Sleeve gastrectomy versus Roux-en-Ygastric bypass for type 2 diabetes andmorbid obesity: double-blindrandomised clinical trial protocol

Rinki Murphy,1 Nicholas J Evennett,2 Michael G Clarke,2 Steven J Robinson,2

Lee Humphreys,2 Bronwen Jones,2 David D Kim,3 Richard Cutfield,3

Lindsay D Plank,4 Hisham Hammodat,2 Michael W C Booth2

To cite: Murphy R,Evennett NJ, Clarke MG, et al.Sleeve gastrectomy versusRoux-en-Y gastric bypass fortype 2 diabetes and morbidobesity: double-blindrandomised clinical trialprotocol. BMJ Open 2016;6:e011416. doi:10.1136/bmjopen-2016-011416

▸ Prepublication history forthis paper is available online.To view these files pleasevisit the journal online(http://dx.doi.org/10.1136/bmjopen-2016-011416).

Received 5 February 2016Revised 13 May 2016Accepted 7 June 2016

For numbered affiliations seeend of article.

Correspondence toDr Rinki Murphy;R.Murphy@auckland.ac.nz

ABSTRACTIntroduction: Type 2 diabetes (T2D) in associationwith obesity is an increasing disease burden. Bariatricsurgery is the only effective therapy for achievingremission of T2D among those with morbid obesity. Itis unclear which of the two most commonly performedtypes of bariatric surgery, laparoscopic sleevegastrectomy (LSG) and laparoscopic Roux-en-Y gastricbypass (LRYGB), is most effective for obese patientswith T2D. The primary objective of this study is todetermine whether LSG or LRYGB is more effective inachieving HbA1c<6% (<42 mmol/mol) without the useof diabetes medication at 5 years.Methods and analysis: Single-centre, double-blind(assessor and patient), parallel, randomised clinicaltrial (RCT) conducted in New Zealand, targeting 106patients. Eligibility criteria include age 20–55 years,T2D of at least 6 months duration and body massindex 35–65 kg/m2 for at least 5 years. Randomisation1:1 to LSG or LRYGB, used random number codesdisclosed to the operating surgeon after induction ofanaesthesia. A standard medication adjustmentschedule will be used during postoperative metabolicassessments. Secondary outcomes include proportionsachieving HbA1c<5.7% (39 mmol/mol) or HbA1c<6.5%(48 mmol/mol) without the use of diabetes medication,comparative weight loss, obesity-related comorbidity,operative complications, revision rate, mortality, qualityof life, anxiety and depression scores. Exploratoryoutcomes include changes in satiety, gut hormone andgut microbiota to gain underlying mechanistic insightsinto T2D remission.Ethics and dissemination: Ethics approval wasobtained from the New Zealand regional ethicscommittee (NZ93405) who also provided independentsafety monitoring of the trial. Study commenced inSeptember 2011. Recruitment completed in October2014. Data collection is ongoing. Results will bereported in manuscripts submitted to peer-reviewedjournals and in presentations at national andinternational meetings.Trial registration numbers:ACTRN12611000751976, NCT01486680; Pre-results.

INTRODUCTIONIt is unclear which of the two major types ofbariatric surgery, laparoscopic sleeve gastrec-tomy (LSG) and laparoscopic Roux-en-Ygastric bypass (LRYGB), achieves the greatestand most durable remission of type 2 dia-betes (T2D) and weight loss.1 2 There arecurrently only two prospective, non-blinded,randomised clinical trials (RCTs) comparingthese two types of bariatric surgery3 4 inpatients with T2D and one blinded studycomparing the ‘mini’–(one anastomosis)gastric bypass with LSG.5 In one study of 150American patients with T2D (body massindex (BMI) 27–43 kg/m2) randomised toLRYGB, LSG or medical therapy, 42% afterLRYGB, 37% after LSG and 12% after

Strengths and limitations of this study

▪ There is limited evidence from randomised clin-ical trials comparing the efficacy of laparoscopicsleeve gastrectomy (LSG) versus laparoscopicRoux-en-Y gastric bypass (LRYGB) to guideoptimum surgery selection for morbidly obesepatients with type 2 diabetes (T2D).

▪ We describe our double-blind, randomised trialdesigned to compare efficacy of LSG and silasticring LRYGB on remission of T2D at 5 yearsamong morbidly obese patients. We used astandard metabolic medication adjustment proto-col after surgery, which should assist cliniciansmanaging patients following bariatric surgeryand researchers planning future bariatric surgerytrials, given that the thresholds for discontinuingand restarting blood pressure, glucose and lipidmedications postoperatively are frequently notreported.

