ORIGINAL RESEARCH

Rationale, Design, and Baseline Characteristicsof the Utopia Trial for Preventing DiabeticAtherosclerosis Using an SGLT2 Inhibitor:A Prospective, Randomized, Open-Label, Parallel-Group Comparative Study

Naoto Katakami . Tomoya Mita . Hidenori Yoshii . Toshihiko Shiraiwa . Tetsuyuki Yasuda . Yosuke Okada .

Yutaka Umayahara . Hideaki Kaneto . Takeshi Osonoi . Tsunehiko Yamamoto . Nobuichi Kuribayashi .

Kazuhisa Maeda . Hiroki Yokoyama . Keisuke Kosugi . Kentaro Ohtoshi . Isao Hayashi . Satoru Sumitani .

Mamiko Tsugawa . Makoto Ohashi . Hideki Taki . Tadashi Nakamura . Satoshi Kawashima . Yasunori Sato .

Hirotaka Watada . Iichiro Shimomura . On behalf of the UTOPIA study investigators

Received: July 20, 2017 / Published online: September 1, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Introduction: Sodium-glucose co-transporter-2(SGLT2) inhibitors are anti-diabetic agents thatimprove glycemic control with a low risk ofhypoglycemia and ameliorate a variety of car-diovascular risk factors. The aim of the ongoingstudy described herein is to investigate the

preventive effects of tofogliflozin, a potent andselective SGLT2 inhibitor, on the progression ofatherosclerosis in subjects with type 2 diabetes(T2DM) using carotid intima-media thickness(IMT), an established marker of cardiovasculardisease (CVD), as a marker.Methods: The Study of Using Tofogliflozin forPossible better Intervention against Atheroscle-rosis for type 2 diabetes patients (UTOPIA) trialis a prospective, randomized, open-label,blinded-endpoint, multicenter, and paral-lel-group comparative study. The aim was torecruit a total of 340 subjects with T2DM but nohistory of apparent CVD at 24 clinical sites andrandomly allocate these to a tofogliflozin treat-ment group or a conventional treatment group

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Electronic supplementary material The onlineversion of this article (doi:10.1007/s13300-017-0292-1)contains supplementary material, which is available toauthorized users.

N. Katakami (&) � I. ShimomuraDepartment of Metabolic Medicine, OsakaUniversity Graduate School of Medicine, 2-2,Yamadaoka, Suita, Osaka 565-0871, Japane-mail: katakami@endmet.med.osaka-u.ac.jp

N. KatakamiDepartment of Metabolism and Atherosclerosis,Osaka University Graduate School of Medicine, 2-2,Yamadaoka, Suita, Osaka 565-0871, Japan

T. Mita � H. WatadaDepartment of Metabolism and Endocrinology,Juntendo University Graduate School of Medicine,Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan

H. YoshiiDepartment of Medicine, Diabetology andEndocrinology, Juntendo Tokyo Koto GeriatricMedical Center, Koto-ku, Tokyo 136-0075, Japan

T. ShiraiwaShiraiwa Medical Clinic, 4-10-24 Hozenji, KashiwaraCity, Osaka 582-0005, Japan

T. YasudaDepartment of Endocrinology and Metabolism,Osaka Police Hospital, 10-31, Kitayama-cho,Tennoji-ku, Osaka 543-0035, Japan

Diabetes Ther (2017) 8:999–1013

DOI 10.1007/s13300-017-0292-1

using drugs other than SGLT2 inhibitors. Asprimary outcomes, changes in mean and max-imum IMT of the common carotid artery duringa 104-week treatment period will be measuredby carotid echography. Secondary outcomesinclude changes in glycemic control, parame-ters related to b-cell function and diabeticnephropathy, the occurrence of CVD andadverse events, and biochemical measurementsreflecting vascular function.Conclusion: This is the first study to address theeffects of SGLT2 inhibitors on the progression ofcarotid IMT in subjects with T2DM without ahistory of CVD. The results will be available inthe very near future, and these findings areexpected to provide clinical data that will behelpful in the prevention of diabeticatherosclerosis and subsequent CVD.Funding: Kowa Co., Ltd.Clinical Trial Registration: UMIN000017607.

