Metabolic Surgery - Journal of the American College of ... · calorie intake, physical activity, and behav-ioral interventions. The energy deﬁcit should generally be w500 to 750

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J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 1 , N O . 6 , 2 0 1 8

ª 2 0 1 8 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N

P U B L I S H E D B Y E L S E V I E R

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Metabolic SurgeryWeight Loss, Diabetes, and Beyond

Manan Pareek, MD, PHD,a,b Philip R. Schauer, MD,c Lee M. Kaplan, MD, PHD,d Lawrence A. Leiter, MD,e

Francesco Rubino, MD,f Deepak L. Bhatt, MD, MPHa

ABSTRACT

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The alarming rise in the worldwide prevalence of obesity is paralleled by an increasing burden of type 2 diabetes mellitus.

Metabolic surgery is the most effective means of obtaining substantial and durable weight loss in individuals with obesity.

Randomized trials have recently shown the superiority of surgery over medical treatment alone in achieving improved

glycemic control, as well as a reduction in cardiovascular risk factors. The mechanisms seem to extend beyond the

magnitude of weight loss alone and include improvements in incretin profiles, insulin secretion, and insulin sensitivity.

Moreover, observational data suggest that the reduction in cardiovascular risk factors translates to better patient

outcomes. This review describes commonly used metabolic surgical procedures and their current indications and

summarizes the evidence related to weight loss and glycemic outcomes. It further examines their potential effects on

cardiovascular outcomes and mortality and discusses future perspectives. (J Am Coll Cardiol 2018;71:670–87)

© 2018 by the American College of Cardiology Foundation.

N 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2017.12.014

m the aBrigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston, Massachusetts; bCardio-

scular and Metabolic Preventive Clinic, Department of Endocrinology, Odense University Hospital, Odense, Denmark; cBariatric

d Metabolic Institute, Cleveland Clinic, Cleveland, Ohio; dObesity, Metabolism and Nutrition Institute, Massachusetts General

spital, Boston, Massachusetts; eLi Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto,

tario, Canada; and the fDepartment of Metabolic and Bariatric Surgery, Diabetes and Nutritional Science Division, King’s

llege Hospital, London, United Kingdom. Dr. Pareek has served on the advisory board of and received speaker’s honoraria from

traZeneca. Dr. Schauer has served on the advisory boards of The Medicines Company, GI Dynamics, Neurotronic, and Pacira;

s been a consultant for Ethicon, The Medicines Company, and Novo Nordisk; and has received research support from Ethicon,

National Institutes of Health, Medtronic, and Pacira. Dr. Leiter has received research funding from, has provided continuing

dical education on behalf of, and/or has acted as an adviser to Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Eli Lilly,

perion, GlaxoSmithKline, Janssen, Merck, Novo Nordisk, Sanofi/Regeneron, Servier, and The Medicines Company. Dr. Rubino

s served on the scientific advisory boards of Fractyl and GI Dynamics; has received consulting fees from Ethicon and Medtronic;

s received speaker’s honoraria from Ethicon and Novo Nordisk; and has received grants from the National Institute for Health

search (UK) and Ethicon. Dr. Bhatt has served on the advisory boards of Cardax, Elsevier Practice Update Cardiology, Medscape

rdiology, and Regado Biosciences; has served on the board of directors of the Boston VA Research Institute and the Society of

rdiovascular Patient Care; has been Chair of the American Heart Association Quality Oversight Committee; has served on the

ta monitoring committees of Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo

nic, and Population Health Research Institute; has received honoraria from the American College of Cardiology (senior associate

itor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research

titute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Com-

nications (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate

itor), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor,

rdiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (continuing medical

ucation steering committees), Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), and VA

RT Research and Publications Committee (chair); has received research funding from Amarin, Amgen, AstraZeneca, Bristol-

ers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi, and The

dicines Company; has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart

ease); has been site co-investigator for Biotronik, Boston Scientific, and St. Jude Medical; has been a trustee of the American

llege of Cardiology; and has conducted unfunded research for FlowCo, Merck, PLx Pharma, and Takeda. Dr. Kaplan has

orted that he has no relationships relevant to the contents of this paper to disclose.

nuscript received September 15, 2017; revised manuscript received December 13, 2017, accepted December 15, 2017.

https://doi.org/10.1016/j.jacc.2017.12.014

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AB BR E V I A T I O N S

AND ACRONYM S

AGB = adjustable gastric

banding

BMI = body mass index

BPD = biliopancreatic diversion

BPDDS = biliopancreatic

diversion with duodenal switch

CI = confidence interval

HbA1c = glycated hemoglobin

HR = hazard ratio

OR = odds ratio

RYGB = Roux-en-Y gastric

bypass

SG = sleeve gastrectomy

T1DM = type 1 diabetes

mellitus

T2DM = type 2 diabetes

mellitus

J A C C V O L . 7 1 , N O . 6 , 2 0 1 8 Pareek et al.F E B R U A R Y 1 3 , 2 0 1 8 : 6 7 0 – 8 7 Metabolic Surgery: Weight Loss, Diabetes, and Beyond

671

T he worldwide prevalence of obesity, character-ized by a body mass index (BMI) $30 kg/m2,has more than doubled from approximately

5% in 1975 to 13% in 2014 (1,2). About 4% of personsare severely obese (BMI $35 kg/m2), whereas 1%have morbid obesity (BMI $40 kg/m2). Assumingunaltered trends, as much as one-fifth of the worldpopulation may have obesity by 2025 (1). In the UnitedStates, more than one-third of adults have obesity,with considerable differences in prevalence depend-ing on race and socioeconomic status (3).

Obesity is a well-known risk factor for type 2 dia-betes mellitus (T2DM) (2). Thus, there has been aparallel increase in the prevalence of T2DM, currentlystanding at 9% worldwide and projected to reachw12% by 2025 (4). When the growing population istaken into account, the global burden of diabetes islikely to rise by more than 50% in the next decade(4,5). The metabolic abnormalities associated withobesity increase the risk of cardiovascular disease,including coronary artery disease and heart failure(6). Indeed, most of the w7% of deaths for which aBMI above 25 kg/m2 appears responsible can berelated to cardiovascular disease or T2DM (2). Theunderlying mechanisms have not been fully eluci-dated, but they may include metabolic, hemody-namic, and inflammatory effects of having anincreased adipose tissue mass (6).

Regardless of how achieved, weight loss has thepotential to mitigate the adverse effects of obesity(6). The purpose of this review is to describecontemporary metabolic surgical procedures, theirindications, and the effects of these procedures onweight loss, glycemic outcomes, cardiovascular out-comes, and mortality among adult individuals.

MEDICAL MANAGEMENT OF OBESITY

Although behaviorally based treatments can deliverstatistically significant weight loss, the magnitude isgenerally modest, and the weight loss is often notdurable (7). A 2014 meta-analysis by Dombrowskiet al. (8) showed a significant, but small difference in1-year weight loss of 1.6 kg with diet and physicalactivity compared with a control group. Conversely,the randomized Look AHEAD (Action for Health inDiabetes) trial (9) provided an example of a successfullifestyle intervention program. Among overweight orobese individuals with T2DM, one-half of thoseassigned to intensive lifestyle intervention (caloriegoal of 1,200 to 1,800 kcal daily and $175 min ofmoderate intensity physical activity weekly) had aclinically meaningful weight loss of $ 5% (mean 4.7%)of their initial weight at 8 years as compared with

approximately one-third of patients in thecontrol group (9). Sustained, modest weightloss with lifestyle improvement versus con-trol was also seen at 10 years in the FinnishDiabetes Prevention Study, but not at 10-yearfollow-up in the Diabetes Prevention Program(10,11).