▪ Limitations include the single-centre studydesign, which may limit generalisability of thefindings.

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medical therapy achieved diabetes remission at12 months defined by HbA1c of ≤6% (42 mmol/mol),with or without diabetes medications. All of thoseachieving the glycaemic threshold in the LRYGB groupdid so without diabetes medications, compared to only72% of patients in the SG group, so the recalculatedproportions for those achieving HbA1c of ≤6%(42 mmol/mol) without diabetes medication in the twobariatric surgery groups was 42% after LRYGB and 27%after SG. In a small study of 41 Israeli patients with T2D(BMI>35 kg/m2), 37 completed 1-year follow-up afterrandomisation to LRYGB or SG.4 There was a similarreduction in HbA1c after LRYGB (by 1.57±1.35% or 17±15 mmol/mol) and LSG (by 2.37±2.22% or 26±24 mmol/mol), p=0.34.4 In a double-blinded, single-centre study of 60 Taiwanese patients with T2D (BMI:25–34 kg/m2), 93% of those randomised to ‘mini’bypass achieved diabetes remission at 12 months com-pared to 47% randomised to LSG, using diabetes remis-sion criteria of fasting glucose <7.0 mmol/L andHbA1c<6.5% (48 mmol/mol) in the absence of diabetesmedications.5 None of these studies reported their medi-cation adjustment protocol after surgery. The assessmentof T2D remission may be affected by participant lifestylefactors and clinician variation in glucose medicationwithdrawal thresholds used. Further studies evaluatingcomparative efficacy of LSG and LRYGB are required,particularly using blinding of patients and investigatorsassessing for T2D remission using standard protocols forpostoperative medical management to minimise bias.The advantages of LRYGB include being fully re-

versible; however, the irreversible LSG is a faster andsimpler procedure with potentially less dumping. Thereare technical difficulties involved in performing LRYGBin severely obese patients, and such patients may havelimited success from LRYGB attributed to pouch dilationand loss of restriction at the gastrojejunal anastomosisover time. The placement of a silastic ring (SR) bandaround the gastric pouch at the time of primary RYGB isconsidered superior to the non-banded RYGB in the super-obese population.6 Other modifications to the LRYGBprocedure include variation in pouch size (10–50 mL),alimentary limb length (50–250 cm) and biliopancreaticlimb length (25–150 cm).2

The underlying mechanisms by which SG and RYGBachieve T2D remission are unclear and may involvechanges in gut hormones,7 inflammatory markers8 andgut microbiota.9 Investigation into the impact of thesetwo types of bariatric surgery on these mechanisms andresulting glucose metabolism, body composition andsatiety is required.The primary objective of this trial is to compare the

efficacy of SR-LRYGB and LSG on remission of T2D,defined by HbA1c<6% (42 mmol/mol) without the useof diabetes medications (as per the consensus defin-ition of complete diabetes remission10), at 5 yearspostsurgery. Secondary objectives are to examine pro-portions achieving alternative glycaemic thresholds

HbA1c<5.7% (39 mmol/mol) or <6.5% (48 mmol/mol)without the use of diabetes medications, extent of weightloss, change in body composition, resting energy expend-iture (REE), operative complications, revision rate, hospi-talisations, mortality, microvascular and macrovascularcomplications, cardiovascular risk factors, quality of life,anxiety and depression scores between the two groups. Inaddition, underlying mechanisms of T2D remission willbe investigated by examining comparative changes in guthormones, inflammatory markers, gut microbiota, inrelation to diabetes remission, changes in body compos-ition, food intake and appetite scores.

METHODSTrial designThis is a parallel (1:1), single-centre, two-arm, rando-mised, double-blind (patient and assessor), superioritytrial (figure 1).

Sample size justification and power calculationAssuming rates of diabetes remission to be 88% inSR-LRYGB and 59% in LSG, a minimum of 42 patientsper arm, will provide 80% power to detect a differencebetween the two groups using a two-sided α of 0.05.These estimates were derived from our unpublishedaudit data. An expected loss to follow-up rate of 20%requires at least 53 patients per arm.