Keywords: Atherosclerosis; Diabetes;Intima-media thickness; SGLT2 inhibitor;Tofogliflozin

INTRODUCTION

Atherosclerotic cardiovascular disease (CVD),which is accelerated in patients with prolongeddiabetes, impairs quality of life and is a majorcause of mortality [1, 2]. Several studies haveshown that abnormal glycemic metabolism playsan important role in the pathogenesis ofatherosclerosis and that poor glycemic controlaccelerates the risk forCVD in subjectswith type2diabetes mellitus (T2DM) [3]. However, recentstudies have cast doubt on the benefits of enforc-ing strict glycemic control on CVD in patientswith established atherosclerosis or longstandingT2DM [4–6] due to attenuation of the beneficialeffects of the former by an increased incidence ofhypoglycemic episodes [7, 8]

T2DM is often closely related with insulinresistance and accompanied by other cardio-vascular (CV) risk factors, such as obesity,hypertension, and dyslipidemia. Thus, earlyand comprehensive medical intervention toaddress these risk factors has been shown to bean effective strategy to prevent the develop-ment of diabetic CVD [9, 10]. Taking into

Y. OkadaFirst Department of Internal Medicine, School ofMedicine, University of Occupational andEnvironmental Health, Japan, 1-1, Iseigaoka,Yahatanishi-ku, Kitakyushu 807-8555, Japan

Y. UmayaharaDepartment of Diabetes and Endocrinology, OsakaGeneral Medical Center, 3-1-56, Bandai-Higashi,Sumiyoshi-ku, Osaka 558-8558, Japan

H. KanetoDepartment of Diabetes, Endocrinology andMetabolism, Kawasaki Medical School, 577Matsushima, Kurashiki, Okayama 701-0192, Japan

T. OsonoiNakakinen Clinic, 745-5, Nakadai, Naka City,Ibaraki 311-0113, Japan

T. YamamotoDiabetes and Endocrinology, Kansai Rosai Hospital,3-1-69, Inabaso, Amagasaki city, Hyogo, Japan

N. KuribayashiMisaki Naika Clinic, 6-44-9, Futawa-higashi,Funabashi City, Chiba, Japan

K. MaedaKitasenri Maeda Clinic, 4-119, Furuedai, Suita,Osaka 565-0874, Japan

H. YokoyamaJiyugaoka Medical Clinic, West 6, South 6-4-3,Obihiro, Hokkaido 080-0016, Japan

K. KosugiKosugi Medical Clinic, 3-9, Tamatsukurimoto-cho,Tennoji-ku, Osaka 543-0014, Japan

K. OhtoshiOtoshi Medical Clinic, 8-47, Kakudacho, OsakaKita-ku, Osaka 530-0017, Japan

I. HayashiHayashi Clinic, 3-9-23 Koshienguchi, Nishinomiya,Hyogo 663-8113, Japan

S. SumitaniCenter for Diabetes and Endocrinology, NissayHospital, 6-3-8, Itachibori, Nishi-ku, Osaka550-0012, Japan

M. TsugawaDepartment of Endocrinology and Metabolism,Ikeda Municipal Hospital, 3-1-18, Jonan, Ikeda,Osaka 563-8510, Japan

M. OhashiCenter for Diabetes Mellitus, Osaka Rosai Hospital,1179-3 Nagasone-cho, Kita-ku, Sakai, Osaka591-8025, Japan

1000 Diabetes Ther (2017) 8:999–1013

account the multifaceted pathogenesis of CVDin diabetes, it would be an advantage to have aspecific intervention which could attenuate CVrisk in a multi-dimensional fashion beyondglycemic control alone.