Healthy lifestyle measures should be pro-moted in all individuals as primary, second-ary, and tertiary prevention for overweight orobesity and associated complications (12,13).In patients with obesity, the major compo-nents of lifestyle therapy consist of reducedcalorie intake, physical activity, and behav-ioral interventions. The energy deficit shouldgenerally be w500 to 750 kcal daily (12,13).Moderate aerobic exercise of >150 min perweek, distributed over 3 to 5 days, combinedwith resistance exercise 2 to 3 times perweek, is recommended. Behavioral changes
(e.g., self-monitoring and goal setting) should beincluded as part of the intervention. The weight lossgoal is 10% in subjects with pre-diabetes or themetabolic syndrome and at least 5% to 15% in thosewho have T2DM (13).
Combining weight loss drugs with lifestyle inter-vention can produce greater weight loss comparedwith lifestyle intervention alone (13,14). These med-ications may reinforce behavioral or lifestyle changes,increase the potential for physical activity, and havebeneficial effects on related comorbidities. Many an-tiobesity drugs have been marketed over the years,but some were later withdrawn because of unac-ceptable adverse effects (15,16). The 5 antiobesityagents currently approved by the U.S. Food and DrugAdministration are orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide(13,17). A 2016 meta-analysis by Khera et al. (18) foundsignificant 1-year weight loss for these drugs in com-parison with placebo, ranging from 2.6 kg with orli-stat to 8.8 kg with phentermine-topiramate.Contemporary guidelines suggest the addition ofantiobesity medication to lifestyle measures inindividuals with BMI $30 kg/m2 or BMI $27 kg/m2

with at least 1 obesity-associated comorbidity who aremotivated, but have failed to lose weight or maintainweight loss by using high-intensity lifestyle inter-vention alone (Table 1) (13,14,17). Drug therapy mayalso be initiated concomitantly with lifestyle therapyin patients with BMI $27 kg/m2 who have (severe)weight-related complications (13). If $5% of bodyweight has not been lost after 3 months of therapy orthere are issues with tolerability or safety, the drugshould be discontinued. If the weight loss criterion is

TABLE 1 Common Cardiovascular and Metabolic

Obesity-Associated Comorbidities

Type 2 diabetes mellitus

Hypertension

Hyperlipidemia

Coronary, cerebral, and peripheral vascular disease

Heart failure

Atrial fibrillation

Venous stasis disease and thromboembolic disorders

Obstructive sleep apnea

Chronic kidney disease

Data from references 12–14, 59, and 104.

Pareek et al. J A C C V O L . 7 1 , N O . 6 , 2 0 1 8

Metabolic Surgery: Weight Loss, Diabetes, and Beyond F E B R U A R Y 1 3 , 2 0 1 8 : 6 7 0 – 8 7

672

met, the drug may be continued. Importantly, there isa risk of weight regain when discontinuing pharma-cotherapy, particularly when behavioral measures arenot used. Given the different efficacy and safetyprofiles, there is no general treatment algorithm, andthe choice of agent should be individualized(13,14,17). So far, only liraglutide has demonstratedclinical cardiovascular benefit (19).

In patients with T2DM and overweight or obesity,the choice of glucose-lowering medications shouldconsider their effects on weight. Antidiabetic agentsassociated with weight loss include biguanides(metformin), a-glucosidase inhibitors, sodium-glucose cotransporter-2 inhibitors, glucagon-likepeptide-1 receptor agonists, and amylin analogues.Sodium-glucose cotransporter-2 inhibitors andglucagon-like peptide-1 receptor agonists appear tobe particularly effective. Dipeptidyl peptidase-4 in-hibitors are considered weight neutral, whereas in-sulin, insulin secretagogues (sulfonylureas,meglitinides), and peroxisome proliferator-activatedreceptor agonists are associated with weight gain.Use of medications for comorbid conditions that areassociated with weight gain (e.g., antipsychotic, an-tidepressant, anticonvulsant and glucocorticoidagents) should be kept to a minimum (13,14,17,20).

METABOLIC SURGERY

Gastrointestinal surgery provides the most substantialand sustainable weight loss in individuals with obesity(21). The procedures are collectively referred to asbariatric (from the Greek words baros [weight] andiatrikos [medicine]) or metabolic (when the intent iscardiometabolic risk reduction) surgery and are amongthe most common gastrointestinal procedures. TheInternational Federation for the Surgery of Obesity andMetabolic Diseases reported that almost 580,000metabolic procedures were performed worldwide in2014 (22). The American Society for Metabolic and

Bariatric Surgery estimated that in the United States179,000 metabolic procedures were done in 2013 and196,000 were performed in 2015 (23). The AmericanHeart Association also acknowledges the growingimportance of these techniques (24).

Weight loss and glycemic effects were traditionallythought to be results of caloric restriction (reducedgastric volume) and/or malabsorption of ingested nu-trients, but more recent studies have demonstratedthat changes in the physiology of energy balance andbody fat mass are the primary mechanisms. Indeed,widespread alterations in the secretion and activity ofhormones and neurotransmitters affecting appetite,satiety, energy expenditure, and glucose metabolismin response to these surgical procedures have beenincreasingly recognized (25–27). All contemporaryprocedures can be done laparoscopically and includeRoux-en-Y gastric bypass (RYGB), sleeve gastrectomy(SG), adjustable gastric banding (AGB), and bil-iopancreatic diversion with duodenal switch (BPDDS)(28,29). The principal anatomic alterations from theseprocedures are shown in Figures 1A to 1D.

RYGB comprises w40% of the metabolic operationscurrently performed and is the most frequent pro-cedure in Latin America, including South America(22,28). In this procedure, a w15- to 30-ml proximalgastric pouch is created, separated from the distalstomach. After transection of the jejunum approxi-mately 50 to 75 cm beyond the ligament of Treitz, thegastric pouch is anastomosed to the distal intestinalsegment, and the proximal intestinal segment isanastomosed to the jejunum, approximately 100 to150 cm more distally (Figure 1C). After this procedure,ingested nutrients flow directly from the gastricpouch into the midjejunum and pass through the 100-to 150-cm Roux (alimentary) limb, thereby bypassingthe duodenum and proximal jejunum (29). Theseanatomic changes lead to alterations in the signalingbetween luminal factors and the intestinal mucosa,thus generating neurohumoral effects that furtherlead to alterations in hunger, satiety, energy balance,modest fat malabsorption, and weight loss (27,30–32).

SG has recently replaced RYGB as the mostcommonly performed weight loss procedure world-wide (28). In this procedure, most of the greater cur-vature of the stomach is resected, resulting in atubular stomach that includes the lesser curvaturethat is resistant to stretching. The pylorus is pre-served (Figure 1B) (29). Resection of the greater cur-vature removes most of the oxyntic (endocrine)mucosa of the stomach and leads to alterations inneurohumoral signaling that are strikingly similar tothose observed after RYGB. Surprisingly, thesechanges also lead to accelerated gastric emptying and

FIGURE 1 Contemporary Procedures for Metabolic Surgery

The 4 contemporarymetabolic surgical procedures: (A) adjustable gastric banding; (B) sleeve gastrectomy; (C)Roux-en-Y gastric bypass; and (D)

biliopancreatic diversionwith duodenal switch. Reprintedwith permission from Piche et al (128). Copyright 2015 Canadian Journal of Cardiology.