Data analysis planStudy analysis will be by intention-to-treat. Prior to per-forming analyses, standard data screening and cleaningprocedures will be applied to detect possible data-entryerrors and to check for outliers, assess the extent and pat-terns of missing data and check that appropriate assump-tions of normality are met whenever necessary. Baselinecharacteristics will be analysed by descriptive statisticsusing means and SDs for all continuous variables with anormal distribution, and medians and IQRs for variableswith a non-normal distribution. Categorical variables willbe summarised with frequencies. For the primary analysis,the difference in proportions achieving T2D remission(HbA1c<6% (42 mmol/mol) without diabetes medica-tion) will be compared between LSG and SR-LRYGB at5 years, adjusting for stratification variables using logisticregression. A two-sided p value of 0.05 will be consideredto indicate statistical significance. Missing data will behandled by multiple imputation as appropriate. Analyseswill be performed with the use of SAS software, V.9.4 orlater (SAS Institute, Cary, North Carolina, USA).

ParticipantsAll patients aged 20–55 years with T2D of at least6 months duration, BMI 35–65 kg/m2 for at least 5 years,who were referred for consideration of bariatric surgeryat a single centre (North Shore Hospital), were invitedto participate and to attend a bariatric surgery studyinformation evening. All participants were given a

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written informed consent form and understood that onentering the randomised study, they would not knowtheir treatment allocation until completion of the studyat 5 years. Other inclusion criteria included being suit-able for either of the two surgical procedures, able togive informed consent and committed to follow-up.Exclusion criteria included postprandial C peptide<350 pmol/L, pregnancy, type 1 diabetes or secondarydiabetes, chronic pancreatitis, oral steroid therapy,

current smokers and those not suitable for generalanaesthesia. The study commenced in September 2011and completed recruitment in October 2014. A total of114 participants were recruited into the study (figure 1).Data collection and follow-up is ongoing.

Baseline assessmentsAll participants were prescribed a very low calorie diet(VLCD) with three servings of Optifast (Nestle, Vevey,

Figure 1 CONSORT diagram showing the proposed flow of participants through the sleeve gastrectomy versus gastric bypass

trial for type 2 diabetes.

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Switzerland), each containing ∼152 calories, plus vegeta-bles preoperatively, for 2 weeks, designed to reduce liverfat and make laparoscopic abdominal surgery safer.Baseline clinical and anthropometric assessments wereconducted before and after the VLCD. Baseline bodycomposition assessment was conducted during theVLCD period, in the week before surgery (table 1).

RandomisationComputer-generated random number codes (Minim,London) managed by an independent study memberwere used to randomise participants 1:1 to either LSG orSR-LRYGB, stratified by age category (20–29, 30–39 or 40–55), BMI category (35–44.9, 45–54.9 and 55–65 kg/m2),ethnicity (Maori, Pacific, NZ European/other), durationof diabetes diagnosis (<5, 5–10 and >10 years) and thepresence of insulin therapy.

Allocation concealment and blindingOn the day of surgery, following induction of generalanaesthesia, allocation to either LSG or SR-LRYGB wasdisclosed only to the operating surgical team. Bothoperations were performed using identical incisions witha four-port technique (optical entry; two 10–12 mmports and two 5 mm ports) and an additional epigastricincision for liver retraction. Participants and all otherresearch and clinical team members remain blinded tosurgical allocation. Only de-identified codes were usedto link participants to their data during the study tomaintain their confidentiality.

InterventionFor SG, a sleeve was fashioned starting 2 cm proximal tothe pylorus using serial applications of an Echelon Flex45 stapler (Ethicon) over a 36Fr oro-gastric bougie. ForSR-LRYGB, a lesser curve-based gastric pouch was fash-ioned over a 32Fr oro-gastric tube, with a 50 cm bilio-pancreatic limb, 100 cm antecolic Roux limb withhand-sewn single layer gastrojejunostomy over a 32Froro-gastric tube. A 6.5 cm SR was then secured aroundthe gastric pouch 2 cm above the gastrojejunostomyanastomosis. Mesenteric defects were closed.

Follow-upPostoperative care and follow-up will be identical forboth groups. All pharmacological agents for diabetesand hypertension will be stopped at the time of surgery.Glucose-lowering therapy will be restarted if mean post-operative capillary glucose exceeds 12 mmol/L. Allparticipants will be reviewed by an endocrinologist at6 weeks, 9 months then annually (table 1) for adjust-ment of all medications and assessment of microvascularand macrovascular complications.11 The medicationadjustment protocol including lipid, blood pressureand glucose-lowering therapy is outlined in figure 2.Microvascular complications will be assessed annuallywith clinical evaluation for peripheral neuropathy symp-toms and signs, retinal photoscreening, measurement of

renal function and urine albumin:creatinine ratio.Macrovascular complications such as incidence of myo-cardial infarction, stroke and peripheral vascular diseasewill also be recorded.

