Bariatric/Metabolic Surgery to Treat Type 2 Diabetes in Patients With a BMI,35 kg/m 2

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1 924 Dibetes Cre Volume 39, June 2016 METABOLIC SURGERY Britric/Metbolic Surgery to Tret Type 2 Dibetes in Ptients With BMI,35 kg/m 2 Dibetes Cre 2016;39: DOI: /dc Dvid E. Cummings 1 nd Ricrdo V. Cohen 2 OBJECTIVE Globl usge of britric surgery hs been dictted for the pst qurter century by Ntionl Institutes of Helth recommendtions restricting these opertions to individuls with BMI 35 kg/m 2. Strong evidence now demonstrtes tht britric procedures mrkedly improve or cuse remission of type 2 dibetes mellitus (T2DM), in prt through weight-independent mechnisms, nd tht bseline BMI does not predict surgicl benefits on glycemic or crdiovsculr outcomes. This impels considertion of such opertions s metbolic surgery, which is used expressly to tret T2DM, including mong ptients with BMI <35 kg/m 2 who constitute the mjority of people with dibetes worldwide. Here, we review vilble evidence to inform tht considertion. RESULTS A met-nlysis of the 11 published rndomized clinicl trils (RCTs) directly compring britric/metbolic surgery versus vriety of medicl/lifestyle interventions for T2DM provides level 1A evidence tht surgery is superior for T2DM remission, glycemic control, nd HbA 1c lowering. Importntly, this is eqully true for ptients whose bseline BMI is below or bove 35 kg/m 2. Similr conclusions derive from metnlyses of high-qulity nonrndomized prospective comprisons. Met-nlysis of ll pertinent published studies indictes tht T2DM remission rtes following britric/ metbolic surgery re comprble bove nd below the 35 kg/m 2 BMIthreshold.The sfety, ntidibetes durbility, nd benefits on other crdiovsculr risk fctors from britric/metbolic surgery pper roughly comprble mong ptients with BMI below or bove 35 kg/m 2. Further studies re needed to extend long-term findings nd mesure hrd mcrovsculr/microvsculr outcomes nd mortlity in RCTs. CONCLUSIONS Extnt dt, including level 1A evidence from numerous RCTs, support new guidelines from the 2nd Dibetes Surgery Summit tht dvocte for the considertion of britric/metbolic surgery s one option, long with lifestyle nd medicl therpy, to tret T2DM mong ptients with BMI <35 kg/m 2. For the pst qurter century, worldwide usge of britric surgery hs lrgely been governed by 1991 set of recommendtions from the Ntionl Institutes of Helth (NIH) tht limit these opertions to severely obese individuls (BMI $40 kg/m 2 )or to ptients with BMI $35 kg/m 2 nd serious obesity-relted comorbidities, such s type 2 dibetes mellitus (T2DM) (1). In the time since those NIH recommendtions were written, lrge new evidence bse hs been generted demonstrting powerful effects of most britric 1 VA Puget Sound Helth Cre System nd Dibetes nd Obesity Center of Excellence, University of Wshington, Settle, WA 2 Center for Dibetes nd Obesity, Oswldo Cruz Hospitl, São Pulo, Brzil Corresponding uthor: Dvid E. Cummings, dvidec@u.wshington.edu. Received 17 Februry 2016 nd ccepted 22 Mrch by the Americn Dibetes Assocition. Reders my use this rticle s long s the work is properly cited, the use is eductionl nd not for profit, nd the work is not ltered. See ccompnying rticles, pp. 857, 861, 878, 884, 893, 902, 912, 934, 941, 949, nd 954.

2 cre.dibetesjournls.org Cummings nd Cohen 925 opertions on T2DM (2,3). It hs lso become very cler within the pst decde tht the ntidibetes impct of some britric procedures results from not only secondry consequences of reduced food intke nd body weight but lso dditionl weight-independent mechnisms (4 6). These findings hve led to prdigm shift of thought in the field, propelling n incresingly populr view tht some opertions should be viewed not just s britric surgery but lso metbolic surgery (7,8). A nturl consequence of this chnge in mind-set is to consider the use of britric/metbolic surgery to tret T2DM in less obese or even merely overweight ptients, with BMI levels below existing NIH cutoffs. Here, we discuss the conceptul logic for contemplting the use of britric/ metbolic surgery to tret T2DM in ptients with BMI,35 kg/m 2, long with vilble evidence pertinent to tht considertion. Elsewhere in this issue of the Dibetes Cre, new guidelines from the 2nd Dibetes Surgery Summit (DSS-II) re published to inform the proper plce for britric/metbolic surgery in the overll T2DM tretment lgorithm (9). These guidelines, which re intended to replce the conspicuously outdted 1991 NIH recommendtions (1), dvocte for the considertion of surgery s one option, long with lifestyle nd medicl pproches, to tret T2DM in ptients with BMI s low s 30 kg/m 2, or s low s 27.5 kg/m 2 for Asin popultions. This rticle evlutes the evidence supporting these new clinicl prctice guidelines. RATIONALE FOR CONSIDERING METABOLIC SURGERY FOR T2DM IN LOWER-BMI PATIENTS Severl lines of evidence nd logic justify contemplting the use of britric/ metbolic opertions in lower-bmi ptients who hve T2DM tht is not dequtely controlled with behviorl/ phrmceuticl interventions. First, the impct of britric/metbolic surgery on T2DM, especilly from opertions involving intestinl bypsses, is very impressive. Although dibetes is trditionlly considered progressive, relentless