Metabolic Surgery in theTreatment Algorithm for Type 2Diabetes: A Joint Statement byInternational DiabetesOrganizationsDiabetes Care 2016;39:861–877 | DOI: 10.2337/dc16-0236

BACKGROUND

Despite growing evidence that bariatric/metabolic surgery powerfully improvestype 2 diabetes (T2D), existing diabetes treatment algorithms do not includesurgical options.

AIM

The 2ndDiabetes Surgery Summit (DSS-II), an international consensus conference,was convened in collaboration with leading diabetes organizations to developglobal guidelines to inform clinicians and policymakers about benefits andlimitations of metabolic surgery for T2D.

METHODS

A multidisciplinary group of 48 international clinicians/scholars (75% nonsur-geons), including representatives of leading diabetes organizations, participatedin DSS-II. After evidence appraisal (MEDLINE [1 January 2005–30 September2015]), three rounds of Delphi-like questionnaires were used to measure consen-sus for 32 data-based conclusions. These drafts were presented at the combinedDSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes(London, U.K., 28–30 September 2015), where they were open to public commentby other professionals and amended face-to-face by the Expert Committee.

RESULTS

Given its role in metabolic regulation, the gastrointestinal tract constitutes ameaningful target to manage T2D. Numerous randomized clinical trials, albeitmostly short/midterm, demonstrate that metabolic surgery achieves excellentglycemic control and reduces cardiovascular risk factors. On the basis of suchevidence, metabolic surgery should be recommended to treat T2D in patients withclass III obesity (BMI ‡40 kg/m2) and in those with class II obesity (BMI 35.0–39.9kg/m2) when hyperglycemia is inadequately controlled by lifestyle and optimalmedical therapy. Surgery should also be considered for patients with T2D and BMI30.0–34.9 kg/m2 if hyperglycemia is inadequately controlled despite optimaltreatment with either oral or injectablemedications. These BMI thresholds shouldbe reduced by 2.5 kg/m2 for Asian patients.

CONCLUSIONS

Although additional studies are needed to further demonstrate long-term benefits,there is sufficient clinical and mechanistic evidence to support inclusion of metabolicsurgery among antidiabetes interventions for people with T2D and obesity. To date, theDSS-II guidelines have been formally endorsed by 45 worldwide medical and scientificsocieties. Health care regulators should introduce appropriate reimbursement policies.

1King’s College London, London, U.K.2Harvard Medical School, Boston, MA3University of Colorado Anschutz MedicalCampus, Aurora, CO4Cleveland Clinic, Cleveland, OH5Imperial College London, London, U.K.6Monash University, Melbourne, Victoria,Australia7University of Pisa, Pisa, Italy8Peking University, Beijing, China9Diabetes India, Mumbai, India10University of Michigan, Ann Arbor, MI11Philadelphia, PA12University of Washington, Seattle, WA

Corresponding authors: Francesco Rubino,francesco.rubino@kcl.ac.uk, and David E.Cummings, davidec@u.washington.edu.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc16-0236/-/DC1.

F.R. and D.E.C. chaired the writing committee forthis report.

*The 2nd Diabetes Surgery Summit voting dele-gates are listed in Table 2.

© 2016 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered.

See accompanying articles, pp. 857, 878,884, 893, 902, 912, 924, 934, 941, 949,and 954.

Francesco Rubino,1 David M. Nathan,2

Robert H. Eckel,3 Philip R. Schauer,4

K. George M.M. Alberti,5 Paul Z. Zimmet,6

Stefano Del Prato,7 Linong Ji,8

Shaukat M. Sadikot,9

William H. Herman,10

Stephanie A. Amiel,1 Lee M. Kaplan,2

Gaspar Taroncher-Oldenburg,11

and David E. Cummings,12

on behalf of the Delegates of

the 2nd Diabetes Surgery Summit*

Diabetes Care Volume 39, June 2016 861

META

BOLIC

SURGER

Y

Several gastrointestinal (GI) operations,including partial gastrectomies (1,2) andbariatric procedures (Fig. 1) (3–5), pro-mote dramatic, durable improvement oftype 2 diabetes (T2D). Given the magni-tude and rapidity of the effect of GIsurgery on hyperglycemia, along withexperimental evidence that rearrange-ments of GI anatomy similar to thosein some bariatric procedures directlyaffect glucose homeostasis (6), GI inter-ventions have been suggested as a treat-ment for T2D (7).

In 2007, the delegates from the 1stDiabetes Surgery Summit (DSS-I), an inter-national consensus conference, reviewedavailable clinical and mechanistic evi-dence and recommended expandingthe use and study of GI surgery to treatdiabetes, including for individuals withonly mild obesity (5,8). In the ensuingyears, the concept of “metabolic sur-gery” or “diabetes surgery” has becomewidely recognized in academic circles,and, accordingly, most major world-wide bariatric surgery societies have

changed their names to include the word“metabolic” (9).

Since DSS-I, a substantial body of addi-tional evidencehas accumulated, includingfrom numerous randomized clinical trials(RCTs), demonstrating that bariatric/metabolic surgery achieves superior glyce-mic control and reduction of cardiovascu-lar risk factors in obese patients with T2Dcompared with various medical/lifestyleinterventions (10–25). Further researchon mechanisms of action of these proce-dures (5,6,26–34) has corroborated evi-dence in animal studies demonstratingan important role for theGI tract in glucosehomeostasis (35), providing a biologicalrationale for the use of GI-based interven-tions to treat T2D. Available data, basedpredominantly on modeling studies, sug-gest that bariatric/metabolic surgery isalso cost-effective, especially in patientswith diabetes (36,37).

On the basis of this mounting evidence,several international professional organiza-tions and government agencies have re-cently suggested expanding the indicationsfor bariatric/metabolic surgery to includepatients with inadequately controlled T2Dand BMI as low as 30 kg/m2, and down to27.5 kg/m2 for Asians (8,9,38,39).

However, whereas obesity guidelines bynational and international societies andgovernment agencies recommend theuse of bariatric surgery in individuals withT2D (9,40), clinical guidelines for diabetescare paradoxically provide little or nomen-tion of a role for surgical interventions forT2D, even in patients with severe obesity(41). Despite the growing popularity of thistopic in scientific communities (9) and themedia (42), most diabetes care providersand patients are still inadequately in-formed about the indications, benefits,and potential risks of surgical treatmentsfor diabetes. Moreover, insurance reim-bursement policies for bariatric/metabolicsurgery continue to reflect only bodyweight–centric criteria and do not in-clude diabetes-related metrics or cost-effectiveness. Consequently, access tosurgery for patients with diabetes is notadequately prioritized. In fact, no existingtreatment algorithm for T2D includes arole for surgical intervention.

Using surgery as a diabetes interven-tion, however, implies conceptual andpractical differences from the traditionalpractice of bariatric surgery for obesity.For instance, the criteria currently usedto select candidates forbariatric/metabolic

Figure 1—Diagrams of the four bariatric/metabolic operations currently in common clinical use.BPD can be performed as the classic type (shown) or with the duodenal switch variant. Reprintedwith permission from the Cleveland Clinic Foundation (CCF).

862 Metabolic Surgery in the Treatment Algorithm for T2D Diabetes Care Volume 39, June 2016

surgery do not include metrics of meta-bolic disease severity, predictors of successof treatment, or an evaluation of risks andbenefits of surgery as contrasted to thoseof alternative diabetes treatment options.In addition, preoperative diagnostics,perioperative management, and postop-erative follow-up of traditional bariatricsurgery are not consistent with the needto identify and monitor diabetes-relatedparameters and complications. Further-more, there are no strategies yet for in-tegrating complementary pharmaceuticaland surgical therapies to optimize out-comes of diabetes management.Whereas selection criteria for bariatric

surgery have been standardized worldwidefor many years through an influential Na-tional Institutes of Health (NIH) consensusstatement (43), that document is now con-spicuously outdated, and there is no refer-ence for surgical treatment of diabetes toglobally raise the standards of such practice.Recognizing theneed to informdiabetes

care providers about the benefits and lim-itations of metabolic surgery, the 2ndDiabetes Surgery Summit (DSS-II) was con-vened in collaboration with six leading in-ternational diabetes organizations: theAmerican Diabetes Association, Interna-tional Diabetes Federation, Chinese Dia-betes Society, Diabetes India, EuropeanAssociation for the Study of Diabetes, andDiabetes UK. The overarching aim of thisconsensus conference was to review avail-able evidence and to develop global rec-ommendations that integrate medical andsurgical therapies in a rational treatmentalgorithm for T2D. Specific goals includedproviding guidance for selection of surgicalcandidates and use of diabetes-specificmeasures in the preoperative workup andpostoperative follow-up of patients.At the time this article went to press,

the DSS-II consensus statements andguidelines had been officially endorsed by45 leading professional societies acrossthe globe, of which 30 are primarily med-ical (diabetes, endocrinology, and gastro-enterology) and 15 are primarily surgicalorganizations (Table 1). Additional medicaland scientific societies are currently con-sidering endorsing these results as well.These recommendations reflect cur-

rently available data and will need to beupdated as new evidence is developed inthe future.Here we report the methods for DSS-II,

the resulting recommendations, and theirsupporting evidence.