Assessment of outcomesHbA1c will be measured by high-performance liquidchromatography (Bio-Rad). Body weight will be recordedto the nearest 0.1 kg using digital scales (SECA, Chino,California, USA). Height will be recorded to the nearest0.5 cm using a stadiometer. Total body fat, left femoralneck bone density and anteroposterior (AP) lumbarspine bone density will be measured by dual-energyX-ray absorptiometry (model iDXA, software V.15,GE-Lunar, Madison, Wisconsin, USA). Per cent body fatwill be calculated as 100× total body fat/body weight.REE will be measured after overnight fast using a venti-lated canopy connected to an open-circuit indirect calor-imeter (Deltatrac Metabolic Monitor MBM-100, DatexInstruments, Helsinki, Finland). Hospitalisations, operativecomplications graded according to the Clavien-Dindo clas-sification,12 mortality, revisional surgery and changes inmedications will be recorded. Hospital anxiety and depres-sion scale13 and 36-item short form14 questionnaires willbe used (table 1).

Ancillary mechanistic studyAlongside the primary trial, participants were able toopt in to an exploratory gut hormone and gut bacteriamechanistic substudy. As part of this study, they wereasked to provide additional data and biosamples duringthe three scheduled visits for body composition assess-ments at baseline, 1 and 5 years. The additional datainclude a 3-day food diary, hunger ratings assessment,fecal samples and a 75 g oral glucose tolerance test.Participants were requested to prospectively record allfoods and drinks taken during the 3-day diary period,including the amounts taken, any dietary supplementstaken and medications taken during the period. Visualanalogue scale hunger ratings will be collected onarrival at the body composition unit in a fasted state atbaseline, 1 and 5 years. Participants will be asked torate their motivation to eat on a horizontal non-gradedline measuring 100 mm, anchored on the left by ‘not atall’ and on the right by ‘very much’ next to fourresponses: How hungry are you? How full do you feel?How strong is your desire to eat? How much food do youthink you could eat? Fecal samples will be self-collected instool containers, sealed and placed into another sealedcontainer filled with water and frozen immediately at −20°C, before being transported in the frozen state to thelaboratory where they will be stored at −80°C. Participantswill be asked to attend these body composition/REE visitsin a fasted state for a 2-hour 75 g oral glucose tolerancetest, with 30 min blood sampling. Blood samples will becollected into EDTA, serum separator tubes and BD P800tubes (BD, Franklin Lakes, New Jersey, USA), containing

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Table 1 Study timeline and investigations

Baseline Week 1 Week 6 3 months 6 months 9 months 12 months 18 months 2 years 3 years 4 years 5 years

Clinical history and

medications

✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

Blood pressure ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓Anthropometrics ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓DEXA/REE* ✓ ✓ ✓Endocrinology review ✓ ✓ ✓ 21 months 33 months 45 months 57 months

Hospital anxiety and

depression score

✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

Short form health survey

instrument (SF-36)

✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

Laboratory tests† ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓HbA1c ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓Stored fasting plasma

and serum

✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

Mechanistic substudy

Food diary ✓ ✓ ✓Satiety questionnaire ✓ ✓ ✓Fecal sample‡ ✓ ✓ ✓Plasma and serum

samples from oral

glucose tolerance test§

✓ ✓ ✓

*Dual-energy X-ray absorptiometry/resting energy expenditure.†Full blood count, C reactive protein, ESR, electrolytes, creatinine, calcium, albumin, bilirubin, liver enzymes, lipids and 25-hydroxy-vitamin D.‡Samples immediately frozen.§Samples also stored in BD P800 tubes for gut hormone analysis.

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protease inhibitors to maximise the stability of guthormones.15

Ethics and disseminationEthics approval has been granted by the New Zealandregional ethics committee (NZ93405). This study was pro-spectively registered at ANZCTR (ACTRN12611000751976)and retrospectively registered at clinicaltrials.gov(NCT01486680). The results of this study and ancillarystudies will be publicised in the form of presentations atnational and international meetings. The study and con-clusions regarding the primary and secondary objectivesand ancillary studies will be presented as manuscriptssubmitted for peer-reviewed journal publication.