disese in which mitigtion of end-orgn complictions is the primry therpeutic gol, lrge mjority of ptients with T2DM who undergo britric/metbolic surgery experience remission of this disese nd therefter mnifest nondibetic glycemi off ll dibetes medictions (2,3,10). For exmple, the T2DM remission rte fter Roux-en-Y gstric bypss (RYGB) is typiclly 70 80%, nd it is even higher for biliopncretic diversion (BPD). Such percentges vry depending on the HbA 1c threshold used to define remission, but by ny definition, these opertions yield T2DM remission in most cses. Across mny studies, the best preopertive predictors of filure to remit dibetes re long durtion of disese, use of insulin, high glycemi, nd very low C-peptide levels. As these probbly ll reflect dvnced dibetes with irreversible b-cell destruction, the impliction is tht surgery should not merely be considered s slvge option to be used fter filing mny yers of other therpies. Although mny people with T2DM who initilly experience postopertive dibetes remission ultimtely develop recurrence, the medin disesefree period mong such individuls fter RYGB is 8.3 yers, for exmple (11). Most of this evidence derives from studies of people with BMI $35 kg/m 2, but there is no priori reson to predict tht the ntidibetes effects of surgery would dispper mong ptients below tht BMI level, which ws defined reltively rbitrrily in 1991 s cutoff for britric surgery (1). Second, lthough high BMI hs trditionlly been used s the primry criterion to select ptients for britric surgery, no dt demonstrte tht bseline BMI predicts the success of such opertions on metbolic, crdiovsculr, or other hrd clinicl outcomes (even though higher bseline BMI does predict greter weight loss). Insted, strong evidence indictes tht preopertive BMI, t lest within the obese rnge, does not predict the benefits of surgery on dibetes prevention (12,13), remission (11,14 19), nd recurrence fter initil remission (15) or the mgnitude of its effects on hert ttcks, strokes (20,21), cncer (22), or deth (11,12,17,18,20,22,23). In contrst, high levels of bseline fsting insulin nd/or glucose (presumbly reflecting insulin resistnce) do predict the benefits of surgery on most of these end points. This strongly suggests tht the dvntges of britric/metbolic surgery on key clinicl outcomes result more from improved glucose homeostsis thn from weight loss per se (12,14,20,22 26). These dt lso indicte tht high fsting insulin nd glucose levels, or some other mesure of insulin resistnce, would be better evidence-bsed criteri for surgicl selection thn BMI is. Third, use of metbolic surgery to tret T2DM in lower-bmi ptients mkes conceptul sense if it improves dibetes t lest in prt through weight-independent effects, nd considerble evidence now demonstrtes such mechnisms (3,5). Regrding RYGB, for exmple, the following five bodies of evidence ttest to weightindependent ntidibetes mechnisms engged by this opertion, in ddition to the well-known glycemic benefits of weight loss (4). 1. Dibetes remission frequently occurs very fst, long before substntil weight loss hs occurred. At lest some of this might result from periopertive cute cloric restriction, which is well known to improve insulin sensitivity nd glycemi, lthough it is not cler why it is observed more fter britric/metbolic surgery thn other gstrointestinl opertions. 2. Glucose homeostsis improves more fter given mount of RYGB-induced weight loss thn with equivlent weight reduction chieved by diet/exercise or lproscopic djustble gstric bnding (LAGB). 3. There is n inconsistent correltion between the mount of weight lost fter RYGB nd the degree of dibetes improvement. 4. Novel experimentl opertions tht replicte some of the intestinl ntomy nd physiology of RYGB without compromising the stomch cn exert powerful ntidibetes effects with little or no weight loss. 5. Rre cses of extreme hyperinsulinemic/ hypoglycemi tht occsionlly develop mny yers fter RYGB (typiclly during prtil weight regin) suggest the possible existence fter surgery of chronic b-cell stimultory effects unrelted to weight chnge. Potentil mechnisms mediting direct ntidibetes effects of metbolic surgery include enhnced secretion of lower intestinl hormones such s glucgon-like peptide 1, ltered physiology due to

3 926 Britric/Metbolic Surgery in Lower-BMI Ptients Dibetes Cre Volume 39, June 2016 excluding ingested nutrients from the upper intestine, upregultion of one or more puttive nti-incretins or decretins, compromised ghrelin secretion, modultions of intestinl nutrient-sensing pthwys tht regulte insulin sensitivity, chnges in bile cid signling, perturbtions of gut microbiot, ltertions of intestinl glucose trnsport nd metbolism, ttenution of intestinl sodium glucose cotrnsport, nd other chnges not yet fully chrcterized (5). Mny of the observtions tht identify these cndidte mechnisms derive primrily from nimlexperimentsndneedtobeverified in humns, but it is n ctive re of reserch. Lst, the 1991 NIH recommendtions tht restrict britric surgery to people with BMI $35 kg/m 2 were bsed lmost exclusively on dt from Cucsin ptients, but ll other lrge rcil groups tend to develop T2DM t lower BMI levels thn those in this popultion (27). Hence, the NIH stndrds deny ccess to