Executive Summary

T2D is associated with complex metabolic dysfunctions, leading to increased morbid-ity, mortality, and cost. Although population-based efforts through lifestyle inter-ventions are essential to prevent obesity and diabetes, people who developthis disease should have access to all effective treatment options.

Given its role in metabolic regulation, the GI tract constitutes a clinically and bi-ologically meaningful target for the management of T2D.

A substantial body of evidence has accumulated, including numerous, albeitmostly short/midtermRCTs, demonstrating that metabolic surgeryddefined here as the use of GIsurgery with the intent to treat T2D and obesitydcan achieve excellent control ofhyperglycemia and reduce cardiovascular risk factors.

Although additional studies are needed to further demonstrate long-term benefits,there is now sufficient clinical and mechanistic evidence to support inclusion of met-abolic surgery among antidiabetes interventions for people with T2D and obesity.

Complementary criteria to the sole use of BMI, the traditional criterion used to selectcandidates for bariatric surgery, need to be developed to achieve a better patientselection algorithm for metabolic surgery.

Metabolic surgery should be a recommended option to treat T2D in appropriate sur-gical candidates with class III obesity (BMI $40 kg/m2), regardless of the level ofglycemic control or complexity of glucose-lowering regimens, as well as in patientswith class II obesity (BMI 35.0–39.9 kg/m2)with inadequately controlled hyperglycemiadespite lifestyle and optimal medical therapy.

Metabolic surgery should also be considered to be an option to treat T2Din patients with class I obesity (BMI 30.0–34.9 kg/m2) and inadequately con-trolled hyperglycemia despite optimal medical treatment by either oral or in-jectable medications (including insulin).

All BMI thresholds should be reconsidered depending on the ancestry of the patient.For example, for patients of Asian descent, the BMI values above should be reducedby 2.5 kg/m2.

Metabolic surgery should be performed in high-volume centers with multidisciplinaryteams that understand and are experienced in the management of diabetes and GIsurgery.

Ongoing and long-term monitoring of micronutrient status, nutritional supplementation,and support must be provided to patients after surgery, according to guidelines forpostoperative management of bariatric/metabolic surgery by national andinternational professional societies.

Metabolic surgery is a potentially cost-effective treatment option in obese patients withT2D. The clinical community shouldwork togetherwith health care regulators to recognizemetabolic surgery as an appropriate intervention for T2D in people with obesity and tointroduce appropriate reimbursement policies.

METHODS

DSS-II Partners and Selection ofVoting DelegatesThe DSS-II organizing committee and thepartner diabetes organizations tasked amultidisciplinary group of 48 interna-tional authorities to develop a set ofevidence-based recommendations. ThisDSS-II Expert Committee included scholarsrepresenting diabetology, endocrinology,internal medicine, cardiology, gastroen-terology, primary care, nutrition, and

surgery, including official representa-tives of partner diabetes organizations(Table 2). To ensuremaximumscholarship,voting delegates were chosen entirelyfrom academicians, with no representa-tives from industry. To further minimizepotential conflicts of interest, nonsur-geons were purposefully overrepresented(75%) and were complemented by aca-demic surgeons with relevant publicationrecords. Two independent, nonvotingmoderators/adjudicators developed

care.diabetesjournals.org Rubino and Associates 863

and administered questionnaires forthe Delphi process and chaired the face-to-facemeeting of voting delegates (videinfra).

Methods for Collection and Evaluationof EvidenceCriteria used for evidence searchingwere based on methods used in previousconsensus development conferences andsystematic reviews of evidence (44,45),adapted to serve the DSS-II objectives.We used a highly selective, diabetes-focused approach (only level-1 evidencefrom RCTs) to assess comparative effec-tiveness of surgery versus nonsurgicaltherapies for T2D and to compare theglycemic effects of different operations.A broader evidence base was used (RCTsplus high-quality observational studies)for matters such as durability of glycemiccontrol, surgical safety, and cardiovascu-lar disease (CVD) risk reduction. Economicimplications of bariatric/metabolic sur-gery were assessed using available stud-ies of cost-effectiveness and systematicreviews with specific reference to patientswith T2D.

Questions for evidence assessment in-cluded the following: 1) long-term effectsof surgery on glycemic control in patientswith T2D; 2) effectiveness of surgery com-paredwithmedical/lifestyle interventionson glycemic control; 3) comparativeeffectiveness of different procedures onT2D; 4) effects of surgery on microvas-cular complications of diabetes, CVD risk,CVD events, and mortality; 5) short- andlong-term surgical safety; and 6) compara-tive safety profile of different operations.

MEDLINE from 1 January 2005 through15 June 2015 was searched to generatethe first draft of the consensus document.New evidence published by 30 September2015 was available for discussion in face-to-face DSS-II meetings and is incorpo-rated into this document, using the sameinclusion/exclusion criteria for evidenceevaluation as in the initial draft.

Studies considered to appraise the evi-dence included RCTs and observationalstudies (case-control and case-series), asappropriate for specific questions (videinfra). For both RCTs and observationalstudies, only reports documenting at least1-year follow-up and with 80% retentionat 2 years and 70% beyond 2 years wereincluded. These criteria are adapted fromthe methods of recent systematic reviewsof bariatric surgery (46).

Table 1—International societies that have ratified and/or endorsed the DSS-IIconsensus statements and guidelines

Partner diabetes organizations that helped develop and have ratifiedthe DSS-II consensus statements and guidelines:

Country

American Diabetes Association (ADA) USA

International Diabetes Federation (IDF) International

Diabetes UK (DUK) UK

Chinese Diabetes Society (CDS) China

Diabetes India (DI) India

Other organizations that formally endorse the DSS-II consensusstatements and guidelines (to date):

American Association of Clinical Endocrinologists (AACE) USA

American College of Surgeons (ACS) USA

American Gastroenterological Association (AGA) USA

American Society for Metabolic and Bariatric Surgery (ASMBS) USA

Argentinian Society of Diabetes (SAD) Argentina

Argentinian Society for Bariatric and Metabolic Surgery (SACO) Argentina

Asia-Pacific Bariatric and Metabolic Surgery Society (APBMSS) International

Association of British Clinical Diabetologists (ABCD) UK

Australian Diabetes Society (ADS) Australia

Belgian Diabetes Association (ABD) Belgium

Brazilian Society of Diabetes (SBD) Brazil

Brazilian Society of Bariatric and Metabolic Surgery (SBCBM) Brazil

British Obesity and Metabolic Surgery Society (BOMSS) UK

Czech Society for the Study of Obesity (CSSO) Czech Republic

Chilean Society of Endocrinology and Diabetes (SCED) Chile

Chilean Society for Bariatric and Metabolic Surgery (SCCBM) Chile

Endocrine Society USA

European Association for the Study of Obesity (EASO) International

French Society of Diabetes (SFD) France

French Society of Bariatric and Metabolic Surgery (SOFFCO) France

German Diabetes Society (DDG) Germany

German Society for Obesity Surgery (CA-ADIP) Germany

Hellenic Diabetes Association (HDA) Greece

International Federation for the Surgery of Obesity & MetabolicDisorders (IFSO) International

Israel Diabetes Association (IDA) Israel

Italian Society of Bariatric & Metabolic Surgery (SICOB) Italy

Italian Society of Diabetology (SID) Italy

Japan Diabetes Society (JDS) Japan

Latin American Association of Diabetes (ALAD) International

Mexican College of Bariatric and Metabolic Surgery (CMCOEM) Mexico

Mexican Society of Nutrition and Endocrinology (SMNE) Mexico

Qatar Diabetes Association (QDA) Qatar

Saudi Diabetes and Endocrine Association (SDEA) Saudi Arabia

Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) USA

Society for Endocrinology (SfE) UK

Society for Surgery of the Alimentary Tract (SSAT) USA

South African Society for Surgery Obesity and Metabolism (SASSO) South Africa

Spanish Society for Bariatric and Metabolic Surgery (SECO) Spain

Spanish Society of Diabetes (SED) Spain

The Obesity Society (TOS) USA

This table indicates the societies that, at the time this article went to press, had officially ratifiedand/or endorsed the DSS-II consensus statements and guidelines. Additional internationalmedical and scientific societies are currently considering endorsing these results as well.

