Low-glycaemic index diet to improveglycaemic control and cardiovasculardisease in type 2 diabetes: design andmethods for a randomised, controlled,clinical trial

Laura Chiavaroli,1,2 Arash Mirrahimi,2,3 Christopher Ireland,1,2 Sandra Mitchell,1,2

Sandhya Sahye-Pudaruth,1,2 Judy Coveney,2 Omodele Olowoyeye,4,5

Tishan Maraj,4,5 Darshna Patel,1,2 Russell J de Souza,2,6 Livia S A Augustin,2,7

Balachandran Bashyam,1,2 Sonia Blanco Mejia,1,2 Stephanie K Nishi,1,2

Lawrence A Leiter,1,8 Robert G Josse,1,8 Gail McKeown-Eyssen,9 Alan R Moody,4,5

Alan R Berger,10 Cyril W C Kendall,2,11 John L Sievenpiper,1,2 David J A Jenkins1,2

To cite: Chiavaroli L,Mirrahimi A, Ireland C, et al.Low-glycaemic index diet toimprove glycaemic controland cardiovascular disease intype 2 diabetes: design andmethods for a randomised,controlled, clinical trial. BMJOpen 2016;6:e012220.doi:10.1136/bmjopen-2016-012220

▸ Prepublication history andadditional material isavailable. To view please visitthe journal (http://dx.doi.org/10.1136/bmjopen-2016-012220).

Received 11 April 2016Revised 31 May 2016Accepted 3 June 2016

For numbered affiliations seeend of article.

Correspondence toDr David JA Jenkins;Nutritionproject@smh.ca

ABSTRACTIntroduction: Type 2 diabetes (T2DM) producesmacrovascular and microvascular damage, significantlyincreasing the risk of cardiovascular disease (CVD),renal failure and blindness. As rates of T2DM rise, theneed for effective dietary and other lifestyle changes toimprove diabetes management become more urgent.Low-glycaemic index (GI) diets may improve glycaemiccontrol in diabetes in the short term; however, there isa lack of evidence on the long-term adherence to low-GI diets, as well as on the association with surrogatemarkers of CVD beyond traditional risk factors.Recently, advances have been made in measures ofsubclinical arterial disease through the use of MRI,which, along with standard measures from carotidultrasound (CUS) scanning, have been associated withCVD events. We therefore designed a randomised,controlled, clinical trial to assess whether low-GIdietary advice can significantly improve surrogatemarkers of CVD and long-term glycaemic control inT2DM.Methods and analysis: 169 otherwise healthyindividuals with T2DM were recruited to receiveintensive counselling on a low-GI or high-cereal fibrediet for 3 years. To assess macrovascular disease, MRIand CUS are used, and to assess microvasculardisease, retinal photography and 24-hour urinarycollections are taken at baseline and years 1 and3. Risk factors for CVD are assessed every 3 months.Ethics and dissemination: The study protocol andconsent form have been approved by the researchethics board of St. Michael’s Hospital. If the studyshows a benefit, these data will support the use oflow-GI and/or high-fibre foods in the management ofT2DM and its complications.Trial Registration number: NCT01063374;Pre-results.

INTRODUCTIONType 2 diabetes (T2DM) is the fastestgrowing chronic disease worldwide and itsprevalence is projected to double over thenext 20 years. Given its prevalence and heavyhealthcare and quality-of-life burden,1 thereis a great need for better treatment options.In uncontrolled T2DM, the macrovascular(cardiovascular disease, CVD) and micro-vascular (eye and kidney) risks are increased.T2DM reduces the lifespan by 10 years,2

chiefly due to CVD deaths, which are twofold

Strengths and limitations of this study

▪ This study will be the first to document theeffects of a dietary intervention on measures ofmacrovascular disease through the detection ofchanges in carotid vessel wall volume assessedby MRI as a surrogate measure of cardiovasculardisease, in high-risk participants.

▪ This study is also the longest to assess theeffect of altering the dietary GI, allowing for theexploration of sustainability of a low-GI diet.

▪ The MRI images obtained from this study willprovide invaluable data on the natural history ofvascular disease progression in type 2 diabetes.

▪ A potential limitation of this study is that partici-pants may be more health conscious thanaverage since they are volunteering to participatein a long-term dietary trial.

▪ Another potential limitation is that those rando-mised to the control high-cereal fibre diet mayhave difficulty avoiding many of the healthyfoods which they are told to as they are on thelow-GI diet (eg, beans and berries).