metbolic surgery for the lrge mjority of ptients with dibetes worldwide who might benefit from this option to tret their disese. For exmple, in Tiwn, the medin BMI of ptients with T2DM is pproximtely 24 kg/m 2, nd,2% hve BMI $35 kg/m 2 (28). Thus, NIH recommendtions exclude.98% of these Est Asin ptients from considering metbolic surgery to tret T2DM. Similr comments pertin to South Asins. Even in the U.S., the pek of the BMI distribution curve for ptients with T2DM lies between 30 nd 35 kg/m 2 (29), so very substntil proportion of Americn ptients with dibetes hve BMI too low to qulify for surgery by existing stndrds. In short, the 1991 NIH recommendtions exclude hundreds of millions of ptients with dibetesfromccesstohighlyeffective T2DM tretment option. EVIDENCE REGARDING THE USE OF BARIATRIC/METABOLIC SURGERY TO TREAT T2DM IN PATIENTS WITH A BASELINE BMI <35 KG/M 2 Effects of Britric/Metbolic Surgery on Dibetes in Ptients With BMI <35 kg/m 2 Severl excellent, recent systemtic reviews nd met-nlyses help summrize nd interpret findings from the lrge, growing number of publictions reporting dt on britric/metbolic surgery for people with preopertive BMI,35 kg/m 2. Before discussing these, it is importnt to note tht evidence in this field is muddied by the fct tht there is no universlly greed-upon stndrd for mesuring the success of britric/ metbolic surgery to tret T2DM, even though stndrd definitions for dibetes remission hve been published by prominent uthorities (30). Vrious investigtors define remission differently, typiclly s n HbA 1c level below some threshold, off dibetes medictions. However, remission rtes differ gretly even within the sme study depending on whether the required HbA 1c threshold is 6.0%, 6.5%, or 7.0%. In ddition, mny physicins commonly leve ptients on metformin even fter normoglycemi is chieved, using it for prevention of relpse, hoped-for crdiovsculr benefits independent of glycemi, polycystic ovrin syndrome tretment, nd so forth. This prctice confounds ny definition of dibetes remission tht requires ptients to be off ll dibetes medictions, nd there is no widely ccepted stndrd in britric/metbolic reserch for how to del with this issue. Müller-Stich et l. (31) recently published high-qulity systemtic review nd pooled met-nlysis of only level 1 nd level 2 evidence from studies directly compring surgicl versus medicl/ lifestyle interventions for T2DM mong ptients, t lest some of whom in ech study hd bseline BMI,35 kg/m 2. This included seven rndomized clinicl trils (RCTs) nd six high-qulity prospective observtionl comprisons, encompssing 818 prticipnts with dibetes, with follow-up of 1 3 yers. No deths were reported. Every one of these studies found tht vrious surgicl interventions were sttisticlly significntly superior to vriety of nonsurgicl interventions in cusing either dibetes remission (i.e., nondibetic HbA 1c levels off ll dibetes medictions) (Fig. 1) nd/or glycemic control (i.e., nondibetic HbA 1c with or without dibetes medictions) (31). The overll odds rtio (OR) for surgicl superiority in dibetes remission ws 14.1 mong ll studies nd 22 mong those tht exclusively exmined ptients with preopertive BMI,35 kg/m 2. These results persisted with fixed- versus rndom-effects models, in subgroup nlyses of only RCTs or only prospective observtionl comprisons, nd with or without djustment for potentil publiction bises. The overll verge percent HbA 1c dropped by 1.5 points more fter surgicl compred with nonsurgicl interventions, even though ptients in the former group used fr fewer dibetes medictions compred with the ltter t the end of these studies. The ORs for surgicl superiority over medicl/ lifestyle interventions regrding dibetes remission were similr for ech individul opertion in this met-nlysis compred with prior met-nlysis of RCTs exmining surgicl versus nonsurgicl T2DM pproches mong ptients with bseline BMI $35 kg/m 2 (32). For exmple, the OR for surgicl superiority in dibetes remission fter LAGB ws12versus5intheformerversus ltter nlysis, respectively, nd pproximtely in both nlyses for RYGB, verticl sleeve gstrectomy (VSG), nd BPD. Not surprisingly, Müller-Stich et l. (31) found tht BMI fell much more with surgery thn medicl/lifestyle interventions in every cse except one. The exception ws n investigtion of n experimentl opertion tht replictes the proximl intestinl bypss of RYGB without ffecting the stomch, i.e., duodenl-jejunl bypss surgery. It cused substntilly greter glycemic control thn did nonsurgicl cre, despite equl weight chnge in both groups, further demonstrting weightindependent ntidibetes effects of proximl intestinl bypss (33). As is commonly observed, the effects of surgery on blood pressure nd plsm lipidswerelessimpressivethnthoseon glycemi. Nevertheless, the surgicl groups overll were four times less likely to hve hypertension nd five times less likely to hve dyslipidemi compred with medicl groups t the end of these studies (31). A smller systemtic review nd met-nlysis recently published by Ro et l. (34) exmined the effects of RYGB on T2DM mong studies whose prticipnts exclusively hd bseline BMI,35 kg/m 2. This encompssed nine publictions, describing totl of 343 prticipnts (bseline BMI rnge kg/m 2, follow-up 1 7 yers.)

