.5) 17.8 ( 8.3 to 44.) 27.7 (.4 to 55.1).11 Hert rte recovery (1 min), bets/min 92.2 (15.2) 87.5 (12.) 4.6 ( 9.2 to ) 1.1 ( 5.8 to 3.5) 1.7 ( 15.9 to 5.5) 1. ( 4.5 to 6.5).1 Abbrevitions: ALT, lnine minotrnsferse; AST, sprtte minotrnsferse; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; IQR, interqurtile rnge; LDL-C, low-density lipoprotein cholesterol; ND, not determined;, Roux-en-Y gstric bypss; WAIT, Weight Achievement nd Intensive Tretment; WBCs, white blood cells. SI conversion fctors: To convert ALT nd AST to microktls per liter, multiply by.167; cretinine to micromoles per liter, 88.4; glucose to millimoles per liter,.555; HDL-C, LDL-C, nd totl cholesterol to millimoles per liter,.259; hemtocrit to proportion of 1.,.1; triglycerides to millimoles per liter,.113; nd WBCs to 1 9 /L, 1.. P vlues represent tretment effects from liner mixed model corrected for bseline, unless otherwise noted. b P vlue for time tretment interction ws lso significnt t P <.5. c P vlue represents time tretment interction; tretment effect ws not significnt. d Direct mesurement ws performed. e Urinry lbumin reported in microgrms of protein per milligrms of cretinine, obtined in spot morning void. f Medin nd IQR re provided nd were nlyzed using the Kruskl-Wllis test for nonprmetric dt. mcotherpies fter the initil success lowering the HbA 1c concentrtion with fewer medictions or lower dosges. At follow-up visits, prticipnts reported their willingness to increse dherence to dietry nd exercise progrms. In contrst, lthough the shorter time to erly ssessment fter compred with could confound the chnge in HbA 1c t this time, weight nd glycemic improvements fter occurred quickly nd were mintined throughout the 1-yer follow-up period. Although the study ws not powered to ssess the effects of interventions on dditionl metbolic mesures, we observed improvements in multiple crdiovsculr risk fctors including substntil differences in improvement in UKPDSclculted crdiovsculr risk scores. These findings concur with crdiovsculr outcomes reductions found in multiple nonrndomized, observtionl, controlled trils nd my portend improved mjor crdiovsculr event rtes for surgicl ptients. Both nd interventions improved selfreported totl, physicl, nd mentl helth sttus (SF-36); problems ssocited with dibetes mngement (PAID); brriers to being ctive; nd dverse effects of weight on life qulity (IWQOL). Erly deteriortion in the SF-36 totl nd physicl helth scores reported in surgicl ptients could be the result of the short postopertive time intervl to the 1% weight lost outcome for this ssessment. At 1 yer, improvements were comprble between the groups. Similr-mgnitude improvements in ptient-reported dibetes burden were chieved in different wys: with resolution of hyperglycemi following nd with eduction, lifestyle, nd mediction chnges 722 JAMA Surgery July 214 Volume 149, Number 7 jmsurgery.com Copyright 214 Americn Medicl Assocition. All rights reserved. Downloded From: on 1/3/218

8 Roux-en-Y Bypss vs Lifestyle Chnges in Dibetes Originl Investigtion Reserch Tble 3. Glycemic Chnges Following nd Dibetes nd Weight Medicl Mngement, No. (%) Primry End Point (n = 19) (n = 19) P Vlue HbA 1c <6.5% nd FPG <126 mg/dl 11 (58) 3 (16).3 Meeting ADA tretment gols HbA 1c <7.% 15 (79) 4 (21).2 LDL-C <1 mg/dl b 15 (79) 9 (47).5 Systolic blood pressure <13 mm Hg 16 (84) 11 (58).4 Meeting ll 3 gols 11 (58) 1 (5).7 Normoglycemi HbA 1c <6.% 6 (32).5 c FPG <1 mg/dl 14 (74) 3 (16).3 Meeting both criteri 6 (32).2 d Abbrevitions: ADA, Americn Dibetes Assocition; FPG, fsting plsm glucose; HbA 1c, hemoglobin A 1c ; LDL-C, low-density lipoprotein cholesterol;, Roux-en-Y gstric bypss; WAIT, Weight Achievement nd Intensive Tretment. SI conversion fctors: To convert HbA 1c to proportion of totl Hb, multiply by.1; LDL-C to millimoles per liter,.259. P vlues re logistic regression between groups corrected for bseline, unless noted. b Direct mesurement ws performed. c P vlue is exct logistic regression corrected for bseline. d P vlue cnnot be djusted for both bseline HbA 1c nd fsting glucose becuse there were no ptients with HbA 1c less thn 6.