673

early exposure of ingested nutrients to the small in-testinal mucosa (27,30,31).

During AGB, a locking silicone ring (band) is placedaround the upper stomach, 1 to 2 cm below thegastroesophageal junction, and connected to a

subcutaneous infusion port through which the banddiameter can be adjusted by injecting or removingsaline. This creates a 30-ml upper gastric pouch(Figure 1A). With AGB, designed to be a less invasive,more purely restrictive operation than RYGB or SG,

TABLE 2 Randomized Controlled Trials of Metabolic Surgery Versus Medical Therapy for Patients With Type 2 Diabetes Mellitus

First Author(Ref. #) Intervention Control

Key InclusionCriteria

SampleSize

PrimaryFollow-UpDuration

Weight Reduction(Intervention vs. Control)

Diabetes Remission(Intervention vs. Control)

Dixon et al. (40) Conventional therapyplus laparoscopicAGB

Conventionaltherapy

Age 20–60 yrsBMI 30–40 kg/m2

T2DM <2 yrs

60 2 yrs 21.1 kg vs. 1.5 kg,p < 0.001

Fasting plasma glucose<126 mg/dl andHbA1c <6.2% withoutantidiabetic drugs:

73% vs. 13%, p < 0.001

Schauer et al.* (41) Intensive medicaltherapy pluseither RYGB orSG (bothlaparoscopic)

Intensivemedicaltherapy

Age 20-60 yrsBMI 27–43 kg/m2

T2DM with HbA1c

>7.0%

150 1 yr RYGB 29.4 kg vs. SG25.1 kg vs. medical5.4 kg

RYGB vs. medical,p < 0.001

SG vs. medical,p < 0.001

RYGB vs. SG, p ¼ 0.02

HbA1c #6.0%:RYGB 42% vs. SG 27% vs.

medical 12%RYGB vs. medical, p ¼ 0.002SG vs. medical, p ¼ 0.008RYGB vs. SG, p ¼ 0.59

Mingrone et al.* (42) Medical therapy pluseitherlaparoscopicRYGB or openBPD

Medical therapy Age 30–60 yrsBMI $35 kg/m2

T2DM $5 yrs withHbA1c $7.0%

60 2 yrs RYGB 33.3% vs. BPD33.8% vs. medical4.7%

RYGB vs. medical,p < 0.001

BPD vs. medical,p < 0.001

Fasting plasma glucose<100 mg/dl andHbA1c <6.5% for at least 1 yrwithout antidiabetic drugs:

RYGB 75% vs. BPD 95% vs.medical 0%

RYGB vs. medical, p < 0.001BPD vs. medical, p < 0.001

Ikramuddin et al.(43)

Intensive medicalmanagement pluslaparoscopicRYGB

Intensivemedicalmanagement

Age 30–67 yrsBMI 30–39.9 kg/m2

T2DM $6 monthswith HbA1c

$8.0% and serumC-peptide>1.0 ng/ml

120 1 yr 26.1% vs. 7.9%,p < 0.001

HbA1c <7.0%, LDL-cholesterol <100 mg/dl,and systolic bloodpressure <130 mm Hg:

49% vs. 19%, p < 0.001

Liang et al. (44) Laparoscopic RYGB Usual care withor withoutexenatide

Age 30–60 yrsBMI >28 kg/m2

T2DM treated withantidiabetic drugsfor >12 months,HbA1c >7.0%,serum C-peptide>0.3 mg/l, andhypertension

108 1 yr Changes in BMI werenot directlyreported

RYGB vs. usual,p < 0.01

RYGB vs. exenatide,p < 0.05

Usual vs. exenatide,p $ 0.05

RYGB 90% vs. usual 0% vs.exenatide 0%

Wentworth et al.(45)

Multidisciplinarydiabetes care pluslaparoscopic AGB

Multidisciplinarydiabetes care


T2DM <5 yrs

51 2 yrs 11.5 kg vs. 1.6 kg,p ¼ 0.002

Fasting plasma glucose<126 mg/dl and 2-h oralglucose tolerancetest <200 mg/dl withoutantidiabetic drugs:

52% vs. 8%, p ¼ 0.001

Courcoulas et al.(46)

RYGB or laparoscopicAGB

Intensivelifestyleweight lossintervention


T2DM with fastingplasma glucose> 126 mg/dl or onantidiabetic drugs

69 1 yr RYGB 26.8 kg vs. AGB17.4 kg vs. lifestyle10.3 kg

RYGB vs. lifestyle,p < 0.001

AGB vs. lifestyle,p ¼ 0.02

RYGB vs. AGB,p ¼ 0.001

HbA1c <5.7%, fasting plasmaglucose #100 mg/dlwithout antidiabetic drugs:

RYGB 17% vs. AGB 23% vs.lifestyle 0%

RYGB vs. lifestyle, p ¼ 0.11AGB vs. lifestyle, p ¼ 0.02RYGB vs. AGB, p ¼ 0.72

Halperin et al. (47) RYGB Intensivemedicaldiabetes andweightmanagementprogram


T2DM >1 yr withHbA1c $6.5% onantidiabetic drugs


p < 0.001 in favor ofRYGB

HbA1c <6.5% and fastingplasma glucose <126 mg/dl:

58% vs. 16%, p ¼ 0.03

Continued on the next page



674

the original anatomy can be restored by removing theband (29). In general, weight loss after AGB is sub-stantially less than that seen after RYGB or SG, and asmany as 75% of AGB devices require removal for lackof weight loss, substantial weight gain, or esoph-agogastric complications (33). As a result, the use of

AGB has declined substantially over the past decade,and it now accounts for only 5% to 10% of bariatricprocedures in the United States (28).

BPDDS accounts for only about 2% of metabolicprocedure now performed (28). In the originalbiliopancreatic diversion (BPD) procedure, the

TABLE 2 Continued

First Author(Ref. #) Intervention Control

Key InclusionCriteria

SampleSize

PrimaryFollow-UpDuration

Weight Reduction(Intervention vs. Control)

Diabetes Remission(Intervention vs. Control)

Parikh et al. (48) RYGB, SG, or AGB (alllaparoscopic), onthe basis ofpatient’spreference

Intensivemedicalweightmanagement

Age NSBMI 30–35 kg/m2

T2DM

57 6 months 17.3 kg vs. 1.8 kg,p < 0.001

Fasting plasma glucose<126 mg/dl, 2-h oralglucose tolerancetest <200 mg/dl, andHbA1c <6.5% withoutantidiabetic drugs:

65% vs. 0%, p < 0.001

Ding et al. (49) Laparoscopic AGB Intensivemedicaldiabetes andweightmanagementprogram


T2DM >1 yr withHbA1c $6.5% onantidiabetic drugs


p ¼ 0.03 in favor ofAGB

HbA1c <6.5% and fastingplasma glucose <126 mg/dl:

33% vs. 23%, p ¼ 0.46

Cummings et al. (50) Laparoscopic RYGB Intensivelifestyle andmedicalintervention


T2DM on antidiabeticdrugs

43 1 yr 25.8% vs. 6.4%, p <

0.001HbA1c <6.0% without

antidiabetic drugs:60% vs. 6%, p ¼ 0.002

*Please see Figure 2 for results at 5 years.