4 cre.dibetesjournls.org Cummings nd Cohen 927 Figure 1 Forest plot of T2DM remission rtes fter britric/metbolic surgery compred with medicl/lifestyle interventions. The effect of ech surgicl vs. nonsurgicl intervention is shown s the OR for T2DM remission with its 95% CI. Overll rndom effect OR 14.1 (95% CI , P, 0.001). AGB, djustble gstric bnding; SG, sleeve gstrectomy. Reprinted with permission from Müller-Stich et l. (31). Agin, there were no deths, nd surgicl compliction rtes were 6 20%, which is similr to published rtes for ptients with bseline BMI $35 kg/m 2 (9). All nine rticles reported significnt HbA 1c reductions fter surgery, with n verge percent HbA 1c lowering of 2.8 points (34). Overll, surgery reduced fsting blood glucose by 60 mg/dl more thn did the vrious nonsurgicl comprtor interventions. Rtes of dibetes remission (defined here s HbA 1c,6.5% off ll dibetes medictions) rnged from 65 to 93%, which is t lest s high s is reported historiclly mong ptients with bseline BMI $35 kg/m 2 (2,3,10). Compring the Effects of Surgery in Ptients With Preopertive BMI Below Versus Above 35 kg/m 2 In considering whether to lower the BMI threshold for contemplting the use of britric/metbolic surgery to tret indequtely controlled T2DM in less obese ptientsds recommended by the new DSS-II guidelines published this issue of the Dibetes Cre (9)d crucil question is whether the ntidibeteseffectsofsurgeryrettenutedin lower-bmi ptients compred with severely obese individuls, who hve been more extensively studied to dte. Intuitively, one might speculte tht rtes of dibetes remission nd/or glycemic control would be lower mong lener ptients becuse such individuls lose less body weight fter surgery (both in percent nd bsolute terms) thn do people with higher BMI vlues. Indeed, we hve herd this view expressed by prominent figures t scientific meetings for some time. However, recent evidence from lrge met-nlyses nd RCTs does not support tht ssertion. Pnunzi et l. (18) performed n extensive systemtic review serching for predictors of dibetes remission fter britric/metbolic surgery. They exmined ll publictions up through 2015 reporting postsurgicl dibetes remission rtes: totl of 94 rticles describing 94,579 surgicl ptients with T2DM (Fig. 2). Notbly, they found tht the overll rte of dibetes remission ws equivlent mong the 60 studies in which men preopertive BMI ws $35 kg/m 2 compred with the 34 studies with men preopertive BMI,35 kg/m 2 (71% vs. 72%, respectively). Rtes of dibetes remission were lso similr within ech individul opertion mong ptients with bseline BMI bove versus below 35 kg/m 2 (overll remission 89% for BPD, 77% for RYGB, 62% for LAGB, nd 60% for VSG). Surprisingly, mong mny bseline ptient chrcteristics exmined, the only significnt predictor of the mgnitude of postopertive fll in HbA 1c ws lower preopertive wist circumference. A mjor strength of this systemtic review is tht it included ll extnt publictions on the topic nd ws thus very lrge. However, the uthors did not limit their nlyses to only high-qulity studies. Accordingly, met-nlysis ws performed for the DSS-II conference exmining only level 1 evidence from the 11 published RCTs directly compring surgicl versus nonsurgicl pproches to dibetes cre, including mong mny ptients with bseline BMI,35 kg/m 2 (9). These trils nlyzed 1,090 rndomized prticipnts. Together they exmined ll four cliniclly prcticed britric/ metbolic opertions (RYGB, VSG, LAGB, nd BPD), s well s vriety of behviorl/ medicl pproches, including very

5 928 Britric/Metbolic Surgery in Lower-BMI Ptients Dibetes Cre Volume 39, June 2016 Figure 2 Forest plots from systemtic review nd met-nlysis of ll published rticles reporting T2DM remission rtes following britric/metbolic surgery. Dt points disply the effectiveness of surgery to promote dibetes remission. Studies re divided into two groups depending on whether the verge preopertive BMI for the study cohort ws,35 kg/m 2 (A)or $35 kg/m 2 (B). DM, dibetes. Reprinted with permission from Pnunzi et l. (18). intensive lifestyle interventions (35) modeled fter Look AHEAD (Action for Helth in Dibetes) nd Dibetes Prevention Progrm (DPP). As shown in Fig. 3A, ll 11 RCTs reported superior results from surgery compred with medicl/lifestyle interventions for dibetes remission nd/ or glycemic control, with n overll OR for surgicl superiority of bout 10. This constitutes unnimous level 1A evidence (i.e., met-nlysis of only RCTs) demonstrting tht surgery improves dibetes more thn medicl/lifestyle interventions do. The only study in which the Peto OR confidence intervls crossed 1 ws for LAGB, which is generlly found to be the lest effective of these four opertions for