% in the progrm; thus, this reported vlue is undjusted for bseline. in the progrm. Brriers to being ctive were similrly improved in both groups. Weight-specific qulity-of-life improvements were proportionl to weight lost. Greter differences between the groups ppered t 1 yer compred with the erlier ssessment. This study hd limittions. Durtion of dibetes nd insulin use, s proxies for β-cell function, were not inclusion or exclusion criteri. Thus, our study popultion hd wide rnge cross these vribles. There were reltively few ptients with dibetes-relted coexisting estblished microvsculr or crdiovsculr disese, limiting the pplicbility of the findings to ptients with more extensive dibetes-relted complictions. It is possible tht prticipnts willing to be rndomized to surgery re not representtive of motivted ptients willing only to prticipte in n intensive medicl-mngement progrm thus ffecting the mount of weight lost in this group. Despite the rndomiztion process, prticipnts in the medicl rm hd numericlly higher bseline HbA 1c concentrtions nd fsting glucose levels nd thus, despite sttisticl corrections for bseline dysglycemi, could be less likely to chieve dichotomous end point. We did not study emerging surgicl pproches, such s the now frequently used gstric sleeve. 29 The smll number of prticipnts vilble t the 1 yer follow-up disllows ssessment of infrequent or longterm dverse events, crdiovsculr or mortlity outcomes, metbolic response durbility over time, or cost-effectiveness. These fctors re especilly relevnt considertions for public helth policy chnges recommending surgicl intervention for dibetes mngement. 3 Serious dverse events were numericlly more frequent in surgicl ptients, nd possible debilitting surgicl events 18 cn substntilly offset ny fvorble metbolic improvements. Individul nd societl risk tolernce my differ. The Americn Recovery nd Reinvestment Act fesibility funding for rndomized tril compring britric nd metbolic surgeries with medicl pproch did not permit extended follow-up. At this time, the potentil effect of long-term nutritionl deficiencies nd lck of dt on crdiovsculr nd mortlity outcomes must temper ny enthusism for n endorsement of surgicl procedures for dibetes mngement. Although resolution of hyperglycemi my not lst indefinitely following surgery, 31 the UKPDS 32 nd Steno-2 Study 33 in ptients with type 2 dibetes nd the Dibetes Control nd Complictions Tril 34 in ptients with type 1 dibetes ll suggest the helth benefits of previous glycemic control my tke yers to emerge. Despite lck of significnt differences in glycemic control during the extended observtionl follow-up period, ptients previously rndomized to intensive control demonstrted significntly lower risk of dibetes complictions. The continuing benefit of erly improved metbolic control hs been termed metbolic memory or legcy effect. These dt suggest tht optiml mintennce of metbolic control my minimize the long-term risk of dibetic complictions, lthough this hypothesis remins controversil nd my not be true for ptients with longer-durtion dibetes Low opertive morbidity permits considertion of britric nd metbolic surgeries specificlly for dibetes mngement, lthough few dt re vilble for ptients with lower mount of excess weight 22 nd currently vilble studies suggest tht improved mortlity my be limited to the ptients with the highest level of obesity. 24 Our tril nd other smll studies 17,19,2 suggest helth benefits for ptients with type 2 dibetes nd lower-degree obesity who ccept surgicl risk. However, the short- nd longterm risk nd benefits need serious evlution. Prospective nd cse-control, but not rndomized, studies suggest significnt benefits ssocited with britric surgery in dibetes tretment nd prevention, reduced incidence of cncer in women, 38 nd reduced crdiovsculr 26,39 jmsurgery.com JAMA Surgery July 214 Volume 149, Number Copyright 214 Americn Medicl Assocition. All rights reserved. Downloded From: on 1/3/218