864 Metabolic Surgery in the Treatment Algorithm for T2D Diabetes Care Volume 39, June 2016

Table 2—The DSS-II voting delegates

DSS-II delegate Affiliation Nationality Specialty

K. George M.M. Alberti* Imperial College London U.K. Diabetology

Nizar Albache Aleppo University Syria Endocrinology

Stephanie A. Amiel* King’s College London U.K. Diabetology

Rachel L. Batterham University College London U.K. Endocrinology

Deepak L. Bhatt Harvard Medical School U.S. Cardiology

Camilo Boza Clınica Las Condes Chile Surgery

William T. Cefalu Pennington Biomedical Research Center,Louisiana State University

U.S. Diabetology

Ricardo V. Cohen* Oswaldo Cruz Hospital Brazil Surgery

Anita P. Courcoulas University of Pittsburgh U.S. Surgery

David E. Cummings*† University of Washington U.S. Endocrinology

Stefano Del Prato University of Pisa Italy Diabetology

Sean F. Dinneen Galway University Hospitals Ireland Endocrinology

John B. Dixon* Baker IDI Heart and Diabetes Institute Australia General Medicine

Robert H. Eckel University of Colorado Anschutz Medical Campus U.S. Endocrinology

Ele Ferrannini University of Pisa Italy Diabetology

Paola Fioretto University of Padova Italy Endocrinology

Gema Fruhbeck University of Navarra, CIBERobn Spain Endocrinology

Michel Gagner Florida International University and Hopital duSacre-Coeur de Montreal

U.S. and Canada Surgery

Richard W. Grant Kaiser Permanente Division of Research U.S. Internal Medicine

William H. Herman University of Michigan U.S. Endocrinology

Sayeed Ikramuddin University of Minnesota U.S. Surgery

Linong Ji* Peking University China Diabetology

Desmond G. Johnston Imperial College London U.K. Diabetology

Lee M. Kaplan*† Harvard Medical School U.S. Gastroenterology

Sangeeta R. Kashyap Cleveland Clinic U.S. Endocrinology

Tracy Kelly Diabetes UK U.K. Nutrition

Tomasz Klupa Jagiellonian University Poland Diabetology

Judith Korner Columbia University U.S. Endocrinology

Blandine Laferrere Columbia University U.S. Endocrinology

Harold E. Lebovitz State University of New York U.S. Diabetology

Wei-Jei Lee Min-Sheng General Hospital Taiwan Surgery

Carel W. le Roux* University College Dublin Ireland Metabolic Medicine

Jeffrey I. Mechanick Icahn School of Medicine at Mount Sinai U.S. Endocrinology

Geltrude Mingrone* Catholic University of Rome Italy Internal Medicine

John M. Morton Stanford University U.S. Surgery

David M. Nathan Harvard Medical School U.S. Diabetology

Walter J. Pories East Carolina University U.S. Surgery

Robert E. Ratner* American Diabetes Association,Chief Scientific and Medical Officer

U.S. Diabetology

Gerry Rayman Ipswich Hospital NHS Trust U.K. Diabetology

Francesco Rubino*† King’s College London and King’s College Hospital U.K. Surgery

Shaukat M. Sadikot* Diabetes India India Diabetology

Philip R. Schauer*† Cleveland Clinic U.S. Surgery

Harvey J. Sugerman Virginia Commonwealth University U.S. Surgery

Luc Van Gaal University of Antwerp Belgium Endocrinology

Josep Vidal Hospital Clinic Spain Endocrinology

Jianping Weng Sun Yat-sen University China Diabetology

Bruce M. Wolfe* Oregon Health & Science University U.S. Surgery/Nutrition

Paul Z. Zimmet* Monash University Australia Diabetology

†DSS-II conference codirectors. *DSS-II conference organizing committee.

care.diabetesjournals.org Rubino and Associates 865

Question-Specific Inclusion Criteriac For evidence related to the effective-

ness of surgery versusmedical/lifestyleinterventions to control T2D, only RCTswere considered. A comprehensive al-gorithm was used to identify all RCTspublished by 30 September 2015 re-porting the effects of bariatric/metabolicsurgery in patients with diabetes. Evi-dence listed includes studies of patientswith BMI$35 kg/m2 and,35 kg/m2. Asimple meta-analysis was performedto present an integrated picture of ex-isting evidence.

c For evidence regarding comparative ef-fectiveness of different surgical proce-dures on T2D, data were obtained onlyfromRCTs inwhich different procedureswere used expressly to treat diabetes.

c For evidence regarding the effect of GIsurgery on CVD events and CVD risk re-duction, data were obtained from RCTswhen available, as well as from long-term case-control studies, and fromthemost recent relevantmeta-analyses.

c For evidence regarding the durability ofpostoperative glycemic control, surgicalsafety in general, and comparativesafety profiles of different operations,data were obtained from RCTs whenavailable, from longitudinal case-seriesand case-control studies, and from themost recent relevant meta-analyses.

Descriptors of Level of EvidenceHerein we use standard level of evidence(LoE) descriptors, defined as follows:IA, evidence from meta-analysis of RCTs;IB, evidence from at least one RCT; IIA,evidence from at least one controlledstudy without randomization; IIB, evi-dence from at least one other type ofquasi-experimental study; III, evidencefrom nonexperimental descriptivestudies (e.g., comparative, correlation,or case-control); IV, evidence from expertcommittee reports, opinions or clinicalexperience of respected authorities, orboth.

Consensus Development ProcessAfter review and appraisal of evidence,two independent moderators developedonline Delphi-like questionnaires (47,48)to measure the degree of consensus for aset of statements and recommendationsthat were believed to summarize and re-flect available evidence. For each of these,we sought to achieve consensus, definedas agreement by a supermajority ($67%)of voting delegates, consistent with other

medical consensus conferences (49). DSS-IIdelegates who did not agree with pro-posed statements were asked to statetheir reasons and propose amendments.Three rounds of questionnaires were ad-ministered to test various amendments tothe original statements that could increaseconsensus levels from the group. Draftconclusions generated through this itera-tive process were presented at the com-bined DSS-II and 3rd World Congress onInterventional Therapies for Type 2 Dia-betes (WCITD 2015, London, U.K., 28–30September 2015). Proceedings were opento public comment by other experts in thefield (members of the Faculty of WCITD)and by the entire audience through opin-ion polls, using real-time electronic voting.Approximately 630 professionals and stake-holders from 50 nations on five conti-nents contributed to those discussions.

Finally, on 30 September 2015, votingDSS-II delegates met face-to-face to de-fine a final consensus document. Severalrelevant professional organizations andstakeholders were invited to observe theproceedings by sending official representa-tives toWCITD2015/DSS-II (SupplementaryTable 1). The document with conclusionsreached by the experts underwent a finalreview by DSS voting delegates and wasthen submitted to the appropriate commit-tees and executive boards of partner orga-nizations for formal approval (Table 1).

Grade of ConsensusWe used a supermajority rule to defineconsensus. Consistent with other stud-ies (8,50), consensus was consideredto have been reached when $67% ofthe experts agreed on a given topic.However, language was iteratively mod-ified to maximize agreement, and thedegree of consensus for each statementwas graded according to the followingscale: grade U 5 100% agreement(unanimous); grade A 5 89–99% agree-ment; grade B 5 78–88% agreement;grade C 5 67–77% agreement (Table 3).This grading scale is meant to indicatestatements that reflect unanimous ornear-unanimous opinions (grade Uand grade A), strong agreement withlittle variance (grade B), or a consensusstatement that reflects an averaging ofmore and possibly extremely diverseopinions (grade C). We report here boththe grade of consensus and the exact per-centage of agreement for each statement.