T2DM tretment. Importntly, the mgnitude of surgicl superiority over medicl/lifestyle interventions for dibetes remission nd/ or glycemic control ws similr mong the trils in which the verge bseline BMI of the study cohort ws below versus bove 35 kg/m 2 (Fig. 3A) (9). There ws no trend towrd reduction in the reltive benefit of surgicl compred with nonsurgicl interventions on these glycemic prmeters bsed on decresing preopertive BMI. Moreover, mong the RCTs tht hve now reported both erly nd lter follow-up dt, the mgnitude of surgicl superiority over medicl/ lifestyle interventions for glycemic outcomesissimilrt1 2 yersndt2 5 yers (Fig. 3B). As with the end points of dibetes remission nd glycemic control, the degree of superiority for lowering HbA 1c levels with surgicl compred with nonsurgicl interventions is similr mong RCTs wherein the study cohorts strted with men bseline BMI below or bove 35 kg/m 2 (Fig. 4). This finding is clerly displyed in the dt from Surgicl Therpy And Medictions Potentilly Erdicte Dibetes Efficiently (STAMPEDE) tril, rgubly the best RCT in this ren to dte. At ll time points over the course of 3 yers, surgicl ptients consistently displyed greter HbA 1c lowering compred to ptients treted with medicl/lifestyle interventions, but this finding ws equivlent mong prticipnts whose verge bseline BMI ws below versus bove 35 kg/m 2 (Fig. 5) (36). A very importnt point to emphsize in interpreting ll of the bove studies compring surgicl versus nonsurgicl pproches to dibetes is tht in most

6 cre.dibetesjournls.org Cummings nd Cohen 929 Figure 3 A: Forest plot of Peto ORs of min glycemic end points (Glyc. Endp.), s defined in ech tril, from published RCTs of britric/metbolic surgery compred with medicl/lifestyle tretments for dibetes. B: Forest plot of the trils depicted in pnel A tht hve published both their initil shorter-term dt nd subsequent longer-term results from the sme study. In both pnels, dt re rrnged in order of scending men bseline BMI; the dotted line seprtes trils performed with cohorts exhibiting n verge bseline BMI bove or below 35 kg/m 2. Study durtion nd HbA 1c end point thresholds re shown in brckets in column 1, where off meds indictes threshold chieved off ll dibetes medictions; otherwise, end points represent HbA 1c thresholds chieved with or without such medictions. ORs.1 indicte positive effect of surgery compred with medicl/lifestyle tretment. For ech study, the OR is shown with its 95% CI. The pooled Peto OR (95% CI) for ll dt were clculted under the ssumption of fixed-effects model. SG, sleeve gstrectomy. of them, the intensity of the lifestyle intervention nd/or rigor of phrmceuticl cre (including use, or more typiclly lck of stndrdized use, of medictionssisted weight loss) ws not s ggressive s is possible. Although some of these RCTs hve involved quite intensive lifestyle/medicl interventions (35,37,38), more work is needed in this domin. Sfety of Britric/Metbolic Surgery in Ptients With Bseline BMI <35 kg/m 2 The sfety of britric/metbolic surgery in lower-bmi ptients hs been exmined most thoroughly in very lrge systemtic review by the Agency for Helthcre Reserch nd Qulity (39). It exmined the sfety nd comprtive effectiveness of surgicl versus nonsurgicl pproches to metbolic conditions such s dibetes mong ptients with preopertive BMI of kg/m 2. The comprehensive report confirmed tht surgery cused greter reductions of BMI, HbA 1c, hypertension, LDL, nd triglycerides thn did medicl/lifestyle interventions. Importntly, the finl summry sttement reported tht rtes of dverse events of surgery were reltively low, surgicl mortlity ws % (which is similr to historicl dt for ptients with BMI $35 kg/m 2 [2]), nd most surgicl complictions were minor nd tended not to require mjor interventions (39). They lso concluded tht excessive (i.e., too much) weight loss is not problem for stndrd proximl RYGB, VSG, or LAGB. Demri et l. (40) nlyzed the Britric Outcomes Longitudinl Dtbse (BOLD) dtbse from the Americn Society for Metbolic nd Britric Surgery exmining 66,264 ptients who hd undergone RYGB; of whom, 235 hd bseline BMI,35 kg/m 2, even though tht is not yet pproved for insurnce coverge. There were no deths within 90 dys following surgery in the low-bmi group, nd the compliction rtes in tht cohort were 3% for LAGB nd 18% for RYGB, nlogous to morbidity rtes for ptients with BMI $35 kg/m 2 (2). Clinicl dibetes remission rtes were lso similr in the higher- versus lower-bmi groups. Long-term Effects of Surgery in Ptients With Bseline BMI <35 kg/m 2 Although long-term dt regrding britric/metbolic surgery in lower-bmi ptients is reltively limited, some pertinent evidence hs begun to emerge in this ren.