9 Reserch Originl Investigtion Roux-en-Y Bypss vs Lifestyle Chnges in Dibetes nd ll-cuse mortlity 24,25,39-41 for obese ptients. Although upstrem bis in ptient selection is possible in these nonrndomized trils, the potentil mgnitude of these benefits, if they re confirmed, is substntil. Without unified longterm outcome tril to compre britric surgery with intensive medicl weight mngement, our study nd other smll Figure 3. Ptient-Reported Outcomes nd Chnge in Body Mss Index (BMI) nd Impct of Weight on Qulity of Life Lite (IWQOL) A 2 Totl Physicl Helth Mentl Helth,c 15,b,b d Chnge in SF-36 Score % WL 1% WL 1% WL B C D 25 Chnge in PAID Score 2 Chnge in Brriers to Being Active Score d e Chnge in EQ-5D VAS Score % WL 2.4 1% WL 1% WL E F R =.72, P < Chnge in IWQOL Score ,b Chnge in IWQOL Score % WL Chnge in BMI 16 A, Short-Form 36 (SF-36). B, Problem Ares in Dibetes (PAID). C, Brriers to Being Active. D, EuroQol 5 Dimensions (EQ-5D) visul nlog scle (VAS). E, IWQOL. F, Reltionship between chnge in BMI nd chnge in IWQOL scores. Dt re grphed by tretment group nd time s bseline-djusted men chnge from bseline nd SE, indicted with limit lines. Bseline men (SD) of ll ptient-reported outcomes re provided in the Supplement (etble 6). indictes Roux-en-Y gstric bypss; WAIT, Weight Achievement nd Intensive Tretment; nd WL, weight loss. P <.1 (within-group comprison). b P <.1 (between-group comprison). c P <.1 (between-group comprison). d P <.1 (within-group comprison). e P <.5 (between-group comprison). 724 JAMA Surgery July 214 Volume 149, Number 7 jmsurgery.com Copyright 214 Americn Medicl Assocition. All rights reserved. Downloded From: on 1/3/218

10 Roux-en-Y Bypss vs Lifestyle Chnges in Dibetes Originl Investigtion Reserch rndomized clinicl trils provide dt to support the observtionl studies nd suggest role for surgicl pproch to dibetes mngement. Conclusions After 1-yer follow-up period in clinicl setting, better weight loss nd glycemi control, s well s improvement in other crdiovsculr risk mrkers, occurred in the present study following compred with n intensive dibetes nd weight mngement progrm. Metbolic improvements hve the potentil to reduce crdiovsculr morbidity nd mortlity, s seen in nonrndomized studies. Thus, our short-durtion study suggests tht my be useful in mnging type 2 dibetes, including for ptients with lower levels of obesity (BMI 3-42). Individul risks nd benefits should be crefully considered. Improvements in ptientreported outcomes were similr t 1 yer despite the different therpeutic pproches. ARTICLE INFORMATION Accepted for Publiction: Jnury 14, 214. Published Online: June 4, 214. doi:1.11/jmsurg Author Contributions: Drs Hlperin nd Ding contributed eqully to the work. Drs Ding nd Simonson hd full ccess to ll the dt in the study nd tke responsibility for the integrity of the dt nd the ccurcy of the dt nlysis. Study concept nd design: Hlperin, Simonson, Hmdy, Abrhmson, Lutz, Goldfine. Acquisition, nlysis, or interprettion of dt: Hlperin, Ding, Simonson, Pnosin, Goebel-Fbbri, Wewlk, Clncy, Foster, Vernon, Goldfine. Drfting of the mnuscript: Hlperin, Ding, Simonson, Pnosin, Foster, Vernon, Goldfine. Criticl revision of the mnuscript for importnt intellectul content: Hlperin, Ding, Simonson, Pnosin, Goebel-Fbbri, Wewlk, Hmdy, Abrhmson, Clncy, Lutz, Goldfine. Sttisticl nlysis: Hlperin, Simonson. Obtined funding: Hlperin, Simonson, Lutz, Vernon, Goldfine. Administrtive, technicl, or mteril support: Hlperin, Ding, Simonson, Pnosin, Goebel-Fbbri, Wewlk, Hmdy, Abrhmson, Clncy, Foster, Vernon, Goldfine. Study supervision: Hlperin, Simonson, Wewlk, Hmdy, Abrhmson, Clncy, Lutz, Vernon, Goldfine. Conflict of Interest Disclosures: Dr Hmdy serves s consultnt for Abbott Nutrition nd Merck Phrmceuticls nd receives reserch support from Neurometrix nd Metgenics. Dr Abrhmson is member of the dvisory bords of Novo Nordisk, Hlozyme, Jnnsen Phrmceuticls, nd WebMD Helth Services. Dr Goldfine receives supplies for investigtor-initited studies from Crco Phrmceuticls; Amnel Phrmceuticls; Novo Nordisk; Lifescn, Division of Johnson & Johnson; Nestle Nutrition; nd Mercodi; nd grnt support from Diichi Snky; nd hs served s consultnt for Novo Nordisk. No other disclosures were reported. Funding/Support: This work ws supported by Ntionl Institute of Dibetes nd Digestive nd Kidney Diseses grnts RC1-DK86918, R56- DK95451, nd P3-DK3836; the Mriett Blu grnt ICM from the Österreichischer Austusdienst; nd the Herbert Gretz Fund. Covidien