SUMMARY OF EVIDENCE:CLINICAL AND BIOLOGICALRATIONALE FOR SURGICALTREATMENT OF T2D

Evidence Supporting SurgicalTreatment of T2DThe GI tract is an important contributorto normal glucose homeostasis (35), andmounting evidence, especially over thepast decade, has demonstrated benefitsof bariatric/metabolic surgery to treatand prevent T2D (3,5,10–25,51–53).Beyond inducing weight loss–relatedmetabolic improvements, some opera-tions engage mechanisms that improveglucose homeostasis independent ofweight loss (6), such as changes in guthormones, bile acid metabolism, micro-biota, intestinal glucosemetabolism, andnutrient sensing (5,6,26–34). Bariatric/metabolic surgery confers sustained favor-ableeffects onglycemiadup to20years inone observational study (52)dalthoughbenefits can decrease over time, with orwithout weight regain (3,51,52,54–56).

Data from a growing number of re-cent RCTs in patients with T2D (10–25),including mainly individuals with BMI$35 kg/m2 (the most commonly usedthreshold for traditional bariatric sur-gery) as well as some patients with BMI,35 kg/m2 (range 25–35 kg/m2), consis-tently demonstrate superior efficacyof bariatric/metabolic surgery in re-ducing weight and lowering glycemiacompared with a variety of medical/lifestyle interventions (LoE IA) (Fig. 2A).Although the antidiabetes benefits ofsurgery often wane over time, the rela-tive superiority of surgery over medical/lifestyle interventions in RCTs is similarthroughout a range of 1–5 years (Fig. 2B).Our analysis of these trials shows amedianHbA1c reduction of 2.0% for surgery versus0.5% for conventional therapies (P ,0.001) (Figs. 2C and 3A). Each of the 11existing surgery-versus-medicine/lifestyleRCTs reported greater HbA1c reductionfollowing surgery (Figs. 2C and 3B). In allof these trials, final HbA1c in the surgicalgroupswasnear6.0%, regardlessof the levelof baseline HbA1c (Fig. 3C). However, themajority of these RCTs have only examined1- to 2-year results, and only a handful ofthem have examined results for 3–5 years.

Several classic “bariatric” operationscause T2D remissionddefined as achiev-ing nondiabetic HbA1c levels off all diabe-tes medicationsdin a majority of cases

866 Metabolic Surgery in the Treatment Algorithm for T2D Diabetes Care Volume 39, June 2016

Figure 2—A: Forest plot of Peto odds ratios (ORs) of main glycemic end points, as defined in each trial, from published RCTs of bariatric/metabolicsurgery compared with medical/lifestyle treatments for diabetes. Data are arranged in order of ascending mean baseline BMI; the dotted lineseparates trials performedwith cohorts exhibiting an average baseline BMI above or below 35 kg/m2. Study duration and HbA1c end point thresholdsare shown in brackets in column 1, where “off meds” indicates a threshold achieved off all diabetes medications; otherwise, end points representHbA1c thresholds achieved with or with such medications. ORs.1 indicate a positive effect of surgery compared with medical/lifestyle treatment.For each study, the OR is shown with its 95% CI. The pooled Peto ORs (95% CI) for all data were calculated under the assumption of a fixed-effectsmodel.Weights represent inverse variance of ORs (ormean differences [MDs]) and provide an indirectmeasure of the relevance of each studywithinthe meta-analysis, as a function of individual study size and variance. B: Forest plot of the trials depicted in Fig. 2A, with data arranged in order ofincreasing length of follow-up. C: Forest plot of MDs of HbA1c serum levels after bariatric/metabolic surgery compared with medical/lifestyletreatments in published RCTs related to diabetes. Data are arranged in order of increasing follow-up time. Negative MDs denote lower HbA1c levelsfollowing surgery than medical/lifestyle treatment. Data for each study are shown as the MD with its 95% CI. A random-effects model was used tocalculate the pooled standardized MD. Glyc. Endp., glycemic end point; mo, month; SG, sleeve gastrectomy.

care.diabetesjournals.org Rubino and Associates 867

(LoE IA) (Fig. 2A). Numerous RCTs withpostoperative follow-up ranging between1 and 5 years have consistently docu-mented sustained diabetes remission in30–63% of patients (LoE IB) (10–25). Avail-able data suggest an erosion of diabetesremission over time: 35–50% or more ofpatients who initially achieve remission ofdiabetes eventually experience recur-rence. However, the median disease-freeperiod among such individuals with Roux-en-Y gastric bypass (RYGB) is 8.3 years(52,56). With or without diabetes relapse,the largemajority of patientswhoundergosurgery maintain substantial improve-ment of glycemic control from baselinefor at least 5 (LoE IB) (20) to 15 (LoE IIA)(52,55–59) years.

Baseline duration of diabetes (e.g.,.8 years) (LoE IB) (19), use of insulin,and poorer glycemic control (LoE IIA)are consistently associated with lowerrates of diabetes remission and/orhigher risk of recidivism (19,52,58).Baseline visceral fat area may also helpto predict postoperative outcomes, es-pecially among Asian patients withT2D, who typically have more visceralfat compared with Caucasians with di-abetes of the same BMI (60).

Beyond improving glycemia, bariatric/metabolic surgery has been shown toconfer additional health benefits inRCTs, including greater reductions com-pared with medical/lifestyle interven-tions in other CVD risk factors (10–25),and enhancements in quality-of-lifemeasures (LoE IB) (15,19,20). Improve-ments in other critical outcomes, such asmicro- and macrovascular complicationsof diabetes, CVD, cancer, and death, havebeen observed only in nonrandomizedstudies (LoE IIA) (3,52,57,61–65).

Small retrospective analyses and arecent prospective multicenter non-randomized study (LoE IIA) (66) sug-gest that bariatric/metabolic surgerymay induce similar benefits in obese ad-olescents with T2D. Teenagers appear toexperience similar degrees of weightloss, diabetes remission, and improve-ment of cardiometabolic risk factorsfor at least 3 years after surgery (66).No randomized trials, however, haveyet compared the effectiveness andsafety of surgery to those of conven-tional treatment options in adolescents.

Available data fromeconomic analyses,albeit predominantly based on modeling

Figure 3—A: Box plot comparing the average changes in HbA1c between surgery and medical/lifestyletreatments in the first reports of the 11 RCTs published to date. The plot shows 15 sample points becausesome RCTs reported results from two different surgical arms separately. Center lines show medians; boxlimits indicate the 25th and 75th percentiles, as determined by R software; whiskers extend 1.5 times theinterquartile range from the 25th and 75th percentiles. Data points are plotted as open circles. B: ChangefrombaselineHbA1c ineachof the11RCTsdisplayed inFig. 3A. In trialswheremore thanone typeof surgerywas studied, each operation is displayed separately, compared with the medical/lifestyle group. C: Dot plotcomparing baseline with final HbA1c levels following surgery in each of the 11 RCTs displayed in Fig. 3A.

868 Metabolic Surgery in the Treatment Algorithm for T2D Diabetes Care Volume 39, June 2016

studies, support cost-effectiveness ofbariatric/metabolic surgery, especially inpatients with T2D (37). Cost per quality-adjusted life-year (QALY) of bariatric/metabolic surgery in general is approxi-mately $3,200–$6,300, well below therange of $50,000/QALY deemed appro-priate for coverage (36,67). In a U.S.study of obese patients, RYGB had incre-mental cost-effectiveness ratios (ICERs)of $7,000/QALY for newly diagnosed di-abetes and $12,000/QALY for estab-lished diabetes (68). As a comparison,other treatments for diabetes, such asintensive glycemic and lipid control, haveICERs of $41,384/QALY and $51,889/QALY, respectively (69). Although somemodels have suggested that bariatricsurgery may even be cost-saving, directmeasurements of health care costs fromclinical studies have not demonstratedthat surgery decreases overall health careexpenditures.A long-term assessment of health

care costs in subjects enrolled in theSwedish Obese Subjects (SOS) studywas performed according to diabetesstatus at baseline, providing a compari-son of drug-related and total health careexpenditure for patients who undergobariatric surgery versus matched con-trol participants over 15 years (37). Drugcosts were lower for the surgery patientswho started with prediabetes ($3,329less per patient) or diabetes ($5,487less per patient). Although total healthcare costs for the surgery group werehigher for patients with euglycemia orprediabetes, there was no difference be-tween the surgery and conventionaltreatment groups for patients with dia-betes at baseline. These findings furthersupport the economic value of bariatric/metabolic surgery, specifically in patientswith obesity and T2D. There are, how-ever, several limitations of economicstudies in this field, warranting furtherresearch (vide infra).