7 930 Britric/Metbolic Surgery in Lower-BMI Ptients Dibetes Cre Volume 39, June 2016 Figure 4 Forest plot of men differences (MDs) of HbA 1c serum levels fter britric/metbolic surgery compred with medicl/lifestyle tretments in published RCTs relted to dibetes. Dt re rrnged in order of scending men bseline BMI; the dotted line seprtes trils performed with cohorts exhibiting n verge bseline BMI bove or below 35 kg/m 2. Study durtion nd HbA 1c end point thresholds re shown in brckets in column 1, where off meds indictes threshold chieved off ll dibetes medictions; otherwise, end points represent HbA 1c thresholds chieved with or without such medictions. Negtive MDs denote lower HbA 1c levels following surgery thn medicl/lifestyle tretment. Dt for ech study re shown s the MD with its 95% CI. A rndom-effects model ws used to clculte the pooled stndrdized MD. We prospectively studied the efficcy nd sfety of RYGB mong 66 ptients with T2DM nd bseline BMI of kg/m 2, who were followed with 100% retention for 6 yers (25). The study cohort hd severe, long-stnding dibetes (t bseline: verge durtion of dibetes 13 yers, men HbA 1c 9.7%, with 40% on insulin nd the rest on orl medictions). Nevertheless, we observed rpid decrese of verge HbA 1c within the first few months, from nerly 10% down to nondibetic levels, with subsequent mintennce of tht degree of improved glycemi for 6 yers (Fig. 6A). At the end of the study, 88% of prticipnts still enjoyed dibetes remission (defined here s HbA 1c,6.5% off ll dibetes medictions), nother 11% clerly hd improved dibetes sttus, nd only 1 ptient out of 66 ws unchnged. We found no reltionship t ny time point from 1 month to 6 yers between the mgnitude of weight loss nd the degree of improvement in ny glycemic vrible (e.g., HbA 1c,fsting plsm glucose, insulinogenic index during stndrdized mel test, nd HOMAinsulin resistnce). Systolic nd distolic blood pressure decresed progressively throughout the study, s did totl cholesterol, LDL cholesterol, nd triglycerides, nd HDL cholesterol incresed progressively for 6 yers. These chnges yielded substntil, highly significnt improvements in estimted 10-yer risks of ftl nd nonftl hert ttcks nd strokes. A lrge, recent study by Hsu et l. (41) reported similr findings mong Est Asin ptients with T2DM nd bseline BMI,35 kg/m 2. Over 5 yers, the uthors exmined the effects of either RYGB or VSG compred with medicl/ lifestyle dibetes cre mong 351 ptients with initil dibetes who were mtched between the surgicl nd nonsurgicl groups for ge, BMI, nd dibetes durtion. Despite this mtching ttempt, the surgicl group hd higher bseline verge HbA 1c (9.1% vs. 8.1%) nd longer durtion of dibetes (5.0 vs. 2.7 yers), both of which introduce conservtive bises ginst finding surgicl Figure 5 Chnge in men 6 SE HbA 1c levels over 3 yers in lrge RCT compring surgicl (either RYGB or VSG) vs. intensive medicl therpy for T2DM. Ech tretment group is divided into two subgroups defined by n verge bseline BMI,35 kg/m 2 vs. $35 kg/m 2, s indicted in the figure. Men vlues in ech group re provided below the grph, with medin vlues in prentheses. P = for comprison between the surgicl nd medicl groups within the subgroup of ptients with bseline BMI,35 kg/m 2 ; P, for tht comprison within the subgroup with bseline BMI $ 35 kg/m 2. Reprinted with permission from Schuer et l. (36).

8 cre.dibetesjournls.org Cummings nd Cohen 931 Figure 6 Long-term studies of britric/metbolic surgery to tret T2DM in ptients with preopertive BMI,35 kg/m 2. A: Chnge in men 6 SE HbA 1c levels following RYGB mong 66 ptients with bseline BMI of kg/m 2, studied with 100% follow-up for 6 yers. HbA 1c decresed from vlues representing poorly controlled dibetes, despite ll ptients being on dibetes medictions t bseline, to nondibetic or norml-rnge levels from 6 months to 6 yers fter RYGB, with 88% of prticipnts off ll dibetes medictions t the end of the study. Reprinted with permission from Cohen et l. (25). B: Chnges over 5 yers in men HbA 1c nd BMI mong 351 Asin ptients with T2DM nd BMI,35 kg/m 2 t bseline who underwent surgicl (RYGB or VSG) vs. medicl/lifestyle cre for T2DM. P, for comprison between the surgicl group nd medicl group, clculted from repeted-mesures model tht considers dt over time. Reprinted with permission from Hsu et l. (41). superiority regrding glycemi. Nevertheless, HbA 1c ndbmiwerebothreduced to fr greter degree in the surgicl group, nd these chnges were lrgely stble from 6 months to 5 yers (Fig. 6B), even though surgery ptients ended up on fewer dibetes medictions, including insulin. Follow-up t 5 yers ws 96% in the surgicl group nd 84% in the medicl/lifestyle group. Mintennce of n HbA 1c,6.5% off ll dibetes medictions t the end of the study ws chieved in 64% of surgery ptients compred with 3% of ptients treted with medicl/lifestyle interventions. At 5 yers, the surgicl group lso displyed greter reductions in wist circumference, centrl diposity, LDL cholesterol, triglycerides, blood pressure, nd the percent of prticipnts with hypertension. Deth rtes were sttisticlly equivlent (1.9% with surgery, 3.0% with medicl/lifestyle interventions). A long-term study of South Asin ptients reported somewht less durble