AGB ¼ adjustable gastric banding; BMI ¼ body mass index; BPD ¼ biliopancreatic diversion; HbA1c ¼ glycated hemoglobin; LDL ¼ low-density lipoprotein; NS ¼ not specified; RYGB ¼ Roux-en-Y gastricbypass; SG ¼ sleeve gastrectomy; T2DM ¼ type 2 diabetes mellitus.


675

duodenum is divided from the pylorus, which isremoved, and the ileum is divided as well. The distalileum is subsequently attached to the stomach andthe proximal ileum, thereby delivering enzymes fromthe pancreas and bile from the liver, and the duo-denum is anastomosed to the terminal ileum. Themore commonly performed BPDDS involves apylorus-preserving SG and a proximal duodenojeju-nostomy that causes ingested nutrients to bypass upto 4 m of the duodenum and jejunum (Figure 1D)(29,34). As with RYGB and SG, the primary mecha-nisms of BPDDS appear to be widespread changes inmetabolic physiology that lead to altered appetite andfood preference, decreased nutrient ingestion, fatand protein malabsorption, and profound weight loss.The extent of reduced fat and protein absorption isgreater than that observed with RYGB because of themore extensive intestinal bypass. Pathologicalmacronutrient malabsorption in the form of proteincalorie malnutrition (5%) can occur, but this is pri-marily an adverse effect of the operation correctableby oral protein augmentation (80 to 100 g/day) orshortening the bypassed portion of the small bowel(27,30,35).

WEIGHT LOSS

Gastrointestinal surgery has been demonstrated tohave substantially greater efficacy than lifestyle orbehavioral and pharmacological treatments forobesity (21,36–38). A 2004 meta-analysis of 136studies, 5 of which were randomized, with a totalof 22,094 patients undergoing metabolic surgery

reported a mean 40-kg weight loss (36). Weightreductions for individual procedure types were 43 kgfor RYGB, 29 kg for AGB, and 46 kg for BPDDS; how-ever, there was no information on follow-up dura-tion. Weight loss with SG, the newest technique,appears to range between that of RYGB and AGB (39).

In a more recent meta-analysis of 11 randomizedcontrolled trials with 796 obese patients, metabolicsurgery resulted in a 26-kg greater weight reductionthan nonsurgical treatment (p< 0.001) (21). Controlledtrials that have directly compared surgery with medi-cal treatment in patients with overweight or obesityand T2DM corroborate these findings (Table 2) (40–50).

However, both meta-analyses and individual trialsshould be interpreted in light of their short-term(usually #2 years) duration (51). Studies that havereported long-term (>5 years) outcomes include theprospective, matched SOS (Swedish Obese Subjects)study, in which mean weight loss at 15 years was 27%for gastric bypass and 13% for gastric bandingcompared with 1% for controls (52–54). Similar find-ings were seen at 20 years. Peak weight loss aftersurgery was achieved at 1 year and was 38% and 21%for RYGB and AGB, respectively. Of note, because theSOS study was begun more than 25 years ago, mostsurgical patients in this study underwent vertical-banded gastroplasty, a procedure that is now rarelyperformed. Another observational study showed a21% greater weight loss at 10 years after RYGBcompared with a matched control cohort that did notundergo surgery (55). Finally, 2 randomized trialshave recently reported 5-year outcomes, demon-strating durable weight reduction after RYGB, SG, and

FIGURE 2 The 5-Year Changes in Body Weight, Rates of Diabetes Remission, and Changes in Glycated Hemoglobin, in Randomized Controlled Trials of Patients

With Obesity and Type 2 Diabetes Mellitus

Abso

lute

Red

uctio

n (k

g)

0

P = 0.17

–37.0±13.8

–44.7±22.4

Mingrone et al.

–10.0±12.2

Changes in Body Weight at 5 Years

P < 0.001

P < 0.001

P = 0.01

–23.2±9.6

–18.6±7.5

Schauer et al.

P = 0.003

P = 0.003

–50

–40

–30

–20

–10

–70

–60

–80

A

31

23

P = 0.003

P = 0.002

P = 0.43

0

Perc

enta

ge R

emitt

ed (%

)

80

37

63

P < 0.001

Mingrone et al.0

Diabetes Remission at 5 Years

Schauer et al.

30

40

50

60

70

10

20

0

B

RYGB BPD SG Medical Therapy

Abso

lute

Red

uctio

n (%

)

0.0

P = 0.59

–2.0±1.5

–2.5±1.8

Mingrone et al.

–1.6±1.0

Changes in Glycated Hemoglobin at 5 Years

P = 0.25P = 0.59

P = 0.67

–2.1±1.8

–2.1±2.3

Schauer et al.

P = 0.003P = 0.003

–3.5–4.0

–2.5–3.0

–2.0

–1.0–1.5

–0.5

–5.0–4.5

–6.0–5.5

C

–5.3±10.8

–0.3±2.0

(A) The absolute reductions in body weight (kg) according to study arm in the 2 randomized controlled trials of patients with obesity and type 2 diabetes mellitus that

have reported 5-year outcomes (56,57). The bars denote mean weight reduction, whereas the lines represent the standard deviation. (B) The percentage of patients

who achieved diabetes remission (bars) according to study arm. Definitions of diabetes remission: Mingrone et al. (56): fasting plasma glucose#100 mg/dl and glycated

hemoglobin #6.5% without drug therapy; Schauer et al. (57): glycated hemoglobin #6.5% without drug therapy. The p value in the study by Mingrone et al. (56) was

based on a chi-square test across all 3 groups. The p values in the study by Schauer et al. (57) were adjusted for multiple comparisons. (C) The absolute reductions in

glycated hemoglobin (%) according to study arm. The bars denote mean glycated hemoglobin reduction, whereas the lines represent the standard deviation.

BPD ¼ biliopancreatic diversion; RYGB ¼ Roux-en-Y gastric bypass; SG ¼ sleeve gastrectomy. Data from Mingrone et al. (56) and Schauer et al. (57).



676

BPD (Figure 2A) (56,57). Interestingly, the change inbody weight was more pronounced with RYGB ascompared with SG (57).

DIABETES AND GLYCEMIC CONTROL

A considerable amount of high-quality evidence hasalso accumulated supporting metabolic surgery asan effective means of treating T2DM (21,36–38).These procedures improve glucometabolic profiles

as seen by reductions in glycated hemoglobin(HbA1c) and concomitant increases in circulatingincretin concentrations, insulin sensitivity, and b-cellfunction (58). Many patients with T2DM who undergothese procedures experience complete remission ofthe diabetes, formally defined as having normal HbA1c

or fasting plasma glucose without needing antidia-betic drugs for duration of at least 1 year (59).

Observational evidence for long-term durability ofsurgically achieved glycemic control is mainly

FIGURE 3 Simplified Model of Potential Effects of Metabolic Surgery on

Glucose Metabolism

Type 2 Diabetes Mellitus

Metabolic Surgery

↓Calories ↑Ileal Nutrient Delivery ↑Bile Acids ΔGut Microbiota

↓Weight ↑Incretins ↓Insulin Resistance ↑Insulin Secretion

↓Cardiovascular Events ↓Mortality

Diabetes Remission/Improvement

Several factors appear to drive the metabolic benefits of surgery, including caloric

restriction, increased nutrient delivery to the distal small intestine, increased bile acid

concentrations, and changes in the gut microbiome. These alterations result in weight loss

and favorable hormonal changes. The improvements in glucose metabolism may reduce

cardiovascular events and mortality. [ ¼ increase; Y ¼ decrease; D ¼ change.