Safety of Bariatric/Metabolic SurgeryProcedures used in bariatric/metabolicsurgery are characterized by distinctanatomic rearrangements (Fig. 1). Thisimplies differences in technical com-plexity, mechanisms of action, clinicaloutcomes, and safety profiles. Safetyof bariatric/metabolic surgery alsovaries across hospitals and surgeons.Empirical data suggest that profi-ciency of the operating surgeon is an

important factor determining mortal-ity, complications, reoperations, andreadmissions (70).

Safety of bariatric/metabolic surgeryin general has improved significantlyover the last two decades, with contin-ued refinement of minimally invasiveapproaches (laparoscopic surgery), en-hanced training and credentialing, andinvolvement of multidisciplinary teams.Mortality rates with bariatric/metabolicoperations are typically 0.1–0.5%, simi-lar to cholecystectomy or hysterectomy(71–75). Morbidity has also dramaticallydeclined with laparoscopic approaches.Major complications rates are 2–6%,with minor complications in up to 15%(71–79), comparing favorably with othercommonly performed elective opera-tions (75).

There are, however, still complica-tions of surgery that may require re-operations and rehospitalizations. Arecent multicenter study showed earlyreoperation and readmission rates afterlaparoscopic operations of 2.5% and5.1% for RYGB, versus 0.6% and 2.0%for laparoscopic adjustable gastricbanding (LAGB), versus 0.6% and 5.5%for vertical sleeve gastrectomy (VSG),after a median 3-year follow-up (76).Long-term studies (.5 years) demon-strate low rates of reoperation aftermost bariatric/metabolic proceduresexcept LAGB, which is associated withremoval or revision rates of.20% over5–10 years (72,77–79). Biliopancreaticdiversion (BPD), classic type or duode-nal switch (BPD-DS), is the most com-plex procedure, requires longer operativetime, and is associated with the highestperioperative mortality and morbidityrates (80). Compared with RYGB, BPD re-sults in more surgical complications andgreater incidence of GI side effects (81),as well as nutritional deficiencies (20)(LoE IB).

Long-term nutritional and micronutrientdeficiencies with related complications,such as anemia, bone demineralization,and hypoproteinemia, may occur withvariable frequency depending on thetype of procedure, requiring lifelongvitamin/nutritional supplementation(82,83). Iron deficiency after bariatricsurgery, with or without clinical ane-mia, has been observed in 5–64% ofadults (84). One study reported irondeficiency in up to 50% of operated ad-olescents (66). Of note, iron deficiency

has been observed in up to 44% ofadults prior to bariatric surgery (85).Hence, differences in baseline iron sta-tus may explain the large variability inreported rates of postoperative irondeficiency.

Nutritional complications, as well asbone demineralization, are more likelywith intestinal bypass operations, par-ticularly BPD (20), and less common/severe with standard RYGB, LAGB, andVSG. Risk of bone fractures after surgeryis unclear. One retrospective cohortstudy showed no increased fracturerisk, whereas another reported a 1.2-fold increase in the surgery versus controlgroups (86,87). Postprandial hypogly-cemia can also occur, especially withRYGB (83,88). The exact prevalence ofsymptomatic hypoglycemia is unknown.In one study, it affected 11% of 450patients who had undergone RYGB orVSG (88). Severe hypoglycemia resistantto conservative therapy, however, israre (89).

Novel Device-Based Interventions forDiabetesThere has recently been increased inter-est in device-based GI interventionsdesigned to reproduce some of the ben-efits of metabolic surgery. Small humanstudies have examined numerous ap-proaches, including space-occupyingendoluminal devices (90), gastric elec-trical stimulation (91), duodenal andgastroduodenal endoluminal barriers(92,93), and duodenal mucosal resurfac-ing (clinical trial reg. no. NCT01927562,clinicaltrials.gov). Preliminary short-termresults show variable degrees of efficacy,depending on the device, in improving gly-cemic and metabolic control in patientswith obesity and T2D. Because of limita-tions in sample size and/or relativelyshort-term follow-up of existing studies,however, the current LoE for these de-vices was not yet deemed sufficient forformal recommendation.

Knowledge GapsAvailable RCTs do not allow an assess-ment of the relative role of surgery ver-sus conventional therapies in manyclinical scenarios, including the long-term effects of the most commonly per-formed current procedure (VSG), or ofthe effectiveness of surgery in differentstages of disease severity. Factors pre-dicting glycemic control after surgery

care.diabetesjournals.org Rubino and Associates 869

are incompletely characterized, andthere is insufficient evidence fromRCTs to clearly define cutoffs in diabetesduration and/or laboratory markersthat could quantitatively predict thesuccess of treatment over time. Fur-thermore, the number of patients withBMI ,35 kg/m2 studied in RCTs is stillmodest, and there are even fewer pa-tients with BMI ,30 kg/m2. Few RCTshave compared surgical procedureshead-to-head, specifically to treat T2D.Further studies are needed to under-stand the roles of different operationsin specific clinical scenarios, especiallyin adolescents and patients with BMI,35 kg/m2, and to determine whatexactly constitutes failure of medical/lifestyle management before surgery isconsidered. The current LoE is not suf-ficient to determine the role of surgeryas a first-line treatment in most clinicalscenarios, especially in mildly obese ormerely overweight patients.Although it is likely that major glyce-

mic improvements and/or prolongeddiabetes remission after bariatric/metabolic surgery lead to reductions indiabetes-related complications, dataregarding micro- and macrovascularevents, cancer, and mortality can be ex-trapolated only from nonrandomizedtrials (3,52,57,61–65,94). There are noavailable long-term RCTs directly com-paring surgery versus modern phar-macological therapies with diabetescomplications or CVD events as primaryend points, or with sufficient size, dura-tion, and completeness of follow-upto conclusively determine the effectsof surgery on these hard outcomes.Such trials, which are clearly war-ranted, should ideally be randomized,with adequate power and follow-up toexamine microvascular and CVD out-comes as primary end points.Although long-term safety and efficacy

of metabolic surgery have been demon-strated in several studies (20,52,55–59),investigations with follow-up beyond5 years are limited. This is particularly rel-evant for some procedures such as VSGbecause of their relatively recent introduc-tion into clinical practice. Further evalua-tion of long-term outcomes of bariatric/metabolic surgery, particularly in compari-sonwith available alternative treatments ofdiabetes, should be pursued. The surgeon’sexperience appears to influence outcomes(70), and there is aneed to identify effective

strategies for assessing the expertise ofteams/centers providing metabolic surgeryto increase standardization of outcomesacross hospitals and geographic areas.

There is also limited evidence regard-ing the appropriate frequency of moni-toring of nutritional status and theeffectiveness of different types and dos-age of nutritional and vitamin supple-mentations. The exact prevalence andcauses of severe hypoglycemia afterbariatric/metabolic surgery remain un-known (89); hence, studies investigatingthe best means of preventing and treat-ing this condition are warranted.

There is a paucity of studies investi-gating the role of multimodality therapywith integration of pharmaceutical andsurgical treatment to optimize out-comes of diabetes management. In par-ticular, little is known about the role ofcomplementary postoperative lifestyleand pharmaceutical interventions to in-crease and maintain diabetes remissionor enhance glycemic control and lowerthe risk of diabetes complications.

Although available data suggest thatmetabolic surgery may be as effective inadolescents as in adults (66), there ispresently no level-1 evidence to assessthe effectiveness of surgery comparedwith conservative treatment in this pop-ulation. In particular, there are minimallong-term data regarding the safety ofmetabolic surgery and the potentialnegative impact of nutritional deficitson growth.

Although preliminary clinical evi-dence for some device-based GI inter-ventions is promising, appropriateRCTs with adequate end points, samplesize, and follow-up are necessary for for-mal consideration of such approaches inthe treatment algorithm for T2D. Studiesshould investigate the role of these ap-proaches in specific clinical scenarios,alone or in combination with medica-tions and/or lifestyle interventions, andtheir potential value to predict surgicaloutcomes (e.g., screening of surgicalcandidates).