effects on dibetes thn were observed in the two rticles highlighted in Fig. 6. Lkdwl et l. (42) performed prospective observtionl nlysis of 52 Asin Indin ptients with BMI of kg/m 2 nd poorly controlled T2DM t bseline who underwent RYGB nd were followed for 5 yers. Although the rte of complete dibetes remission t 1 yer ws high t 73% (similr to tht typiclly seen t this time point fter RYGB in ptients with BMI $35 kg/m 2 [2,3,10]), full remission hd dropped to 58% by 5 yers. However, this type of erosion of dibetes remission rtes over time is comptible with wht is observed mong ptients with preopertive BMI $35 kg/m 2,inwhom35 50% of individuls who initilly chieve dibetes remission lso eventully experience relpse (11,15,16,36). With or without dibetes recurrence, the lrge mjority of ptients with bseline BMI either bove or below 35 kg/m 2 who undergo britric/metbolic surgery mintin substntil improvement of glycemic control for mny yers, nd Lkdwl et l. (42) reported tht 96% of their study prticipnts hd improved metbolic sttus t 5 postopertive yers. Overll, these findings mong lower-bmi ptients compre fvorbly with long-term studies of britric/metbolic surgery for individuls with T2DM nd bseline BMI $35 kg/m 2 (11 13,43). However, prt

9 932 Britric/Metbolic Surgery in Lower-BMI Ptients Dibetes Cre Volume 39, June 2016 from the bove-mentioned 3-yer dt from STAMPEDE (36), long-term results from RCTs of lower-bmi ptients re still pending. Another understudied re is thereltivecost-effectiveness of britric/ metbolic surgery compred with conventionl cre mong less obese ptients with T2DM, nd RCTs powered to observe hrd outcomes such s crdiovsculr events, cncer, nd deth re needed mong ptients of ny BMI level. CONCLUSIONS Numerous RCTs nd high-qulity nonrndomized comprisons now demonstrte tht britric/metbolic surgery is more effective thn vriety of medicl/ lifestyle interventions for weight loss, glycemic control, T2DM remission, nd improvements in other crdiovsculr disese risk fctors, with cceptble complictions for t lest 1 5 yers (2). Even though individuls with lower bseline BMI levels lose less weight fter surgery thn do more obese people, the sfety nd efficcy of surgery for improving T2DM nd other metbolic disorders pper to be similr mong ptients with bseline BMI below versus bove 35 kg/m 2, the threshold used to determine surgicl cndidcy for the pst 25 yers. Avilble evidence indictes tht this rther rbitrry cut point should be lowered for ptients with T2DM, in ccordnce with new DSS-II guidelines published in this issue of Dibetes Cre (9). Funding. D.E.C. is supported by NIH grnts RO1 DK103842, RO1 DK084324, RO1 DK089528, nd U34 DK Dulity of Interest. D.E.C. is principl investigtor on the Comprison of Surgery vs. Medicine for IndinDibetes(COSMID) tril, whichis funded by Johnson & Johnson, nd the Allince of Rndomized Trils of Medicine vs Metbolic Surgery in Type 2 Dibetes (ARMMS-T2D) tril, which is funded by Johnson & Johnson nd Covidien, in conjunction with NIH. R.V.C. is principl investigtor for the Microvsculr Outcomes After Metbolic Surgery (MOMS) tril, which is funded by Johnson & Johnson nd the Oswldo Cruz Germn Hospitl Bioscience Institute. None of these studies re discussed in this rticle. No other potentil conflicts of interest relevnt to this rticle were reported. References 1. Consensus Development Conference Pnel. NIH conference. Gstrointestinl surgery for severe obesity. Ann Intern Med 1991;115: Schuer PR, Mingrone G, Ikrmuddin S, Wolfe B. Clinicl outcomes of metbolic surgery: efficcy of glycemic control, weight loss, nd remission of dibetes. Dibetes Cre 2016;39: Rubino F, Schuer PR, Kpln LM, Cummings DE. Metbolic surgery to tret type 2 dibetes: clinicl outcomes nd mechnisms of ction. Annu Rev Med 2010;61: Thler JP, Cummings DE. Minireview: Hormonl nd metbolic mechnisms of dibetes remission fter gstrointestinl surgery. Endocrinology 2009;150: Btterhm RL, Cummings DE. Mechnisms of dibetes improvement following britric/ metbolic surgery. Dibetes Cre 2016;39: Cohen R, Crvtto PP, Corre JL, et l. Glycemic control fter stomch-spring duodenljejunl bypss surgery in dibetic ptients with low body mss index. Surg Obes Relt Dis 2012; 8: Cummings DE, Cohen RV. Beyond BMI: the need for new guidelines governing the use of britric nd metbolic surgery. Lncet Dibetes Endocrinol 2014;2: 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 2010;251: Rubino F, Nthn DM, Eckel RH, et l.; Delegtes of the 2nd Dibetes Surgery Summit. Metbolic surgery in the tretment lgorithm for type 2 dibetes: joint sttement by interntionl dibetes orgniztions. Dibetes Cre 2016;39: Buchwld H, Estok R, Fhrbch K, et l. Weight nd type 2 dibetes fter britric surgery: systemtic review nd met-nlysis. Am J Med 2009;122: e5 11. 