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higher in men and fourfold higher in women than inthose without diabetes.3 Further, 40% of new end-stagerenal disease is accounted for by diabetic nephropathyand diabetes is a major cause of renal transplants.4

Damage to retinal vessels can result in diabetic retinop-athy (retinopathy), and macular oedema, which aremajor causes of vision loss in Western Nations.5 6 Thecost of medical care for those with diabetes in WesternNations is two to three times higher than those without dia-betes, and has doubled over the past decade,7 8 largelyrelated to CVD. To reduce the risk of these complications,there is a continued focus on controlling elevated bloodglucose levels through lifestyle and pharmaceutical means.Prospective cohort studies and large clinical trials havedemonstrated that good glycaemic control in diabetes isassociated with a reduced risk of microvascular complica-tions.9–14 However, the results of three large randomisedtrials published in 2008 (ACCORD, ADVANCE andVADT)15–17 failed to show significant CVD benefit forimproved glycaemic control over a 3-year to 5-year period.At the same time, concern about the cardiovascular safetyof rosiglitazone and other antidiabetic medications led theUS Food and Drug Administration to require demonstra-tion of the cardiovascular safety of all new antidiabeticagents.18 Longer term follow-up of some of these trials(UKPDS and VADT),19 20 as well as the recently publishedEMPA REG OUTCOME study21 with the SGLT2 inhibitor,empagliflozin, have demonstrated CVD benefit. Acarbosehas shown promise in reducing CVD and incident hyper-tension22 when assessed as a secondary outcome in a largerandomized controlled trial in participants with pre-diabetes, and a larger CVD study with acarbose in patientswith diabetes is underway. Acarbose converts dietary carbo-hydrate into a slow release or low-glycaemic index (GI)food by inhibiting pancreatic amylase and small intestinalbrush border sucrase-isomaltase. Low-GI foods, althoughrecommended for diabetes control by many diabetes agen-cies,12–14 23 have not been tested specifically on vascularoutcomes despite cohort studies suggesting that low-GIdiets, especially in women, are associated with reducedCVD.24 Additionally, a randomised trial, the PREDIMEDstudy, that reduced the GI and GL of the diet25 andincluded the use of nuts and olive oil to achieve thiseffect also reduced CVD, especially stroke.26 We havedemonstrated the greater effectiveness of low-GI diets inreducing HbA1c and blood pressure in T2DM.27 28 Wetherefore designed a randomised, controlled, clinical trialto assess whether dietary advice on either a low-GI or ahigh-cereal fibre diet will make a significant difference oncarotid plaque burden and other surrogate markers ofCVD, microvascular disease and long-term glycaemiccontrol in high-risk participants with T2DM.

METHODS AND ANALYSISStudy designRecruitmentIn 2010, potential T2DM participants were recruitedthrough newspapers and subway advertisements, and by

phoning previous study participants from our researchcentre who had expressed interest in further studies.After initial telephone screening, information sessionswere arranged at St. Michael’s Hospital. Those inter-ested, attended a screening visit at the clinic for a bloodtest to determine eligibility (box 1). All participants gaveinformed consent prior to participating in any screeningprocedures. Physicians were contacted to ensure thatthose responsible for diabetes care approved participa-tion. Those satisfying initial eligibility criteria werescheduled for a screening 2D carotid ultrasound (CUS)to assess carotid artery thickening by intima media thick-ness (IMT). Our original screening cut point was amaximum IMT ≥2.0 mm; however, a larger than antici-pated number of participants were ineligible (∼66%

Box 1 Inclusion and exclusion criteria

Inclusion criteria: individuals with type 2 diabetes (T2DM)▸ Taking oral hypoglycaemic agents at a stable dose for

≥8 weeks;▸ HbA1c ≥6.5 to ≤8.0% at initial screening visit;▸ HbA1c ≥6.5% at prestudy visit (visit just prior to

randomisation);▸ Diabetes diagnosed >6 months;▸ Stable weight for 2 months (within 3%);▸ Valid Ontario Health Insurance Plan (OHIP) card and a family

physician;▸ If prescribed lipid medication, stable dose for ≥2 weeks;▸ If prescribed blood pressure medication, stable dose for

≥1 week;▸ Can keep written food records, with the use of a digital scale;▸ Carotid maximum IMT ≥1.2 mm (originally ≥2.0 mm,

≥1.5 mm in early 2012, ≥1.2 mm in late 2012).Exclusion criteria▸ Take insulin, steroids, warfarin (Coumadin);▸ Gastrointestinal disease (gastroparesis, celiac disease, ulcera-

tive colitis, Crohn’s disease, irritable bowel syndrome);▸ Major cardiovascular event (stroke or myocardial infarction) or

major surgery in the past 6 months;▸ Major debilitating disorder;▸ Clinically significant liver disease (aspartate transaminase

(AST) or alanine transaminase (ALT) >130 U/L), excludingnon-alcoholic fatty liver disease or non-alcoholicsteatohepatitis;

▸ Hepatitis B or C;▸ Renal failure (high serum creatinine >150 mmol/L);▸ Serum triglycerides ≥6.0 mmol/L;▸ History of cancer, except non-melanoma skin cancer (basal

cell, squamous cell);▸ Food allergies to study food components;▸ Elevated blood pressure (>145/90 mm Hg) unless approved by

family physician;▸ Acute or chronic infections (bacterial or viral);▸ Chronic inflammatory diseases (eg, rheumatoid arthritis,

lupus and ulcerative colitis);▸ Other conditions which in the opinion of any of the investiga-

tors would make them unsuitable for the study;▸ Any condition or circumstance preventing an MRI (eg, metal

workers, prostheses, metal implants or those excessivelyclaustrophobic).