Although most studies suggest a sig-nificant positive economic impact ofbariatric/metabolic surgery, especiallyin patients with T2D, current evidencehas limitations.Most assessments of theeconomic impact of bariatric/metabolicsurgery derive from modeling studiesrather than from direct measurementsof economic costs from clinical trials.

Modeling studies are prone to risks ofoverestimating cost-savings becausethey make assumptions about the dura-bility of clinical benefits from metabolicsurgery. For instance, weight regain anddiabetes relapse have not been prop-erly accounted for in many economicanalyses. Variations in nonsurgical treat-ments of obesity and diabetes, pluscosts across different types of payers(private versus public) and across coun-tries, also are likely to determine differ-ent levels of return on investment.Uncertainty also exists about the cost-effectiveness or savings of bariatric/metabolic surgery for patients withlower BMIs. On the other hand, moststudies so far examined patients re-ceiving bariatric surgery primarily for se-vere obesity and with a relatively lowprevalence of diabetes; these studiesmight underestimate economic value ofsurgery because cost-effectiveness ap-pears to be greater in obese patientswith diabetes at baseline comparedwith those without diabetes (37). Addi-tional cost-effectiveness studies of spe-cific metabolic surgery procedures indifferent clinical scenarios, and basedon RCT data, would greatly facilitatethe decision-making process of policy-makers determining insurance coveragefor surgical treatment of T2D.

Finally, although numerous physio-logical consequences of GI operationsappear to contribute to the antidiabetesand weight-reducing benefits of bariatric/metabolic surgery (5,6,26,28–34), theexact mechanisms mediating diabetesremission after various procedures arenot fully known. Studies designed tofurther elucidate these mechanismsrepresent an important research prior-ity. Such knowledge holds promise toinform decisions regarding the choiceof procedures for individual patients,to optimize surgical design, and hope-fully to provide targets for novel device-based and/or pharmaceutical approachesto T2D.

STATEMENTS ANDRECOMMENDATIONS

(See Table 3.)

Metabolic Surgery Versus TraditionalBariatric SurgeryAlthough obesity and T2D are oftenassociated with one another, T2D is a dis-ease entity with significant heterogeneity

870 Metabolic Surgery in the Treatment Algorithm for T2D Diabetes Care Volume 39, June 2016

that presents distinct challenges for clin-ical care. Therefore, the traditional modelof bariatric surgery practice, which isshaped around the goal to induce weightloss and treat severe obesity, is not con-sistent with the principles and standardsof modern diabetes care. A few examplesbelow provide an idea of the conceptualand practical ramifications of using a dis-ease-specific model of care when surgeryis used specifically to treat T2D.Offering GI surgery with the primary

intent to treat T2D, instead of just as aweight reduction therapy, can influencethe demographic characteristics andbaseline disease states of patients whoelect to undergo surgery. Patientschoosing bariatric surgery are typicallyyoung, predominantly female, with re-latively low prevalence of T2D fortheir BMI (3,4,95). In contrast, a studycomparing patient populations in a“metabolic surgery” program versus atraditional “bariatric surgery” programwithin the same academic centershowed that despite being similarlyobese, patients who sought metabolicsurgery were older, were more oftenmale, and had more severe T2D andCVD at baseline (95). Although notsurprising, these differences can signif-icantly influence the outcomes of sur-gery (e.g., rates of diabetes remission/control, cost-effectiveness, etc.), andthey have important ramifications forall aspects of patient care. These implica-tions, rather than the BMI of the targetpopulation, represent the fundamen-tal distinction between bariatric andmetabolic surgery, necessitating thedevelopment of a new, disease-basedmodel of practice.Traditional bariatric surgery is primar-

ily conceived of as an intervention thatreduces the risk of future disease (i.e., toprevent metabolic or CVD complicationsof severe obesity) rather than as an ap-proach to treat established disease.Such (mis)conception is reflected inthe fact that most guidelines and criteriafor coverage of bariatric surgery todaymake no recommendation for early in-tervention and often delay access tosurgery. However, T2D is a progressivedisease associated with increased riskfor CVD and microvascular complica-tions. Furthermore, evidence showsthat metabolic improvement followingsurgery in patients with T2D correlateswith shorter diabetes duration at

baseline, possibly reflecting more pre-served b-cell function (19,52,96). Thissuggests that unnecessarily delaying ac-cess to surgerymight reduce health ben-efits and cost-effectiveness of surgery inpatients with diabetes. Moreover, exist-ing criteria used for coverage of bariatricsurgery are of low relevance for meta-bolic surgery. For example, because BMIis not a standard diagnostic parameteror a measure of severity of T2D, usingBMI thresholds as stand-alone criteriafor metabolic surgery does not allowhealth care providers to appropriatelyselect candidates for such operationsor to define criteria for prioritization ofthis type of approach.

Defining Goals and Success ofMetabolic SurgeryThe loss of 50% of excess body weight(a somewhat arbitrary metric) is consideredto be a successful outcome of tradi-tional bariatric surgery. T2D, however,describes a continuum of hyperglyce-mic states, is a heterogeneous disorder,and is associated with complex meta-bolic dysfunctions that increase CVDrisk, as well as morbidity and mortality.Thus, it is necessary to define meaning-ful definitions of goals and successfultreatment when surgery is used withthe primary intent to treat T2D. Becauseeven temporary (months to years) nor-malization of glycemic control or majorlong-term improvement of glycemia with-out remission confers potential benefitsfor patients with T2D, remission of diabe-tes, although desirable, should not beregarded as the only goal of metabolicsurgery or the only measure of success.The success of metabolic surgery needsto be defined in the larger context ofcomprehensive diabetes care plans.Metabolic surgery should be considereda means to achieve the glycemic controlnecessary to reduce risk of microvascu-lar complications and CVD. To date, nohigh-quality (RCT) data have directlydemonstrated reductions in microvas-cular complications or CVD events, com-pared with standard therapy.

An ADA expert panel in 2009 definedpartial and complete remission of T2Das achievement of HbA1c ,6.5% and,6.0%, respectively, off all diabetesmedications, and maintenance of theseglycemic levels for at least 1 year (97).Although these definitions have helpedto improve standardization of reporting

outcomes, their applications in routineclinical practice and research are prob-lematic. The DSS delegates felt that re-mission as currently defined should notbe considered to be the sole clinical ben-efit justifying metabolic surgery usage,especially since remission requires re-moval of all diabetes medications, andmetformin is often used in individualswithout diabetes. Furthermore, comple-mentary pharmaceutical therapies suchas metformin should not be discontin-ued simply to meet the definition ofremission, and metformin as well asACE inhibitors and statins should bemaintained as needed to sustain ade-quate glycemic control and preventdiabetes complications. Additional stud-ies are warranted to identify more reli-able biological and/or clinical markers foran exact definition of remission and/orcure in diabetes.

Patient SelectionPatient selection for metabolic surgeryshould be based on balancing surgicaland other long-term risks with potentiallong-term benefits to individual pa-tients, as with any operation (Fig. 4).This trade-off needs to take into accountfactors such as baseline CVD risk due tometabolic disease and hyperglycemiathat do not adequately respond to non-surgical treatments, as well as condi-tions that could contraindicate anyelective operation, such as prior abdom-inal surgery, risk of anastomotic dehis-cence, or risks of deep vein thrombosisand pulmonary embolism.

In addition, preoperative indicatorsother than BMI should be establishedto make patient selection for metabolicsurgery diabetes relevant. There areno data showing that baseline BMI pre-dicts metabolic surgery success. In-stead, strong evidence indicates thatpreoperative BMI, at least within theobese range, does not predict thebenefits of GI surgery with regard to di-abetes prevention (51,57), remission(11,20,52,53,56,98,99), relapse afterinitial remission (20), or the magni-tude of its effects on CVD events(62,100), cancer (61), or death (LoE IIA)(51,53,56,61–63,98). Of note, a recentmeta-analysis of all studies reportingdiabetes remission rates following bari-atric surgerydincluding 94,579 surgicalpatients with T2Ddshowed that the rateof remission was equivalent among the

care.diabetesjournals.org Rubino and Associates 871

60 studies in which mean preoperativeBMI was $35 kg/m2 compared withthe 34 studies with mean preoperativeBMI ,35 kg/m2 (71% versus 72%, re-spectively) (98). Overall, the surgicalvalue seems to be more related toimproved glucose homeostasis thanweight loss per se (11,12,51,54,55,61–63).Although baseline BMI per se does

not predict outcomes in metabolic sur-gery, available evidence, including allexisting RCTs, is based on studies thathave included BMI ranges among theirprimary criteria for eligibility. The numberof patients with BMI ,35 kg/m2 in suchstudies is also limited. Inevitably, anduntil additional studies identify morerobust predictors of outcomes, BMIranges remain necessary to select pa-tients who might benefit from metabolic

surgery, based on extant data. However,additional diabetes-specific parametersshould help to identify clinical scenarioswhere surgical treatment of T2D shouldbe prioritized.