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 2013;23: Crlsson LM, Peltonen M, Ahlin S, et l. Britric surgery nd prevention of type 2 dibetes in Swedish obese subjects. N Engl J Med 2012;367: Adms TD, Dvidson LE, Litwin SE, et l. Helth benefits of gstric bypss surgery fter 6 yers. JAMA 2012;308: Mingrone G, Pnunzi S, De Getno A, et l. Britric surgery versus conventionl medicl therpy for type 2 dibetes. N Engl J Med 2012;366: Mingrone G, Pnunzi S, De Getno A, et l. Britric-metbolic surgery versus conventionl medicl tretment in obese ptients with type 2 dibetes: 5 yer follow-up of n open-lbel, single-centre, rndomised controlled tril. Lncet 2015;386: Sjöström L, Peltonen M, Jcobson P, et l. Assocition of britric surgery with long-term remission of type 2 dibetes nd with microvsculr nd mcrovsculr complictions. JAMA 2014;311: Sjöholm K, Pjunen P, Jcobson P, et l. Incidence nd remission of type 2 dibetes in reltion to degree of obesity t bseline nd 2 yer weight chnge: the Swedish Obese Subjects (SOS) study. Dibetologi 2015;58: Pnunzi S, De Getno A, Crnicelli A, Mingrone G. Predictors of remission of dibetes mellitus in severely obese individuls undergoing britric surgery: do BMI or procedure choice mtter? A met-nlysis. Ann Surg 2015;261: Pnunzi S, Crlsson L, De Getno A, et l. Determinnts of dibetes remission nd glycemic control fter britric surgery. Dibetes Cre 2016;39: Sjöström L, Peltonen M, Jcobson P, et l. Britric surgery nd long-term crdiovsculr events. JAMA 2012;307: Elisson B, Likopoulos V, Frnzén S, et l. Crdiovsculr disese nd mortlity in ptients with type 2 dibetes fter britric surgery in Sweden: ntionwide, mtched, observtionl cohort study. Lncet Dibetes Endocrinol 2015;3: 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 2009;10: 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 2007;357: Schuer PR, Kshyp SR, Wolski K, et l. Britric surgery versus intensive medicl therpy in obese ptients with dibetes. N Engl J Med 2012;366: Cohen RV, Pinheiro JC, Schivon CA, Slles JE, Wjchenberg BL, Cummings DE. Effects of gstric bypss surgery in ptients with type 2 dibetes nd only mild obesity. Dibetes Cre 2012;35: Sjöström L. Review of the key results from the Swedish Obese Subjects (SOS) trild prospective controlled intervention study of britric surgery. J Intern Med 2013;273: Chiu M, Austin PC, Mnuel DG, Shh BR, Tu JV. Deriving ethnic-specific BMI cutoff points for ssessing dibetes risk. Dibetes Cre 2011;34: Lee WJ, Wng W, Lee YC, Hung MT, Ser KH, Chen JC. Effect of lproscopic mini-gstric bypss for type 2 dibetes mellitus: comprison of BMI.35 nd,35 kg/m2. J Gstrointest Surg 2008;12: Bys HE, Chpmn RH, Grndy S; SHIELD Investigtors Group. The reltionship of body mss index to dibetes mellitus, hypertension nd dyslipidemi: comprison of dt from two ntionl surveys. Int J Clin Prct 2007;61: Buse JB, Cprio S, Ceflu WT, et l. How do we define cure of dibetes? Dibetes Cre 2009; 32: Müller-Stich BP, Senft JD, Wrschkow R, et l. Surgicl versus medicl tretment of type 2 dibetes mellitus in nonseverely obese ptients: systemtic review nd met-nlysis. Ann Surg 2015;261: Gloy VL, Briel M, Bhtt DL, et l. Britric surgery versus non-surgicl tretment for obesity: systemtic reviewnd met-nlysis of rndomised controlled trils. BMJ 2013;347:f Geloneze B, Geloneze SR, Chim E, et l. Metbolic surgery for non-obese type 2 dibetes: incretins, dipocytokines, nd insulin secretion/ resistnce chnges in 1-yer interventionl clinicl controlled study. Ann Surg 2012;256:72 78

10 cre.dibetesjournls.org Cummings nd Cohen Ro WS, Shn CX, Zhng W, Jing DZ, Qiu M. A met-nlysis of short-term outcomes of ptients with type 2 dibetes mellitus nd BMI # 35 kg/m2 undergoing Roux-en-Y gstric bypss. World J Surg 2015;39: Cummings DE, Arterburn DE, Westbrook EO, et l. Gstric bypss surgery vs. intensive lifestyle nd medicl intervention for type 2 dibetes: the CROSSROADS rndomized controlled tril. Dibetologi 2016;59: Schuer PR, Bhtt DL, Kirwn JP, et l.; STAMPEDE Investigtors. Britric surgery versus intensive medicl therpy for dibetes 3-yer outcomes. N Engl J Med 2014;370: Ikrmuddin S, Korner J, Lee WJ, et l. Roux-en-Y gstric bypss vs intensive medicl mngement for the control of type 2 dibetes, hypertension, nd hyperlipidemi: the Dibetes Surgery Study rndomized clinicl tril. JAMA 2013;309: Courcouls AP, Goodpster BH, Egleton JK, et l. Surgicl vs medicl tretments for type 2 dibetes mellitus: rndomized clinicl tril. JAMA Surg 2014;149: Mglione MA, Gibbons MM, Livhits M, et l. Britric surgery nd non-surgicl therpy in dults with metbolic conditions nd body mss index of 30.0 to 34.9 kg/m 2.In AHRQ Comprtive Effectiveness Reviews. Rockville, MD, Agency for Helthcre Reserch nd Qulity, 2013 Jun. Report No. 12(13)- EHC139-E 40. Demri EJ, Winegr DA, Pte VW, Hutcher NE, Ponce J, Pories WJ. Erly postopertive outcomes of metbolic surgery to tret dibetes from sites prticipting in the ASMBS britric surgery center of excellence progrm s reported in the Britric Outcomes Longitudinl Dtbse. Ann Surg 2010;252: ; discussion Hsu CC, Almulifi A, Chen JC, et l. Effect of britric surgery vs medicl tretment on type 2 dibetes in ptients with body mss index lower thn 35: five-yer outcomes. JAMA Surg 2015; 150: Lkdwl M, Shikh S, Bndukwl S, Remedios C, Shh M, Bhsker AG. Roux-en-Y gstric bypss stnds the test of time: 5-yer results in low body mss index (30-35 kg/m(2)) Indin ptients with type 2 dibetes mellitus. Surg Obes Relt Dis 2013;9: Brethuer SA, Aminin A, Romero-Tlmás H, et l. Cn dibetes be surgiclly cured? Longterm metbolic effects of britric surgery in obese ptients with type 2 dibetes mellitus. Ann Surg 2013;258: ; discussion