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ineligible). Therefore, in early 2012, the cut point wasreduced to ≥1.5 mm (∼44% ineligible) in accordancewith the Mannheim carotid IMT consensus29 where≥1.5 mm defined the beginning of atheromatouschanges. It was later further reduced in late 2012 to≥1.2 mm (∼23% ineligible), the median between theMannheim consensus (1.5 mm) and the EuropeanSociety of Hypertension and the European Society ofCardiology Practice Guidelines for the management ofarterial hypertension (0.9 mm).30 These changesallowed completion of recruitment by June 2013, whileincluding participants with some carotid thickening. Atthe screening CUS scan, if the maximum IMT measurewas greater than or equal to the inclusion cut point of1.2 mm (or the cut point at the time of CUS scan), thesonographer also completed a 3D CUS scan.If individuals had a recent medication change that

made them ineligible at screening or prior to random-isation, they were able to return for a rescreen after therequired time had elapsed.

Baseline measures and randomisationEligible consenting participants had a baseline carotidMRI scan at the Medical Imaging Department atSunnybrook Health Sciences Centre. A gadolinium contrastagent, Gadovist (gadobutrol, Bayer, Mississauga, Canada),approved by Health Canada and one of several productscommonly used for contrast during MRIs, was used afterthree safety procedures were passed. First, participants hadto consent after being informed of the risks. Second, MRIsafety forms were completed with the participant andreviewed by the study physician and staff at Sunnybrook.Third, forms were reviewed again by study staff atSunnybrook immediately before the MRI. If it was deemedsafe to proceed, MRI was undertaken with Gadovist. Thesame safety procedure was repeated for each of the two add-itional MRI scans at years 1 and 3 of the study. If Gadovist isdeemed unsafe or the participant declines consent, theMRI scan is done without the use of Gadovist.A baseline retinal examination was conducted by a

vitreoretinal subspecialist ophthalmologist at theDepartment of Ophthalmology at St. Michael’s Hospitaland each participant had standardised seven-field dia-betic retinal photographs taken.Two baseline clinical visits occurred at St. Michael’s

Hospital, on average 2 weeks apart, but no more than5. At the first baseline clinic visit, anthropometric andfasting blood measures were obtained and if HbA1c was≥6.5%, participants could proceed. If HbA1c was <6.5%,participants could return for a retest after 2 weeks.Participants were given detailed instruction on how tocomplete a 7-day food record and 24-hour urine collec-tion using the kit provided; both were returned at thesecond visit.At the second baseline clinic visit, anthropometric and

fasting blood measures were again obtained and eachparticipant was randomised to receive dietary advice oneither a low-GI or high-cereal fibre diet. Randomisation

was stratified by sex, HbA1c (≤7.1%, >7.1%), smoking(yes or no) and statin use (yes or no) as documentedduring the first baseline visit. Participants were providedwith a dietary instruction sheet based on the diet towhich they were randomised (see online supplementaryappendix figures S1 and S2). These diets were reviewedin detail with a study dietitian in a 30 min discussion.Blinding the participants or the dietitians delivering

the dietary advice is not possible due to the very differ-ent nature and physical form of the foods. However, itwas stressed to the participants that both treatmentshave been considered to confer benefits in cohortstudies in order to balance participant expectation oftreatment benefit. To remove the possibility of bias, phy-sicians and technical staff who are obtaining measure-ments are blinded to the treatments, as was thestatistician who randomised the coded participants andwho will analyse the data. Participants were randomisedafter the baseline (zero week) blood sample to avoidrandomising participants who for any reason did notintend to start the study. Dropout is therefore defined asquitting post randomisation.

Outcomes and study measuresFigure 1 depicts the timing and frequency of all studymeasures described in detail. MRI, CUS, 24-hour urinarycollections and retinal assessments are taken at baselineand years 1 and 3 with anthropometric, fasting bloodmeasures and 7-day food records at 3-month intervals. Atthe 3-monthly clinic visits, the participants’ medications,noting any changes, as well as any unusual or adverseevents, including illness or stressful issues, that occurredsince the last clinic visit are recorded in detail.The primary outcome of the trial is change in carotid

plaque volume assessed as vessel wall volume (VWV) byMRI at year 3.At the time of the grant submission, IMT by CUS was

designated as the primary outcome based on its associ-ation with CVD when used as a screening tool. However,meta-analyses31–33 have since shown that IMT seems sub-optimal for assessing changes from interventions,although it still relates overall to risk of CVD when usedfor screening.34 The original protocol proposed MRI ofthe carotid arteries as a secondary outcome. Over thelast 6 years, advances in MRI technology produced highaccuracy and reproducibility by minimising interopera-tor and intraoperator variability of image acquisitionand so now make this the preferred modality for asses-sing change and monitoring therapeutic interventionsin clinical trials.35–37 Accordingly, we adopted this as ourprimary outcome and adjusted our power calculations toreflect recent MRI data.38