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derived from the large SOS study (60). In patientswho underwent surgery versus those who did not, the2-year diabetes remission rates, defined as bloodglucose levels lower than 110 mg/dl and no diabetesmedications, were 72% and 16% (p < 0.001), respec-tively, whereas the corresponding rates at 15 yearswere 30% and 7% (p ¼ 0.001) respectively. These in-vestigators also explored the preventive effect ofmetabolic surgery and found a significantly lower15-year risk of T2DM among individuals who under-went surgery compared with a control group(adjusted hazard ratio [HR]: 0.17; 95% confidenceinterval [CI]: 0.13 to 0.21; p < 0.001) (61). Results fromthe SOS study were included in a meta-analysis of 21cohort studies (6,373 individuals) with at least 2 yearsof follow-up that showed an overall 65% chance ofdiabetes remission in patients who underwentsurgery, with the highest remission rate for BPDDS(99%), followed by RYGB (74%), SG (61%), and AGB(33%) (38). Importantly, the included studies useddifferent criteria for diabetes remission.

The meta-analysis of randomized controlledtrials by Gloy et al. (21) also reported a significantlygreater chance of achieving diabetes remission inpatients treated with metabolic surgery than innonsurgically treated controls (relative risk: 22.1;95% CI: 2.3 to 154.3; p ¼ 0.002). Additionally, arecent pooled analysis of randomized controlledtrials including patients with T2DM demonstrated amean 1.14% greater drop in HbA1c after surgical versusmedical treatment (p < 0.001) (62). Results from ran-domized trials of metabolic surgery among patientswith T2DM are summarized in Table 2. Despiteconsiderable variations in study design, includingvaried inclusion criteria and procedures used, resultshave consistently and strongly favored metabolicsurgery (40–50).

The STAMPEDE (Surgical Treatment and Medica-tions Potentially Eradicate Diabetes Efficiently) trialwas a randomized controlled study that examined therole of metabolic surgery in the diabetic population(41). A total of 150 patients with T2DM and BMI of 27to 43 kg/m2 were randomized to RYGB, SG, or inten-sive medical therapy alone. At 1 year, 12% of patientsin the medical therapy group had achieved diabetestreatment targets (HbA1c #6.0%) compared with 42%in the RYGB group (p ¼ 0.002) and 37% in the SGgroup (p ¼ 0.008). The effects of metabolic surgerywere durable, with a substantially greater effect at 5years than medical treatment (Figure 2B) (57,63).

The study by Mingrone et al. (42), in which medicaltherapy was compared with RYGB and BPD in 60patients with T2DM and BMI $35 kg/m2, also showedfavorable outcomes with metabolic surgery. Rates of

diabetes remission (fasting plasma glucose <100 mg/dland HbA1c <6.5% without drug treatment) 2 yearsafter RYGB, BPD, and medical therapy were 75%, 95%,and 0%, respectively (p < 0.001 for both comparisonswith surgery vs. medical therapy). At 5 years, the HbA1c

level was significantly lower in the combinedsurgical group than in the medical group (p ¼ 0.04)(Figure 2C) (56).

Outcomes of metabolic surgery in patients withtype 1 diabetes mellitus (T1DM) are much less studiedcompared with those for T2DM. A 2016 review of 17retrospective case studies including just 107 patientswith T1DM and moderate to severe obesity(BMI >35 kg/m2) demonstrated significant weight loss(BMI decrease w10 kg/m2), reduced insulin re-quirements, and improved HbA1c (reduction of 0.5%)(64). However, there was a concerning incidence ofpost-operative diabetic ketoacidosis as high as 20% to25%, as well as significant hypoglycemia, thatsuggested the need for diligent post-operativeglucose monitoring and management. Furthermore,gastrointestinal dysmotility conditions includingpost-operative ileus, intractable nausea and



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vomiting, and acute gastric remnant dilation havebeen reported at higher rates compared with thoseseen in patients with T2DM. Given that many patientswith T1DM have underlying autonomic neuropathyand gastroparesis, such occurrences should be antic-ipated and managed accordingly. Because of thecurrent paucity of outcome data, a clear role ofmetabolic surgery for T1DM in severely obese patientsis yet to be determined.

MECHANISMS OF ACTION

After metabolic surgery, diabetes starts to improvewithin days to weeks, whereas weight loss occursmuch more slowly (65). This suggests that themechanisms of metabolic benefit extend beyond themagnitude of weight loss alone, a concept that hasbeen demonstrated in animal models even at long-term follow-up (66). The pathophysiological alter-ations involved are not completely understood, butthe major paradigm revolves around the pivotalphysiological role of the gastrointestinal tract inglucose homeostasis (Figure 3) (30,67,68).

Caloric restriction with or without metabolic sur-gery can lead to depletion of liver fat within a week,followed by improved hepatic insulin sensitivity andclearance (69,70). In fact, short term improvementsin insulin sensitivity and b-cell function are similarfor very low-calorie diets and RYGB (69). After sur-gery, post-load insulin secretion is also enhanced,possibly secondary to increased glucagon-like pep-tide-1 secretion observed after RYGB, SG, and BPDDS(71,72). The accelerated food entry into the distalportion of the small intestine with a resultantincreased delivery of undigested nutrients may beinvolved in the alteration of hormonal responses(30,73). Glucagon-like peptide-1 stimulates post-prandial secretion of insulin and inhibits that ofglucagon (67). It also slows gastric emptying andenhances satiety, thus leading to weight loss, and theanorexigenic effects may be augmented by aconcomitantly increased secretion of peptide YY(26,72,74). The rapid distention of the small intestinemay further diminish appetite (75). Increasedglucagon-like peptide-1 secretion and insulin secre-tion may possibly be seen after a very low-caloriediet, but studies have reported inconsistent findings(69,70,76).

Changes in inflammatory and adipokine profilesmay also affect glucose metabolism, although theirroles after metabolic surgery appear to be lessimportant (77). Both C-reactive protein andinterleukin-6 levels decrease considerably, in

parallel with the increased insulin sensitivity (78).Concentrations of the satiety-inducing hormone lep-tin decrease because of its close correlation with totalbody fat mass (79–81). Persons with obesity havedramatically increased leptin levels, but they alsohave leptin resistance, which counterbalances theotherwise catabolic effects of leptin. Interestingly,even though weight loss through calorie restrictionincreases leptin sensitivity, metabolic surgery doesnot seem to have such an effect (82). Concentrationsof ghrelin, an appetite-stimulating hormone, initiallydecrease, but they subsequently increase andapproach pre-operative levels (72,81). Anotherpotentially important concept is the deposition ofectopic, including visceral, fat, which is associatedwith many metabolic abnormalities in individualswith obesity. Patients whose T2DM, hypertension,and other conditions resolve after metabolic surgeryappear to have greater ectopic fat mobilization thando patients whose same disorders do not resolve, aneffect that is independent of the degree ofweight loss (83,84).