Preoperative WorkupIndications for surgical treatment of T2Dshould be evaluated by a multidisciplinaryclinical team following a comprehensivepreoperative assessment of diabetes andmetabolic health. Exact diagnosis of thetype of diabetes, screening for diabetescomplications, and measurement of resid-ual insulin secretory reserve have specialrelevance for the practice of metabolicsurgery. This knowledge can informclinicians about patients’ counseling(e.g., the likelihood of diabetes remis-sion after surgery), risks of postoperativediabetic ketoacidosis (for patients with

unrecognized type 1 diabetes [T1D]),planning the frequency of postoperativemonitoring of glycemic control anddiabetes complications, and use ofcomplementary postoperative medicaltherapy.

Choice of ProcedureThe choice of surgical procedure shouldbe based on evaluation of the risk-to-benefit ratio in individual patients,weighing long-term nutritional hazardsversus effectiveness on glycemic controland CVD risk.

It is too early to establish a gold stan-dard operation for metabolic surgery be-cause of the paucity of RCTs comparingsurgical procedures head-to-head. How-ever, available RCTs and nonrandom-ized studies specifically designed tocompare different procedures against

Figure 4—Algorithm for the treatment of T2D, as recommended by DSS-II voting delegates. The indications above are intended for patients who areappropriate candidates for elective surgery. meds, medications.

872 Metabolic Surgery in the Treatment Algorithm for T2D Diabetes Care Volume 39, June 2016

Table 3—Statements and recommendations

Grade; LoC

Generalities1. Given its role in metabolic regulation, the GI tract constitutes a clinically and biologically meaningful target for

the management of T2D.Grade U; LoC 100%

2. There is now sufficient clinical andmechanistic evidence to support inclusion of GI surgery among antidiabetesinterventions for people with T2D and obesity.

Grade A; LoC 97%

3. Algorithms for treating T2D should include specific scenarios in which metabolic surgery is considered to be atreatment option in addition to lifestyle, nutritional, and/or pharmacological approaches.

Grade A; LoC 92%

4. The development of an integrated chronic disease care model of lifestyle, nutritional, pharmacological, andsurgical approaches is an important priority for modern diabetes care.

Grade U; LoC 100%

5. The clinical community should work together with health care regulators to recognize metabolic surgery as avalid intervention for T2D in people with obesity and to introduce appropriate reimbursement policies.

Grade U; LoC 100%

Metabolic surgery versus traditional bariatric surgery6. Metabolic surgeryddefined here as the use of GI surgery with the intent to treat T2D and obesitydrequires

the development of a diabetes-based model of clinical practice consistent with international standards ofdiabetes care.

Grade U; LoC 100%

7. Complementary criteria to the sole use of BMI, the traditional criterion used to select candidates for bariatricsurgery, need to be developed to achieve a better patient selection algorithm for metabolic surgery.

Grade U; LoC 100%

8. RYGB, VSG, LAGB, and BPD classic or duodenal switch variant (BPD-DS), are common metabolic operations, eachwith its own risk-to-benefit ratio. All other metabolic operations are considered to be investigational at this time.

Grade A; LoC 91%

9. Metabolic surgery should be performed in high-volume centers with multidisciplinary teams that understandand are experienced in the management of diabetes and GI surgery.

Grade U; LoC 100%

Defining goals and success of metabolic surgery10. Althoughmore studies are needed to further demonstrate long-term benefits, evidence exists for GI surgery to

be considered as an additional approach beyond lifestyle modifications and current medical therapies toreduce complications of T2D.

Grade A; LoC 97%

11. The aimofmetabolic surgery inpeoplewithT2Dand obesity is to improve their hyperglycemia andothermetabolicderangements, while reducing their complications of diabetes, in order to improve their long-term health.

Grade A; LoC 97%

Patient selection12. Patients’ eligibility for metabolic surgery should be assessed by a multidisciplinary team including surgeon(s),

internist(s) or diabetologist(s)/endocrinologist(s), and dietitian(s) with specific expertise in diabetes care.Also, depending on individual circumstances, other relevant specialists could be consulted to evaluate thepatient.

Grade B; LoC 85%

13. Contraindications formetabolic surgery include diagnosis of T1D (unless surgery is indicated for other reasons,such as severe obesity); current drug or alcohol abuse; uncontrolled psychiatric illness; lack of comprehensionof the risks/benefits, expected outcomes, or alternatives; and lack of commitment to nutritionalsupplementation and long-term follow-up required with surgery.

Grade A; LoC 93%

14. Metabolic surgery is recommended as an option to treat T2D in patients with the following conditions:c Class III obesity (BMI $40 kg/m2), regardless of the level of glycemic control or complexity of glucose-

lowering regimens.Grade U; LoC 100%

c Class II obesity (BMI 35.0–39.9 kg/m2) with inadequately controlled hyperglycemia despite lifestyle andoptimal medical therapy.

Grade A; LoC 97%

15. Metabolic surgery should also be considered to be an option to treat T2D in patients with class I obesity (BMI30.0–34.9 kg/m2) and inadequately controlled hyperglycemia despite optimal medical treatment by eitheroral or injectable medications (including insulin).

Grade B; LoC 87%

16. All BMI thresholds used in these recommendations should be reconsidered depending on the ancestry of thepatient. For example, for patients of Asian descent, the BMI values above should be reduced by 2.5 kg/m2.

Grade B; LoC 86%

17. Given the lack of level-1 evidence involving the effects of metabolic surgery on T2D in adolescent patients, theDSS-II committee feels a recommendation for use of GI surgery in this population is inappropriate at present.However, the committee does consider this a high priority for future research.

Grade U; LoC 100%

Preoperative workup18. Preoperative patient evaluation should include assessment of endocrine, metabolic, physical, nutritional, and

psychological health.Grade U; LoC 100%

19. Preoperative evaluation should include a combination of routine clinical tests and diabetes-specific metrics.The following tests are recommended by the DSS-II expert group:

Grade A; LoC 98%

c Standard preoperative tests used for GI surgery at individual providers’ institutions.c Recent tests to characterize current diabetes statusdfor example, but not limited to, HbA1c, fasting

glucose, lipid profile, and tests for retinopathy, nephropathy, and neuropathy.c Tests to distinguish T1D from T2D (fasting C-peptide; anti-GAD or other autoantibodies).

20. In order to reduce the risk for postoperative infection due to hyperglycemia, an attempt should be made toimprove glycemic control before surgery.

Grade A; LoC 95%

Choice of procedure21. RYGB is a well-standardized surgical procedure, and among the four accepted operations for metabolic

surgery, it appears to have a more favorable risk-benefit profile in most patients with T2D.Grade U; LoC 100%

Continued on p. 874

care.diabetesjournals.org Rubino and Associates 873

medical/l ifestyle interventions orother operations in patients with T2Dshow a gradient of efficacy among thefour accepted surgical approachesfor weight loss and diabetes remission,as follows: BPD.RYGB.VSG.LAGB.The opposite gradient exists for com-parative safety of these operations(10–25,72,76–79,101–104). Evidencefrom these studies can be summarizedas follows:

c RYGB versus BPD: BPD promotesgreater T2D remission but more

metabolic complications comparedwith RYGB (LoE IB).

c RYGB versus LAGB: RYGB achievesgreater diabetes remission com-pared with LAGB (LoE IA). RYGB isassociated with higher risk of earlypostoperative complications butlower risk of long-term reoperations(LoE IIA).

c RYGB versus VSG: Compared with VSG,RYGB promotes higher diabetes remis-sion rates (LoE IA), better lipid control(LoE IA), similar risk of reoperation(LoE IA), better quality of life (LoE IB),

and higher incidence of postoperativecomplications (LoE IA).