Magnetic resonance imagingMRI scans are being performed in the Medical ImagingDepartment at Sunnybrook Health Sciences Centre MRIresearch unit at a single site using a Philips 3-Teslawhole body scanner (Philips Healthcare, Markham,

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Canada) with a 16-channel neurovascular coil(16-NV-SENSE). Participants are centred at the indexcarotid artery bifurcation as determined by carotid IMT(ie, ‘index’ is the side of the artery, left or right, with thehighest IMT), and a shim coil covering a 10 cm regionover the neck is used to improve magnetic field homo-geneity. With a standardised protocol, six contrastweightings of the carotid artery are obtained: 2D precon-trast and postcontrast enhanced T1-weighted (T1W),proton density weighted, and T2-weighted sequences, aswell as 3D T1W gradient recalled echo and time offlight MR angiography sequences. Images are obtainedof the left and right carotid arteries. Gadobutrol (Bayer)is used as the contrast agent when criteria are met at anintravenous injection of 0.1 mmol/kg (0.2 mL/kg).Sequence parameters are described in onlinesupplementary appendix table S1. Total scan time is anaverage of 60 min and allows coverage of 2D imagingcapturing a 32 mm segment (2 mm thickness×16matched images among the four weightings), while 3Dimaging captures the entire carotid artery from its originto the Circle of Willis. The cardiovascular imaging soft-ware, VesselMASS (Medis, the Netherlands), is used forimage analysis. Image grading is performed during theanalysis (see online supplementary appendix table S2)and images with poor quality (grade <3) or with missingimages will be excluded from analyses. Location match-ing of the available MR images is performed using thebaseline index carotid artery over the different timepoints before lumen and outer wall contours are identi-fied. VWV is automatically generated from the soft-ware.39–41 Intraclass correlation values for measurementsare above 0.9 (good to excellent);42–44 however, a single,trained and blinded reader will assess all measurements.MRI will also allow assessment of several secondary

outcomes that are surrogate markers of CVD: changes inintraplaque haemorrhage, lipid-rich necrotic core and

carotid artery calcium status,37 38 45 46 each of which hasan intraclass correlation value for measurements above0.9 (good to excellent).42 44

B-mode carotid ultrasound (CUS)An additional secondary outcome assessing macrovascu-lar disease is IMT by 2D B-mode CUS, a measure that isrelated to CVD risk.34

Standardised CUS scanning and reading protocols areused following a similar protocol to the ACAPS47–49 andSECURE50 51 trials, which was validated in ACAPS.49

CUS imaging and reading is performed by two trainedand certified sonographers who are unaware of the treat-ment assignment on a Philips iU22 Ultrasound system(Philips Healthcare, Andover, Massachusetts, USA) atSunnybrook. Most participants are scanned with theL9-3 linear high-frequency transducer; however, whenthe vessel is very superficial, the 12-5 transducer is usedin order to visualise the near wall. Each participant ispositioned supine on the examination table, with theneck extended and rotated away from the side of interest.Transverse and longitudinal views of each carotid arteryare obtained from the common carotid artery to the bifur-cation and the internal carotid artery (ICA). The ICA isdifferentiated from the external carotid artery based onits low resistance spectral Doppler flow pattern. On thelongitudinal view, each carotid artery is divided into threesegments 1 cm long defined relative to the carotid flowdivider (figure 2). Twelve IMT measurements of the nearand far walls at each carotid segment are made using elec-tronic calipers and the mean maximum IMT is computedas the average of the segment maximum IMTs.Further secondary outcomes significantly related to

CVD risk include anthropometric, urine and blood mea-sures,52 which will be analysed as previously described.28

Briefly, anthropometric data include body weight, seatedblood pressure measured as the mean of triplicate

Figure 1 Schematic representation of the study protocol. GI, glycaemic index.