Finally, other factors may include increased bileacid concentrations and altered gut microbiota(30,68). Serum concentrations of bile acids increaseafter RYGB and are positively associated with peaksecretion of glucagon-like peptide-1. Therefore, it hasbeen suggested that bile acids directly stimulateglucagon-like peptide-1 secretion (30). Patients withobesity have an increased Firmicutes to Bacteroidesbacteria ratio compared with lean control subjects,and this difference disappears after weight loss. Othergut changes associated with metabolic surgery mayfurther alter the microbiome. Because its compositionplays an important role in energy extraction, the gutmicrobiota could potentially be involved in thedevelopment of obesity and associated metaboliccomplications (30).

Most of the pathophysiological evidence comesfrom subjects who have undergone RYGB. Indeed,time to diabetes remission is longer, and the corre-lation between weight loss and improved glycemiccontrol is seemingly stronger, among patients un-dergoing AGB, findings suggesting that unlike theother metabolic procedures, AGB does not inducesignificant weight loss independent effects onglucose homeostasis (40,42). AGB also does not affectglucagon-like peptide-1 concentrations, and its ef-fects on inflammation and adipokines are far lesspronounced than after the other procedures (80,85).It has been suggested that the effects of AGB are notthe result of mechanical restriction, but rather reflectenhanced satiety (86).

TABLE 3 Potential Complications Associated With Specific Types

of Metabolic Surgery

Complications RYGB SG AGB BPDDS

Stricture or stenosis � � �Band erosion, leakage, or slippage �Gallstone � � � �Gastrogastric fistula �Gastric remnant dilation �Marginal ulcer � �Nutritional deficiencies � � (�) �Small bowel obstruction � �Reflux � � �

Parentheses indicate that the risk is not zero but is lower than the other procedureswith an � sign. Data from Hanipah and Schauer (29) and Schauer et al. (62).

BPDDS ¼ biliopancreatic diversion with duodenal switch; � ¼ potentialcomplication; other abbreviations as in Table 2.

FIGURE 4 General Complications of Metabolic Surgery

0 2 4 6

0.1-5.6

1.0-4.0

0.3-1.3

0.1-0.3

Approximate Frequency (%)

Bleeding

Cardiopulmonary

Death

Sepsis

Important general complications of metabolic surgery. The bars denote the full range of

the estimated frequencies. Data from Hanipah and Schauer (29) and Schauer et al. (62).


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CARDIOVASCULAR RISK AND MORTALITY

There has been a growing interest in exploring theinfluence of metabolic surgery on cardiovascularoutcomes (24). Randomized trials have now shownpromising long-term changes in the burden of car-diovascular risk factors (56,57), whereas informationon subclinical damage and, in particular, cardiovas-cular events and mortality is mainly derived fromobservational studies (65,87–89).

Vest et al. (87) conducted a systematic review of 73cardiovascular risk factor studies (3 randomized) witha total of 19,543 individuals who underwent metabolicsurgery. These investigators found significant re-ductions in traditional cardiovascular risk factors, asseen by resolution or improvement of diabetes in 73%,hypertension in 63%, and hyperlipidemia in 65%,during an average 4.8-year follow-up period.A minority of the included studies reported C-reactiveprotein levels, which decreased by 73% post-operatively. Finally, imaging studies showed im-provements in left ventricular structure and diastolicfunction, independent of improvements in bloodpressure, benefits that may extend to systolic functionand coronary artery calcium (87,90,91).

There is increasing evidence that the reduced car-diovascular risk factor burden after metabolic surgerytranslates to better patient outcomes because obser-vational studies have consistently shown reductions incardiovascular events and mortality (77). For instance,a recent meta-analysis of 4 observational studies withcontrol groups found that patients with a BMI$30 kg/m2 who were undergoing metabolic surgeryhad significantly lower risks of all-cause mortality(odds ratio [OR]: 0.55; 95%CI: 0.46 to 0.65),myocardialinfarction (OR: 0.71; 95% CI: 0.54-0.94), stroke(OR: 0.66; 95% CI: 0.49 to 0.89), and the composite of

myocardial infarction or stroke (OR: 0.67; 95% CI: 0.54to 0.83) as compared with controls (88).

At a median of 14.7 years, the observational SOSstudy had the longest follow-up duration of theincluded studies (53). Sjöström et al. (92) reportedsignificantly reduced risks of cardiovascular mortality(adjusted HR: 0.47; 95% CI: 0.29 to 0.76; p¼0.002) andof composite cardiovascular events (fatal or nonfatalmyocardial infarction or stroke) (adjusted HR: 0.67;95%CI: 0.54 to 0.83; p<0.001) withmetabolic surgery.These investigators also demonstrated a reduction inall-cause mortality during an average of 10.9 years(adjusted HR: 0.71; 95% CI: 0.54 to 0.92; p ¼ 0.01) (92).Finally, surgery lowered the risk of macrovascularoutcomes (coronary artery disease, cerebrovasculardisease, or peripheral artery disease) among patientswith T2DM at baseline (adjusted HR: 0.68; 95% CI: 0.54to 0.85; p ¼ 0.001) (60).

Favorable outcomes for other types of cardiovas-cular events that are associated with obesity anddiabetes have been reported as well. The SOS in-vestigators recently reported a significantly lowerlong-term risk of atrial fibrillation in surgically versusmedically treated patients (HR: 0.71; 95% CI: 0.60 to0.83; p < 0.001) (93). A second large Scandinaviancohort study further showed a decreased risk of heartfailure in patients with obesity who were treatedsurgically versus those who were not (HR: 0.54; 95%CI: 0.36 to 0.82), and similar findings were noted in alarge U.S. case-control study (p ¼ 0.008) (89,94).

COMPLICATIONS

The health benefits of metabolic surgery must becarefully weighed against the possible complications

TABLE 4 Vitamin and Mineral Supplementation After

Metabolic Surgery

Vitamin B1: $12 mg (preferably 50 mg) daily

Vitamin B12: oral/sublingual 350–500 mg daily, subcutaneous/intramuscular 1,000 mg monthly, or nasal, targeted tonormal levels

Folate: 400–800 mg (800–1,000 mg in women of childbearingage) daily

Iron: $18 mg (45–60 mg after RYGB, SG, or BPDDS or in menstruatingfemale patients) daily

Calcium citrate: 1,200–1,500 mg (1,800–2,400 mg after BPDDS) daily

Vitamin D: 3,000 IU daily, titrate serum 25-hydroxyvitamin D levelsto >30 ng/ml

Vitamin A: 5,000 IU (5,000-10,000 IU after RYGB or SG, 10,000 IUafter BPDDS) daily

Vitamin E: 15 mg daily

Vitamin K: 90–120 mg (300 mg after BPDDS) daily

Zinc: 8–11 mg (8–22 mg after RYGB, 16–22 mg after BPDDS) daily

Copper: 1 mg (2 mg after RYGB or BPDDS) daily

Data from Mechanick et al. (104) and Parrott et al. (105).

Abbreviations as in Tables 2 and 3.



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(Table 3, Figure 4) (29,37,62,95,96). Potential risk fac-tors for such complications includemale sex, smoking,older age, greater BMI, increasing number of comor-bidities, procedure type, and prolonged operative time(95,97–99). Fortunately, over the past 2 decades, theoverall risk of these procedures has declined as a resultof increased surgical experience and training, use oflaparoscopic approaches, improved perioperative andpost-operative care, and mandatory quality re-quirements and reporting (100,101).