provided funds for the surgicl costs of prticipnts with BMI less thn 35 who were rndomized to undergo surgery; Lifescn, Division of Johnson & Johnson, provided home glucose monitoring supplies; Nestle Nutrition Inc provided Boost; nd Mercodi provided ssy mterils. Additionl Contributions: We cknowledge the support of the Joslin Clinicl Reserch Center nd thnk its philnthropic donors. REFERENCES 1. Ali MK, Bullrd KM, Sddine JB, Cowie CC, Impertore G, Gregg EW. Achievement of gols in US dibetes cre, N Engl J Med.213; 368(17): Ntionl Institutes of Helth. Highest priority chllenge topics [pge 2]. /rchive/grnts/funding/chllenge_wrd/high _Priority_Topics.pdf. Accessed April 23, Knowler WC, Brrett-Connor E, Fowler SE, et l; Dibetes Prevention Progrm Reserch Group. Reduction in the incidence of type 2 dibetes with lifestyle intervention or metformin. N Engl J Med. 22;346(6): Wdden TA, West DS, Delhnty L, et l; Look AHEAD Reserch Group. 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11 Reserch Originl Investigtion Roux-en-Y Bypss vs Lifestyle Chnges in Dibetes 24. Adms TD, Gress RE, Smith SC, et l. Long-term mortlity fter gstric bypss surgery. N Engl J Med. 27;357(8): Sjöström L, Nrbro K, Sjöström CD, et l; Swedish Obese Subjects Study. Effects of britric surgery on mortlity in Swedish obese subjects. N Engl J Med. 27;357(8): Sjöström L, Peltonen M, Jcobson P, et l. Britric surgery nd long-term crdiovsculr events. JAMA. 212;37(1): Vest AR, Heneghn HM, Agrwl S, Schuer PR, Young JB. Britric surgery nd crdiovsculr outcomes: systemtic review. Hert. 212;98(24): Johnson BL, Blckhurst DW, Lthm BB, et l. Britric surgery is ssocited with reduction in mjor mcrovsculr nd microvsculr complictions in modertely to severely obese ptients with type 2 dibetes mellitus. J Am Coll Surg. 213;216(4): Buchwld H, Oien DM. Metbolic/britric surgery worldwide 211. Obes Surg. 213;23(4): Rubino F, Kpln LM, Schuer PR, Cummings DE; Dibetes Surgery Summit Delegtes. The Dibetes Surgery Summit consensus conference: recommendtions for the evlution nd use of gstrointestinl surgery to tret type 2 dibetes mellitus. Ann Surg.21;251(3): Arterburn DE, Bogrt A, Sherwood NE, et l. A multisite study of long-term remission nd relpse of type 2 dibetes mellitus following gstric bypss. Obes Surg. 213;23(1): Holmn RR, Pul SK, Bethel MA, Mtthews DR, Neil HA. 1-Yer follow-up of intensive glucose control in type 2 dibetes. N Engl J Med. 28;359 (15): Gede P, Lund-Andersen H, Prving HH, Pedersen O. Effect of multifctoril intervention on mortlity in type 2 dibetes. N Engl J Med. 28; 358(6): Nthn DM, Clery PA, Bcklund JY, et l; Dibetes Control nd Complictions Tril/Epidemiology of Dibetes Interventions nd Complictions (DCCT/EDIC) Study Reserch Group. Intensive dibetes tretment nd crdiovsculr disese in ptients with type 1 dibetes. N Engl J Med. 25;353(25): Gerstein HC, Miller ME, Byington RP, et l; Action to Control Crdiovsculr Risk in Dibetes Study Group. Effects of intensive glucose lowering in type 2 dibetes. N Engl J Med. 28;358(24): Ptel A, McMhon S, Chlmers J, et l; ADVANCE Collbortive Group. Intensive blood glucose control nd vsculr outcomes in ptients with type 2 dibetes. N Engl J Med. 28;358(24): Duckworth W, Abrir C, Moritz T, et l; VADT Investigtors. Glucose control nd vsculr complictions in veterns with type 2 dibetes. N Engl J Med. 29;36(2): Sjöström L, Gummesson A, Sjöström CD, et l; Swedish Obese Subjects Study. Effects of britric surgery on cncer incidence in obese ptients in Sweden (Swedish Obese Subjects Study): prospective, controlled intervention tril. Lncet Oncol. 29;1(7): Flum DR, Dellinger EP. Impct of gstric bypss opertion on survivl: popultion-bsed nlysis. J Am Coll Surg. 24;199(4): Christou NV, Smplis JS, Libermn M, et l. Surgery decreses long-term mortlity, morbidity, nd helth cre use in morbidly obese ptients. Ann Surg. 24;24(3): McDonld KG Jr, Long SD, Swnson MS, et l. The gstric bypss opertion reduces the progression nd mortlity of non insulindependent dibetes mellitus. J Gstrointest Surg. 1997;1(3): JAMA Surgery July 214 Volume 149, Number 7 jmsurgery.com Copyright 214 Americn Medicl Assocition. All rights reserved. Downloded From: on 1/3/218