Postoperative Follow-upRegardless of the level of diabetescontrol and/or remission achieved bypatients following surgery, diabetesmanagement should includedin additionto optimizing glycemic controldmonitoringand ameliorating CVD risk factors,such as hypertension and dyslipide-mia, because it is reasonable to assumethat these patients remain at higher riskof CVD complications and disease

Table 3—Continued

Grade; LoC

22. Although longer-term studies are needed, current data suggest that VSG is an effective procedure that resultsin excellent weight loss and major improvement of T2D, at least in the short to medium term (1–3 years) inwhich outcomes have been measured in RCTs. It could be a valuable option to treat diabetes, especially inpatients for whom concerns exist about the risk of operations that involve bowel diversion.

Grade B; LoC 80%

23. LAGB is effective in improving glycemia in patients with obesity and T2D, to the degree that it causes weightloss. The procedure, however, is associated with greater risk for reoperation/revision compared with RYGBdue to failure or band-related complications, e.g., slippage/migration, erosion, etc.

Grade B; LoC 85%

24. Although clinical evidence suggests that BPD/BPD-DS may be the most effective procedure in terms ofglycemic control and weight loss, the operation is associated with significant risk of nutritional deficiencies,making its risk-benefit profile less favorable than that of the other bariatric/metabolic procedures formost patients. BPD/BPD-DS should be considered only in patients with extreme levels of obesity (e.g.,BMI .60 kg/m2).

Grade B; LoC 83%

Postoperative follow-up25. After surgery, patients should continue to be managed by multidisciplinary teams including diabetologists/

endocrinologists, surgeons, nutritionists, and nurses with specific diabetes expertise.Grade A; LoC 98%

26. Postoperative follow-up should include surgical and nutritional evaluations at least every 6 months, and moreoften if necessary, during the first 2 postoperative years and at least annually thereafter.

Grade U; LoC 100%

27. Unless patients have a documented, stable condition of nondiabetic glycemia, glycemic control should bemonitored with at least the same frequency as in standard diabetes care of nonoperated patients.

Grade U; LoC 100%

28. In patients who have reached stable normalization of hyperglycemia for at least 6 months, monitoring ofglycemic control should be performed with the same frequency as recommended for patients withprediabetes because of the potential for relapse.

Grade A; LoC 95%

29. Patients with a stable condition of nondiabetic glycemia for less than 5 years should be monitored forcomplications of diabetes at the same frequency as before remission. Once remission reaches the 5-yearmark, monitoring of complications can be done at a reduced frequency, depending on the status of eachcomplication. Complete cessation of screening for a particular complication should be considered only ifnondiabetic glycemia persists and there is no history of that complication.

Grade B; LoC 85%

30. Within the first 6 months after surgery, patients should be carefully evaluated for glycemic control andantidiabetes medication(s) tapered according to the professional opinion of the physician(s). Further medicaltreatment of T2D after this initial 6-month period should be dosed accordingly, but not discontinued untillaboratory proof of stable glycemic normalization is obtained. Stable nondiabetic glycemia (i.e., HbA1c in thenormal range) should be documented for at least two 3-month HbA1c cycles (6 months in total) beforeconsidering complete withdrawal of glucose-lowering drugs, although withdrawal of certain frontlinemedications (e.g., metformin) should be considered more carefully.

Grade B; LoC 82%

31. In the event of plasma glucose levels rapidly approaching the normal range early postoperatively, appropriateadjustments to medical therapy (medication types and dosage) should be implemented to preventhypoglycemia. Metformin, thiazolidinediones, GLP-1 analogs, DPP-4 inhibitors, a-glucosidase inhibitors, andSGLT2 inhibitors are suitable drugs for early postoperative diabetes management due to their low risk ofinducing hypoglycemia.

Grade A; LoC 98%

32. Ongoing and long-termmonitoring of micronutrient status, nutritional supplementation, and support must beprovided to patients after surgery, according to guidelines for postoperative management of metabolic/bariatric surgery by national and international societies (for example, AACE/TOS/ASMBS, IFSO, BOMSS).

Grade U; LoC 100%

Grade U 5 100% agreement (unanimous); grade A 5 89–99% agreement; grade B 5 78–88% agreement; grade C 5 67–77% agreement. AACE,American Association of Clinical Endocrinologists; ASMBS, American Society forMetabolic and Bariatric Surgery; BOMSS, British Obesity &MetabolicSurgery Society; DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide 1; IFSO, International Federation for the Surgery of Obesity andMetabolic Disorders; LoC, level of consensus; SGLT2, sodium–glucose cotransporter 2; TOS, The Obesity Society.

874 Metabolic Surgery in the Treatment Algorithm for T2D Diabetes Care Volume 39, June 2016

relapse than does the general popula-tion. Thus, until surgery-specific pre-dicting factors of diabetes relapse arebetter developed, patients should con-tinue to be monitored by primary carephysicians, endocrinologists, and inter-nal medicine specialists as appropriateand have regular postoperative screen-ing for development and/or progressionof microvascular complications of T2D(e.g., retinopathy, nephropathy, andneuropathy). Because sudden im-provement of prolonged hyperglyce-mia can acutely worsen microvasculardisease, particularly intensive earlypostoperative monitoring is warrantedin patients known to be afflicted(Table 3).

Future ResearchThe DSS delegates identified the follow-ing arenas for future research in meta-bolic surgery:

1. Develop and evaluate criteria forsurgery that are more appropriatethan BMI alone in people withT2D.

2. Investigate the long-term effect ofsurgery on microvascular diseaseand CVD in high-quality studies(RCTs especially and prospective,well-matched case-control studies).

3. Refine the structure of therapeuticalgorithms to incorporate meta-bolic surgery.

4. Establish appropriate national/international registries of metabolicsurgery in patients with T2D, es-pecially designed to facilitatestandardized collection of qualitylong-term data about CVD, mortal-ity, and other relevant outcomes.

5. Investigate the long-term effec-tiveness and safety of metabolicsurgery in adolescents as com-pared with alternative treatmentoptions.

6. Determine which operation is theoptimal choice for individualpatients.

7. Determine the optimal time to inter-vene in individual patients.

8. Identify specific clinical scenarios inpatients with diabetes that warrantescalation of treatment and earlierconsideration of surgery.

9. Define the optimal use of therapiesthat combine surgical, pharmacological,

and postoperative lifestyle-basedtreatments.

10. Identify optimal definitions of out-come to be used across treatmentmodalities.

11. Increase understanding of surgicalmechanisms, so as to improve use ofcurrent treatmentoptionsanddevelopeffective, new alternative therapies.

12. Investigate the role of device-basedGI interventions (“interventionaldiabetology”) to treat T2D, in combi-nation with lifestyle and/or pharma-ceutical approaches.

13. Investigate cost-effectiveness ofspecific procedures and of the useof surgery in distinct clinical scenar-ios to inform policymakers aboutoptimal strategies to prioritize sur-gical access.

Funding and Duality of Interest. The DSS-IIand WCITD 2015 were supported by the In-ternational Diabetes Surgery Task Force(a nonprofit organization), King’s College Lon-don, King ’s College Hospital , Johnson &Johnson, Medtronic, Novo Nordisk, Fractyl,DIAMOND MetaCure, Gore, MedImmune, andNGM Biopharmaceuticals. These sponsorsplayed no role in the selection of voting dele-gates, the Delphi process, the DSS-II and WCITD2015 programs, or the writing of this article.None of the DSS-II codirectors, members ofthe organizing committee, or voting delegatesreceived payment for their efforts. No otherpotential conflicts of interest relevant to thisarticle were reported.Author Contributions. F.R. and D.E.C. chairedthe writing committee for this article and spear-headed its development. D.M.N., R.H.E., P.R.S.,K.G.M.M.A., P.Z.Z., S.D.P., L.J., S.M.S., W.H.H.,S.A.A., L.M.K., and G.T.-O. contributed to thepreparation of this report. The 48 voting dele-gates listed in Table 2 participated in a 4-month-long Delphi-like process to craft the 32 consensusstatements, culminating in the DSS-II conferencein London, U.K. F.R., D.E.C., P.R.S., and L.M.K.served as codirectors of DSS-II.

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