A 2007 meta-analysis reported a total 30-day mor-tality rate of 0.28% and amortality rate from 30 days to2 years of 0.35% for metabolic surgery (102). The riskwas higher with BPDDS than with RYGB, SG, and AGB.It was also higher for open versus laparoscopic surgery.Subsequently published observational studies,including the LABS (Longitudinal Assessment of Bar-iatric Surgery) study, have confirmed these findings(95,96,98). In addition, data from the U.S. NationwideInpatient Sample database have shown a stable 0.1%risk of in-hospital death (103). Themost common causeof death is venous thromboembolism, followed byother cardiopulmonary events and complications ofgastrointestinal leaks (95,98).

The LABS consortium reported a 30-day morbidityrate of w4%, whereas the Nationwide InpatientSample data showed an in-hospital morbidity rate ofw9% (95,103). These nonfatal complications includecardiovascular and pulmonary events, anastomoticleakage, bowel obstruction, internal hernia,infection, hemorrhage, and nutritional deficiency(37,95,97,98,103).

Nutritional deficiencies resulting from inade-quate intake, malabsorption, or both comprise themost common long-term complications after meta-bolic surgery and more often occur after BPDDS orRYGB than after SG or AGB (104,105). Manymicronutrient deficiencies, especially of vitamin D,calcium, and iron, are prevalent pre-operatively inpatients with obesity and are likely to persist orworsen post-operatively. Anemia has been reportedin up to three-fourths of all cases and is mainlycaused by deficiencies of iron and vitamin B12, aswell as inflammation (106,107). Post-operative de-ficiencies of folate, selenium, zinc, copper, and vi-tamins A, B1, B2, B6, C, D, E, and K can also occur,although there is wide variation in reported oc-currences (104,105). Low vitamin D and calciummay lead to a significant reduction in bone mineraldensity (108). Correction of these micronutrientdeficiencies is generally possible with appropriatevitamin, iron, and calcium supplementation, butregular lifelong follow-up is required to ensureoptimal nutritional status (104,105). Guideline rec-ommendations for post-operative supplementationare summarized in Table 4. Besides calcium,vitamin D, and vitamin B12, the deficiencies canoften be corrected with 1 (AGB) or 2 (other pro-cedures) multivitamin tablets.

Severe hypoglycemia is another important long-term complication. A Swedish cohort study foundthat the risk of this condition more than doubled afterRYGB, although the absolute risk remained low at0.2% (109). Interestingly, AGB did not increase therisk of hypoglycemia. The underlying mechanismsare unclear (110).

CURRENT GUIDELINES AND

CHOICE OF PROCEDURE

Recent clinical guidelines have stated that metabolicsurgery should be recommended in patients with aBMI $40 kg/m2 without concomitant medical prob-lems and in patients with a BMI $35 kg/m2 who haveat least 1 severe obesity-associated comorbidity,(e.g., poorly controlled T2DM) (Table 1)(12,13,17,59,104). Comorbidity prevalence in patientswith a BMI of 35 to 39.9 kg/m2 is high, approximately50%, 10%, and 20% for hypertension, diabetes, anddyslipidemia, respectively (111). Metabolic surgeryshould also be considered in patients with a BMI of30 to 34.9 kg/m2 and poorly controlled T2DM(17,59,104). Because of the differences in the re-lationships among BMI, visceral fat, and cardiovas-cular and metabolic risk in patients of Asian descent,

FIGURE 5 Algorithm for the Treatment of Type 2 Diabetes Mellitus, as Suggested by the International Diabetes Organizations

Patients withType 2 Diabetes

ObeseBMI ≥30 kg/m2

or ≥27.5 for Asians

Class III ObeseBMI ≥40 kg/m2

or ≥37.5 for Asians

Expedited Assessmentfor Metabolic Surgery Optimal Lifestyle and Medical Rx Optimal Lifestyle and Medical Rx

(including injectable meds and insulin)

Class II ObeseBMI 35.0-39.9 kg/m2

or 32.5-37.4 for Asians

Class II Obesewith Poor

Glycemic Control

RecommendMetabolic Surgery

ConsiderMetabolic Surgery

NonsurgicalTreatment

Class II Obesewith Adequate

Glycemic Control

Class I Obesewith Poor

Glycemic Control

Class I Obesewith Adequate

Glycemic Control

Class I ObeseBMI 30.0-34.9 kg/m2

or 27.5-32.4 for Asians

NonobeseBMI <30 kg/m2

or <27.5 for Asians

Flowchart depicting an algorithm for treatment of type 2 diabetes mellitus, according to obesity class and degree of glycemic control, as suggested by international

diabetes organizations. The indications are intended for patients who are considered appropriate candidates for elective surgery. Reprinted with permission from

Rubino et al. (59). Copyright 2016 by Diabetes Care. BMI ¼ body mass index; Meds ¼ medications; Rx ¼ treatment.


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it has been suggested that BMI cutoffs be lowered by2.5 kg/m2 in this population (17,59). Figure 5 sum-marizes the role of metabolic surgery in treatingT2DM, as recently proposed by the internationaldiabetes organizations (59).

Candidates for metabolic surgery should be care-fully selected using a multidisciplinary teamapproach. Patients must have an acceptable operativerisk, be motivated to lose weight, and have respondedinadequately to behaviorally based treatment. How-ever, optimization of glycemic control should beattempted. Metabolic surgery is contraindicated inpatients with current alcohol or substance abuse,uncontrolled psychiatric disorder, poor understand-ing of the risks and benefits, and lack of commitmentto nutritional supplementation and long-term post-operative follow-up (17,59,104).

There is insufficient evidence to recommend aspecific metabolic procedure clearly over another forindividual patients (59,104). For now, the choice de-pends on the patient’s preference and characteristics,local expertise, and treatment goals, including care-fully balancing the risk of long-term nutritional andgastrointestinal sequelae with that of achievingsatisfactory glycemic control and cardiovascular riskreduction. Scoring tools, such as the IndividualizedMetabolic Surgery Score, may assist in clinical deci-sion making (112). Furthermore, cost issues and ac-cess to surgery may play important roles. Although SGis now the most commonly performed metabolicprocedure, presumably because of its simpler tech-nique as compared with RYGB, the use of thesesurgical procedures is still much more prevalent inhigh-income countries. For example, the United

CENTRAL ILLUSTRATION Potential Approach to Patients With Varying Degrees of Obesity and Type 2Diabetes Mellitus

Patient with Obesity and/orType 2 Diabetes Mellitus

Lifestyle ModificationConsider Antidiabetic DrugsConsider Weight Loss Drugs

Assess Severity

Class I Obesity andAdequate Glycemic Control

Lifestyle and MedicalTreatment

Consider SG, RYGB, orAGB*

Recommend SG, RYGB, orAGB*

Recommend SG, RYGB,AGB*, or BPDDS

Class I Obesity andPoor Glycemic Control

Class II Obesity withSignificant Comorbidity or

Poor Glycemic ControlClass III Obesity

Pareek, M. et al. J Am Coll Cardiol. 2018;71(6):670–87.

Flowchart depicting a potential algorithm for treatment of patients with obesity and/or type 2 diabetes mellitus. Lifestyle modification is indicated for all patients,

whereas drug treatment may be considered. Metabolic surgery and its degree of invasiveness are based on the degree of obesity and glycemic control. *AGB is steadily

declining in popularity because of high revision rates and suboptimal long-term weight loss. AGB ¼ adjustable gastric banding; BPDDS ¼ biliopancreatic diversion with

duodenal switch; RYGB ¼ Roux-en-Y gastric bypass; SG ¼ sleeve gastrectomy.