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measures made with an automatic sphygmomanometer(Omron HEM 907XL, OMRON Healthcare, Burlington,Ontario, Canada), and waist (at the umbilicus, 2 inchesabove and lying down) and hip circumference.Twenty-four-hour urine is collected by discarding thefirst urine on waking, noting the time and then collect-ing each subsequent excretion up to and including thefirst void at the same time on waking the next morning.Urinary measures include C-peptide, urea, creatinineand electrolytes. Blood measures include HbA1c, fastingglucose, fasting lipids and liver function.Other study outcomes include 50° stereoscopic colour

fundus photographs of seven standard fields (retinalphotography) to assess degree of retinopathy following asimilar protocol to the ACCORD study.53 Vitreoretinalsubspecialist ophthalmologists blinded to the interven-tion will read the photos to assess any changes.Dietary assessments are being made using participant

completed 7-day food records that are analysed using acomputer program (ESHA Food Processor SQL V.10.9;ESHA, Salem, Oregon, USA) based on a United StatesDepartment of Agriculture (USDA) database,54 supplemen-ted with the Canada Nutrient File,55 with GI values frominternational GI tables,56 substituted with GI testingthrough the University of Toronto at Glycemic IndexLaboratories, Canada, using the bread scale (wherebread=100; for the glucose scale, bread scale values aremultiplied by 0.71). Product data are updated with manu-facturers’ nutrient information and with relevant foods ana-lysed by Covance Laboratories (Madison, Wisconsin, USA).

InterventionsParticipants were randomised to receive dietary adviceon either a low-GI or high-cereal fibre diet for 3 yearstogether with advice on the National CholesterolEducation Program Adult Treatment Panel III (NCEPATP III) diet. Diet histories recorded for the 7 days priorto clinic visits are being assessed for detail and consist-ency by the dietitian in the participant’s presence, andused to guide dietary advice. Assessment is made ofsatiety (using a 9-point bipolar semantic scale) and onpalatability and sustainability (using 10-point scales).Both diets conform as closely as possible to NCEP ATP

III guidelines with <7% saturated fat and <200 mg

dietary cholesterol daily57 and provide the same level offibre (up to 35 g/day). Advice encouraging all partici-pants to reach ideal body weight is standard advice forthose with diabetes, 85–90% of whom are overweight,together with encouragement to exercise at a level theycan sustain prior to and over the course of the study.The consistency of exercise is checked at each clinic visitand any deviations recorded.Low-GI dietary advice encourages use of intact grains,

including specific low-GI breads, pasta, parboiled rice,coarse cut oats, Red River and All Bran Buds with psyl-lium breakfast cereals, cooked dried or canned peas,beans or lentils, barley and low-GI temperate climatefruit, including apples, oranges and berries (see onlinesupplementary appendix figure S1).High-cereal fibre dietary advice encourages use of

whole grains, including whole wheat breads, wheat fibrecereals, cream of wheat hot cereal, brown rice and trop-ical fruit, including bananas, mangos and pineapples(see online supplementary appendix figure S2). Samplenutritional profiles of each diet demonstrating a 13-unitdifference in GI between test and control as demon-strated in our previous 6-month trial27 is provided inonline supplementary appendix table S3.Dietary advice is provided through half-hour individ-

ual sessions with the dietitian every 3 months at clinicvisits, as well as through monthly phone calls for the first3 months and thereafter, at least one 10 minute phoneinterview for 1-day diet recalls between dietitian inter-views, with additional phone interviews for those withpoor (<75%) adherence to the study protocol (ie, poordiet and missed visits).

Sample sizeOur original power calculation was based on IMT byCUS which was the original primary end point. We hadestimated that 160 participants would need to be rando-mised with 120 participants completing the study (25%attrition). A total of 169 participants were randomised.For our primary outcome, VWV by MRI, the magni-

tude of difference between the groups that can be seenwith 169 randomised participants was calculated usingthe estimate of variance of the measurement as observed(SD=252) in Saam et al.38 This showed that a treatmentdifference of 10% can be detected with 80% power andα=0.05, assuming a 25% attrition.Furthermore, with a sample size of 160 participants,

we will be able to detect changes in the important sec-ondary end point, HbA1c, which could influence arter-ial damage. For HbA1c, if 120 of the randomised 169participants complete the study, we will be able to detecta 0.3% treatment difference with a pooled SD of thetreatment difference of 0.578 at a two-tailed significancelevel (α)=0.05 and power (1−β)=0.8 using a two-treatment parallel design, with an independent-samplest-test. This calculation is based on our previous studyin T2DM using similar treatments over a 6-monthperiod.27

Figure 2 Diagrammatic example of a right common carotid

artery scan. The far wall of the bifurcation segment as well as

part of the internal carotid artery are narrowed by a plaque.

Adapted from Lonn et al.51

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Statistical analysis plannedAll randomised participants will be included in theintention-to-treat analyses. Results will be expressed asmeans±SEM or 95% CIs.

Primary analysisThe primary analysis will assess the between-treatmentdifference in change from baseline in VWV, wherechange is assessed as years 1 and 3 adjusted for baselineusing a repeated-measures mixed model (PROC MIXEDin SAS 9.4) (SAS Institute: SAS/STAT ProprietarySoftware 9.4. Cary, NC: SAS Institute; 2002–2012) in anintention-to-treat analysis, without adjustment for covari-ates. Every effort will be made to obtain final vascularimaging and blood samples from those who do notprovide these in clinic due to attrition or loss tofollow-up.