DISCUSSIONThis is the first double-blind, randomised trial tocompare SR-LRYGB and LSG for the treatment of T2D inmorbidly obese patients including those with BMI up to65 kg/m2. The use of a standard metabolic medicationadjustment protocol is a strength of the study design, ineffort to reduce heterogeneity in management of bloodpressure, lipids and T2D postoperatively. The ancillarystudies interrogating comparative changes in gut micro-biota and gut hormones may uncover novel mechanisticinsights into how diabetes remission is achieved throughthese two contrasting surgical procedures.The term ‘remission’ with ‘partial’ and ‘complete’

descriptors has been used within the bariatric surgery

Figure 2 Endocrinology evaluation and treatment protocol for trial patients.

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literature with distinct thresholds of HbA1c and fastingglucose, generally in the absence of glucose loweringtherapy, to represent varying degrees of diabetesimprovement.10 However, these are controversial giventhat the diagnosis of diabetes itself is not dichotomousand rather thresholds of glycaemia have been defined onthe basis of the associated risk of microvascular and macro-vascular complications. It is not yet known whether thesethresholds remain true in a postbariatric surgery popula-tion, and consequently, diagnostic criteria for prediabetesand diabetes validated for a non-surgical population maybe misleading when applied in reverse, to those who haveundergone bariatric surgery. Similarly, there is a paucity ofevidence to guide the development of valid and reliableprotocols for discontinuing cardiovascular risk-modifyingmedications after bariatric surgery for optimum medicalmanagement. Nonetheless, we have selected one of themost commonly accepted HbA1c thresholds for classifyingdiabetes remission16 and used a standard medical man-agement to reduce complacency in medical therapy afterabrupt withdrawal of medications postoperatively.Limitations of this study include the single-centre

design and the relatively small sample size. However, byemploying stratification for confounding variables inrandomisation, this will ensure that these factors (suchas duration of T2D, insulin use, ethnicity and age) willbe matched across both treatment groups. SR-LRYGBwas chosen due to superior long-term weight loss out-comes, largely due to reduction in weight regain whencompared to non-banded LRYGB.17–19 However, thismodification of LRYGB is possibly not widely adopteddue to unfamiliarity with placing it and potential issuesregarding food intolerance and band-related complica-tions.6 Some of these concerns are ill conceived andhence currently the use of SR type of LRYGB may limitgeneralisability of the study.

CONCLUSIONThis article presents the protocol and data analysis planfor a single-centre, randomised, double-blinded clinicalstudy comparing LSG and SR-LRYGB in the treatmentof T2D in morbidly obese patients, including those whoare super-obese. The results of this study, when com-pleted, will assist in decision-making between LSG andLRYGB for the treatment of T2D in morbidly obesepatients. In the interim, we hope this description of thestudy design and metabolic medication adjustmentprotocol will assist clinicians looking after patients fol-lowing bariatric surgery and researchers in planningfuture bariatric surgery trials.

Author affiliations1Faculty of Medical and Health Sciences, Department of Medicine, Universityof Auckland, Auckland, New Zealand2Department of Surgery, North Shore Hospital, Waitemata District HealthBoard, Auckland, New Zealand3Department of Endocrinology, North Shore Hospital, Waitemata DistrictHealth Board, Auckland, New Zealand

4Faculty of Medical and Health Sciences, Department of Surgery, University ofAuckland, Auckland, New Zealand

Contributors MWCB and RM conceived this study. HH, LDP, RC, DDK, SJR,MGC, NJE and LH contributed to study design. MWCB, HH, NJE and SJRwere primarily responsible for the surgical aspects of the protocol. RC, DDKand RM were primarily responsible for the medical assessment protocol ofparticipants. LDP is primarily responsible for the body compositionassessment and energy expenditure protocol. RM is primarily responsible forthe gut microbiota and gut hormone substudy protocol. RM wrote the firstdraft of this manuscript. All authors read and contributed to the final draft ofthe paper.

Funding We acknowledge the funding support from Waitemata DistrictHealth Board, which provides limited publically funded bariatric surgery(∼100 cases annually). Additional funding for blood sample storage and aresearch nurse salary was provided by Johnson and Johnson (NZ), Covidien(NZ) and Obex (NZ). DEXA scanning for body composition was provided bythe Diabetes Research Fund (NZ) and Maurice & Phyllis Paykel Trust (NZ).Sample collection for the gut microbiota and gut hormone substudy wasfunded by a grant from the Maurice Wilkins Centre, New Zealand. None ofthese funders had any role in study design or data analysis or interpretation.

Competing interests None declared.

Patient consent Obtained.

Ethics approval New Zealand regional ethics committee.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement All enquiries regarding data from this study shouldbe made to the corresponding author.

Open Access This is an Open Access article distributed in accordance withthe Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, providedthe original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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