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States accounts for approximately one-third of suchprocedures performed worldwide (22). In terms ofbariatric-metabolic efficacy, BPDDS is the mosteffective, followed by RYGB, SG, and AGB, respec-tively (41,42,46,48,56,57,59,63). As alluded to in theprevious section, a reverse gradient is seen for safety.Revision rates for RYGB and SG are similar, but SG iseasier to perform and slightly safer because it doesnot involve multiple anastomoses. AGB is associatedwith low perioperative complication rates but highrevision rates, and it is the least effective for weightloss. BPDDS should be reserved for those patientswith extreme obesity (e.g., BMI >60 kg/m2) becauseof the substantial risk of nutritional deficits; in pa-tients with the most severe obesity, this procedure isoften performed in 2 steps, with an initial SG, fol-lowed after a period of weight loss by addition of theduodenojejunal bypass component (29,59,65,104).

Patients who undergo metabolic surgery need long-term monitoring. This is best managed by a

multidisciplinary team approach similar to that usedpre-operatively. The frequency of follow-up dependson the procedure and the burden of comorbidities. Theminimum recommended surgical and nutritionalfollow-up frequency is every 6 months during the first2 years and annually thereafter, whereas glycemiccontrol should generally be monitored with the sameintervals as for medically treated patients. Insulin andsulfonylurea dosages should be progressively reducedto avoid hypoglycemia, and cessation of antidiabeticmedication may be considered if a normal HbA1c levelhas been observed for at least 6 months. The healthylifestyle measures described should be maintainedafter surgery. Patients who fail to lose weight or whoregain it should be evaluated for their compliance withlifestyle or behavioral measures, including maladap-tive eating patterns, use of medications that mayadversely affectweight, psychological complaints, andmedical conditions or surgical complications associ-ated with weight gain (17,59,104).


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CONCLUSIONS AND PERSPECTIVES

Metabolic surgery is highly effective in obtaining sig-nificant and durable weight loss at a low perioperativerisk when appropriate patient selection and long-termfollow-up are ensured. High-quality evidence fromrandomized controlled trials shows the superiority ofsurgical over medically based treatment for enhancingglycemic control and achieving diabetes remission.Observational data suggest that these benefits lead toless adverse cardiovascular risk profiles with a conse-quent reduction in macrovascular events and mortal-ity. Additional benefits may include improved qualityof life and a reduced risk for other obesity-related anddiabetes-related disorders, including microvasculardisease, sleep apnea, fatty liver disease, andmalignantdiseases (60,113–115).

Comparable glycemic benefits of surgery havebeen observed in patients with lower initial BMIs<35 kg/m2. In the STAMPEDE trial, the antidiabeticeffects of surgery were the same in patients withbaseline BMIs higher and lower than 35 kg/m2

(41,57,63). Shah et al. (116) demonstrated a substantialbenefit of RYGB in Indian patients with an initialBMI <35 kg/m2, and similar BMI-independent benefitsof surgery have been established in meta-analyses(117,118). As a result, current guidelines support theuse of metabolic surgery in individuals with mildobesity and poorly controlled T2DM (12,59,104).Although the antidiabetic effects of AGB appear lesspowerful than those of other metabolic operations, 1study nonetheless demonstrated the ability of AGB toinduce remission of T2DM, defined as fastingglucose <126 mg/dl and post-load glucose during a2-h oral glucose tolerance test <200 mg/dl, at least2 days after cessation of antidiabetic medication,among overweight (BMI 25 to 30 kg/m2) individuals(45). The utility of metabolic surgery in specific dis-ease populations, such as those with congestive heartfailure, and defining the benefit-to-risk profile of eachprocedure for treating diabetes in different pop-ulations, need further investigation. Conclusive dataregarding end-organ damage, particularly renal out-comes (e.g., urinary albumin excretion), are also notavailable, but the role of metabolic surgery for suchendpoints is currently being investigated (119–121).Similarly, although surgery appears to have beneficialeffects on blood pressure and lipid levels, some pa-tients do not experience a reduction in risk factorburden, and durability is uncertain (122). Reportedpredictors of nonresolution of hypertension includeolder age, concomitant diabetes, less weight loss, andAfrican-American race (123). With respect to lipid

levels, matters may be complicated by alterations insome, but not all, cholesterol subtypes, as well as theeffect of dietary patterns (124,125). Finally, althoughthese procedures appear to be beneficial with respectto weight loss and cardiometabolic risk reduction inadolescents with obesity, more studies of long-termefficacy and safety in this setting are needed (126).

In some patients, the bariatric and metabolic ef-fects of gastrointestinal surgery may diminish overtime, with relapse of T2DM in patients who hadinitially achieved full remission. Even in these pa-tients, however, the recurrent diabetes is generallyfar less severe, requires less intensive medicationregimens, and is more easily controlled than beforethe metabolic surgery. Patients who are older, useinsulin, regain weight, or have greater baseline waistcircumference, longer diabetes duration, or poor pre-operative glycemic control appear to be at highest riskfor late post-operative diabetes recurrence(65,117,127). Even in the setting of diabetes relapse,however, a legacy effect may exist. Finally, the effectof post-operative antidiabetic medications in patientswhose diabetes failed to remit or recurred late aftersurgery is currently being examined (Canagliflozin vs.Placebo for Post Bariatric Patients With PersistentType 2 Diabetes [CARAT]; NCT02912455). Many of theunanswered questions about metabolic surgery andlong-term risk will be clarified through long-termcardiovascular outcomes data from randomized tri-als (Surgical Versus Medical Treatment of Insulin-Dependent Type 2 Diabetes Mellitus in Patients Witha Body Mass Index Between 26 and 35 kg/m2 [Diasurg 2];DRKS00004550). In addition, a more thorough un-derstanding of the mechanistic alterations associatedwith metabolic surgery could help enhance its effec-tiveness and durability and help define which oper-ations are most appropriate in specific patients.

The traditional concept of reserving metabolicsurgery for persons exceeding a certain BMI thresholdis rapidly evolving. Safer procedures and expandedtreatment indications have added to the complexitiesof choosing the right procedure for the right patient.Potentially, the future approach for patients withvarying degrees of obesity and T2DM will be lifestylemodification for all, pharmacological treatment ofobesity and T2DM for many, and metabolic surgeryfor the growing number of patients whose metabolicdisease is severe or refractory to less invasive ap-proaches. Thus, much as coronary artery disease istreated with medical therapy, percutaneous coronaryintervention, and coronary artery bypass grafting onthe basis of the severity of disease, comorbidities, andresponse to noninvasive measures, a similar approach

https://clinicaltrials.gov/ct2/show/NCT02912455

http://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00004550



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is evolving for the treatment of obesity and T2DM(Central Illustration). Because both the prevalence andthe severity of these disorders are still increasing, andas the global burden rises, metabolic surgery is likelyto play an increasingly important role in improvingcardiovascular health.

ADDRESS FOR CORRESPONDENCE: Dr. Deepak L.Bhatt, Brigham and Women’s Hospital Heart &Vascular Center, Harvard Medical School, 75 FrancisStreet, Boston, Massachusetts 02115. E-mail:[email protected].

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KEY WORDS bariatric, cardiovascular risk,diabetes, metabolic, obesity



























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Metabolic Surgery - Journal of the American College of ... · calorie intake, physical activity, and behav-ioral interventions. The energy deﬁcit should generally be w500 to 750