Sensitivity analysisRobustness will be assessed of our primary finding tomodel assumptions: (1) To address the impact of poten-tial imbalance in prognostic factors, we will repeat theprimary analysis using mixed models but controlling forage, sex, duration of diabetes, waist circumference, chol-esterol medication use, baseline VWV, smoking, bloodpressure and family history of CVD, together withdietary variables (baseline GI, saturated fat, dietary chol-esterol, dietary pulse and nut intake). Missing data forcovariates will be handled using the missing indicatormethod; (2) To assess the robustness of our primary ana-lysis of missing data, we will repeat the primary analysisusing completer and per-protocol analyses, and multipleimputations to generate missing data and (3) To assessthe impact of participant-level factors on the primaryoutcome, we will examine changes in indices of vasculardamage separately in (a) those who meet HbA1c targetversus those with less good glycaemic control (eg,HbA1c≤7% vs HbA1c>7% at the end of the study); (b)those with good compliance, that is, by quartiles ofchange in GI at years 1 and 3, those in the highest quar-tiles of specific low-GI components (dietary pulses, tem-perate climate fruit, nuts, etc) and high-fibre completersby quartiles of change in fibre and (c) by IMT at studyentry. Exploratory assessment of the significance ofbetween-subgroup changes in the primary outcome willbe undertaken with Wald tests of the interaction terms.

Exploratory analysesWe anticipate that this study will yield a rich data set. Wehave therefore mapped out some exploratory analyses:(1) to assess response trajectories, by comparing treat-ment slopes across all post-treatment measures, that is,an assessment of whether year 1 values differ from year3 values; (2) to assess treatment differences in medica-tion use over all post-treatment values; (3) further ana-lyses will examine causal pathways between diet,metabolic parameters and measures of arterial function

using methods of path analysis and structural equationmodelling, as appropriate.

ETHICS AND DISSEMINATIONThe protocol and consent forms were approved by theresearch ethics board of St. Michael’s Hospital. Thestudy was registered with clinicaltrials.gov (identifier:NCT01063374).

Participant safetyPrivacy will be enhanced by data deidentification.Databases with personal health information will be pass-word protected. Paper forms with personal health infor-mation (eg, participant charts) will be kept in lockedcabinets and in locked rooms, and the department doorlocked after hours.Electronic files will identify participants only through

identification codes. Access to paper and electronic datafiles is limited to the principle investigator (PI), statisti-cians, dietitians, students and data entry personnelworking on the project.A separate chart with routine clinical information is

maintained for contact with participants’ family physi-cians and will be accessible only to the PI and study staff.A Data Safety Monitoring Board will periodically

review (approximately once per year or when safetyissues arise) the progress of the trial to oversee partici-pant safety and provide advice on the status and continu-ation of the overall study.HbA1c is reviewed at each visit and as necessary with

one of the physicians of the Safety Committee who arenot involved in the day-to-day running of the trial (RGJ,LAL) with participants identified only by code.Participants will be referred to his/her family physicianfor treatment if HbA1c exceeds the 8.5% threshold ofrecommended targets for glycaemic control, accordingto diabetes guidelines,11 12 on two successive occasions,or if hypoglycaemic symptoms associated with low bloodglucose levels occur. If a participant’s physician consid-ers that a change in dosage or medication is required, apredetermined paradigm will be used, and the SafetyCommittee notified. Blood pressure is also reviewed. Iflevels surpassed the screening cut-off of 145/90 mm Hg,the participant’s physician is notified. Adverse events willbe dealt with on a case-by-case basis depending onwhether the situation is likely to resolve spontaneouslyor whether medical intervention is required.

Discussion and implicationsThis study will be the first to document the effects of adietary intervention on measures of macrovasculardisease through the detection of changes in carotidVWV as a surrogate measure of CVD, in high-risk partici-pants. We believe this will open the way for other investi-gators to use vascular MRI in their research and for usein clinical practice as a diagnostic tool and especially forfollow-up. It is also the longest trial to date to assess the

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effect of altering the dietary GI and will also provideinvaluable data on the natural history of vasculardisease. In view of the global rise in the incidence ofT2DM and the associated vascular complications, includ-ing increased CVD risk, therapeutic approaches thataddress microvascular and macrovascular risk factors arenow urgently required.At present, diabetes is an immense burden on the

healthcare system of Western Nations, projected to con-tinue to increase, and largely related to CVD and micro-vascular complications.7 8 A 25% sparing of T2DMmicrovascular complications would result long termfrom a 0.9% reduction in HbA1c according to theUKPDS data.58 We achieved a 0.5% reduction in HbA1cin our previous 6-month randomised, controlled trial ofsimilar low-GI dietary advice in those with T2DM,27 sowe expect a similar reduction in this investigation. Theeconomic (let alone social) impact of even one-thirdthe reduction in HbA1c seen in the UKPDS58 is likely tobe considerable. If low-GI diets can be shown to reducemacrovascular disease risk factors in addition to redu-cing microvascular disease, results will not only increaseunderstanding of the role of diet and nutrition inmacrovascular disease development in T2DM but willalso influence guidelines for the treatment of dia-betes and the nature of the products produced by thefood industry, and the savings in cost and suffering willbe significant.

Author affiliations1Department of Nutritional Sciences, Faculty of Medicine, University ofToronto, Toronto, Ontario, Canada2Clinical Nutrition and Risk Factor Modification Center, St. Michael’s Hospital,Toronto, Ontario, Canada3Faculty of Health Sciences, School of Medicine, Queen’s University, Kingston,Ontario, Canada4Department of Medical Imaging, Sunnybrook Health Sciences Centre,Toronto, Ontario, Canada5Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada6Department of Clinical Epidemiology and Biostatistics, Faculty of HealthSciences, McMaster University, Hamilton, Ontario, Canada7National Cancer Institute “Fondazione G. Pascale”, Naples, Italy8Division of Endocrinology and Metabolism, St. Michael’s Hospital, Toronto,Ontario, Canada9Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario,Canada10Department of Ophthalmology, St. Michael’s Hospital, Toronto, Ontario,Canada11College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon,Saskatchewan, Canada

Acknowledgements The authors thank Dr Rajeev Muni for his help as one ofour vitreoretinal subspecialist ophthalmologists from the Department ofOphthalmology at St. Michael’s Hospital. MRI contrast was provided by BayerHealthcare (Bayer, Mississauga, Canada).

Contributors DJAJ, LAL, RGJ, GMK-E, ARM, CWCK and JLS conceived thestudy and wrote the study protocol. LC, AM, CI, SM, SS-P, JC, OO, TM, DP,RJdS, LSAA, BB, SBM, SKN, ARM, ARB and DJAJ contributed significantly tothe acquisition of the data. LC, AM, CI, RGJ, GMK-E, ARM and DJAJ significantlycontributed to the planning of analyses of the data. LC and DJAJ drafted themanuscript and all authors revised the manuscript critically for importantintellectual content. All authors reviewed and approved the final manuscript andagree to be accountable for all aspects of the work.

Funding This work was supported by the Canadian Institutes of HealthResearch (CIHR), as well as Loblaws Inc., and Barilla. DJAJ was funded bythe Government of Canada through the Canada Research Chair Endowment.None of the funders had a role in the study design, collection, analysis orinterpretation of the data; in the writing of the report; and in the decision tosubmit the paper for publication.

Competing interests LC has received research support from the CanadianInstitutes of Health Research (CIHR). LC is a clinical research coordinator andSKN is a clinical research dietitian at Glycemic Index Laboratories, Toronto,Ontario, Canada. RJdS is funded by a CIHR Postdoctoral Fellowship Awardand has received research support from the CIHR, the Calorie Control Council,the Canadian Foundation for Dietetic Research and The Coca-Cola Company(investigator initiated, unrestricted grant). RJdS has served as an externalresource person to WHO’s Nutrition Guidelines Advisory Group and receivedtravel support from the WHO to attend group meetings. RJdS is the leadauthor of systematic reviews and meta-analyses commissioned by the WHOon the relation of SFAs and trans-fatty acids with health outcomes. LSAA hasreceived an honorarium from the Nutrition Foundation of Italy (NFI) toco-organise a glycaemic index summit. ARM is currently consultant forJansen/Johnson and Johnson. JLS has received research support from theCIHR, American Society of Nutrition (ASN), Canadian Diabetes Association(CDA), Banting & Best Diabetes Centre (BBDC), Calorie Control Council, TheCoca-Cola Company (investigator initiated, unrestricted), Dr Pepper SnappleGroup (investigator initiated, unrestricted), Pulse Canada and the InternationalTree Nut Council Nutrition Research and Education Foundation. He hasreceived travel funding, speaker fees and/or honoraria from American HeartAssociation (AHA), American College of Physicians (ACP), ASN, NationalInstitute of Diabetes and Digestive and Kidney Diseases (NIDDK) of theNational Institutes of Health (NIH), CDA, CNS, University of South Carolina,University of Alabama at Birmingham, Oldways Preservation Trust, NFI,Calorie Control Council, Diabetes and Nutrition Study Group of the EuropeanAssociation for the Study of Diabetes (EASD), International Life SciencesInstitute (ILSI) North America, ILSI Brazil, Abbott Laboratories, Pulse Canada,Canadian Sugar Institute, Dr Pepper Snapple Group, The Coca-Cola Company,Corn Refiners Association, World Sugar Research Organization, Dairy Farmersof Canada and Società Italiana di Nutrizione Umana (SINU). He has consultingarrangements with Winston & Strawn LLP, Perkins Coie LLP and Tate & Lyle.He is on the Clinical Practice Guidelines Expert Committee for NutritionTherapy of the CDA and EASD, as well as being on an ASN writing panel for ascientific statement on sugars. He is a member of the InternationalCarbohydrate Quality Consortium (ICQC) and Board Member of the Diabetesand Nutrition Study Group of the EASD. He serves an unpaid scientificadvisor for the International Life Science Institute (ILSI) North America, Food,Nutrition, and Safety Program (FNSP) and the Committee on Carbohydrates.His wife is an employee of Unilever Canada. CWCK has received researchgrants, travel funding, consultant fees, honoraria and served on the scientificadvisory board for Abbott Laboratories, Advanced Food Materials Network,Agriculture and Agri-Food Canada (AAFC), Almond Board of California,American Peanut Council, American Pistachio Growers, Barilla, Bayer,California Strawberry Commission, Calorie Control Council, CIHR, CanolaCouncil of Canada, The Coca-Cola Company, Danone, General Mills, HainCelestial, International Nut and Dried Fruit Council, International Tree NutCouncil Nutrition Research and Education Foundation, Kellogg, Kraft, LoblawBrands Ltd, NFI, Oldways Preservation Trust, Orafti, Paramount Farms, PeanutInstitute, Pepsi-Co, Pulse Canada, Sabra Dipping Co., Saskatchewan PulseGrowers, Solae, Sun-Maid, Tate & Lyle, Unilever and White Wave Foods. He ison the Dietary Guidelines Committee for the Diabetes Nutrition Study Groupof the European Association for the Study of Diabetes. DJAJ has receivedresearch grants from Saskatchewan Pulse Growers, the AgriculturalBioproducts Innovation Program through the Pulse Research Network, theAdvanced Foods and Material Network, Loblaw Companies Ltd., Unilever,Barilla, the Almond Board of California, Agriculture and Agri-food Canada,Pulse Canada, Kellogg’s Company, Canada, Quaker Oats, Canada, Procter &Gamble Technical Centre Ltd., Bayer Consumer Care, Springfield, New Jersey,Pepsi/Quaker, International Nut & Dried Fruit (INC), Soy Foods Association ofNorth America, the Coca-Cola Company (investigator initiated, unrestrictedgrant), Solae, Haine Celestial, the Sanitarium Company, Orafti, theInternational Tree Nut Council Nutrition Research and Education Foundation,the Peanut Institute, the Canola and Flax Councils of Canada, the CCC, the

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CIHR, the Canada Foundation for Innovation and the Ontario Research Fund.He has been on the speaker’s panel, served on the scientific advisory boardand/or received travel support and/or honoraria from the Almond Board ofCalifornia, Canadian Agriculture Policy Institute, Loblaw Companies Ltd, theGriffin Hospital (for the development of the NuVal scoring system, theCoca-Cola Company, EPICURE, Danone, Saskatchewan Pulse Growers,Sanitarium Company, Orafti, the Almond Board of California, the AmericanPeanut Council, the International Tree Nut Council Nutrition Research andEducation Foundation, the Peanut Institute, Herbalife International, PacificHealth Laboratories, Nutritional Fundamental for Health, Barilla, Metagenics,Bayer Consumer Care, Unilever Canada and Netherlands, Solae, Kellogg,Quaker Oats, Procter & Gamble, the Coca-Cola Company, the Griffin Hospital,Abbott Laboratories, the Canola Council of Canada, Dean Foods, the CaliforniaStrawberry Commission, Haine Celestial, PepsiCo, the Alpro Foundation,Pioneer Hi-Bred International, DuPont Nutrition and Health, SpherixConsulting and WhiteWave Foods, the Advanced Foods and Material Network,the Canola and Flax Councils of Canada, the Nutritional Fundamentals forHealth, Agri-Culture and Agri-Food Canada, the Canadian Agri-Food PolicyInstitute, Pulse Canada, the Saskatchewan Pulse Growers, the Soy FoodsAssociation of North America, the NFI, Nutra-Source Diagnostics, theMcDougall Program, the Toronto Knowledge Translation Group (St. Michael’sHospital), the Canadian College of Naturopathic Medicine, The Hospital forSick Children, the Canadian Nutrition Society (CNS), the ASN, Arizona StateUniversity, Paolo Sorbini Foundation and the Institute of Nutrition, Metabolismand Diabetes. He received an honorarium from the US Department ofAgriculture to present the 2013 W.O. Atwater Memorial Lecture. He receivedthe 2013 Award for Excellence in Research from the International Nut andDried Fruit Council. He received funding and travel support from the CanadianSociety of Endocrinology and Metabolism to produce mini cases for the CDA.He is a member of the ICQC. His wife, Alexandra L Jenkins, is a director andpartner of Glycemic Index Laboratories, Inc., and his sister received fundingthrough a grant from the St. Michael’s Hospital Foundation to develop acookbook for one of his studies.

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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