Sodium-glucose cotransporter 2 (SGLT2)inhibitors are a new class of anti-diabetic agentsthat lower blood glucose concentrations byenhancing urinary glucose excretion [11].Although they lack direct action on insulinsecretion from b-cells, it is expected that theirglucose-lowering effect will reduce glucotoxic-ity and improve b-cell function and insulinsensitivity in subjects with T2DM [12–15]. Sincethe mode of action of SGLT2 inhibitors isindependent of insulin secretion, these agentsare associated with a low risk of hypoglycemia,which is linked to an increased of CV events[7, 8, 16]. They have also been demonstrated toameliorate a variety of CV risk factors andpotential pathways: these agents, as monother-apy or in combination with other glucose-low-ering drugs, reduce visceral adipose tissue, bodyweight, blood pressure, and circulating uric acidlevels as well as improve serum lipid profiles[17]. These findings indicate a strong rationalefor expecting that these compounds will protectagainst CV events.

Indeed, the EMPA-REG OUTCOME trial, aclinical trial designed to clarify the effects of theSGLT2 inhibitor empagliflozin on clinical CVoutcomes in patients with T2DM and estab-lished CV manifestations, showed that thisagent markedly reduced the risk of CV mortality

compared to placebo [18]. Interestingly, how-ever, although CV mortality and worseningheart failure were dramatically decreased,empagliflozin treatment failed to reducemacrovascular events, such as non-fatalmyocardial infarction and stroke. Thus, clinicalevidence regarding the therapeutic effect ofSGLT2 inhibitors on atherosclerosis in patientswith diabetes remains to be established.

Tofogliflozin is an SGLT2 inhibitor with2900-fold greater selectivity for SGLT2 thanSGLT1 and the highest selectivity of all clini-cally developed inhibitors [19]. These charac-teristics suggest that this agent provides efficacywith a low risk of hypoglycemia since glucose isreabsorbed by SGLT1 at a low plasma glucoselevel. This potent selectivity would also con-tribute to relatively fewer adverse events (AEs)compared to other SGLT2 inhibitors [20].

The efficacy and safety of tofogliflozin as ahypoglycemic agent have been assessed inclinical trials. A multicenter, placebo-con-trolled, randomized, double-blind paral-lel-group study involving 230 Japanese T2DMpatients with inadequate glycemic control ondiet/exercise therapy demonstrated that tofo-gliflozin 10, 20, or 40 mg administered orallyonce daily for 24 weeks significantly decreasedglycated hemoglobin (HbA1c), fasting bloodglucose, and body weight compared to placebo[21]. A body weight reduction may be associatedwith a compensatory reduction of visceral fatresulting from the loss of calories followingincreased urinary glucose excretion [22]. Tofo-gliflozin also tended to reduce blood pressure toa greater extent than placebo and improvedhigh-density lipoprotein (HDL) cholesterollevels and triglyceride levels [21]. A slightdecrease in uric acid was also observed [21]. Inaddition, the incidence of hypoglycemia waslow, and most AEs were classified as mild ormoderate [21]. Another article on two phase 3multicenter open-label randomized controlledtrials in Japanese patients with T2DM alsoreported that tofogliflozin was well toleratedand showed sustained efficacy when patientswere treated with 20 or 40 mg tofogliflozin asmonotherapy or in combination with other oralantidiabetic agents for 52 weeks [23]. Thesefindings indicate that tofogliflozin may

H. TakiDiabetes Center, National Hospital OrganizationOsaka National Hospital, 2-1-14, Hoenzaka,Chuo-ku, Osaka 540-0006, Japan

T. NakamuraDepartment of Internal Medicine, KawasakiHospital, 3-3-1, Higashiyamacho, Kobe Hyogo-ku,Hyogo 652-0042, Japan

S. KawashimaKanda Naika Clinic, 5-21-3, Hannancho, OsakaAbeno-ku, Osaka 545-0021, Japan

Y. SatoDepartment of Global Clinical Research, GraduateSchool of Medicine, Chiba University, 1-8-1Inohana, Chuo-ku, Chiba 260-8677, Japan

Diabetes Ther (2017) 8:999–1013 1001

ameliorate some of the metabolic abnormalitiesassociated with T2DM.

However, to date, no study has evaluated thelong-term anti-atherosclerotic effects of tofo-gliflozin in patients with T2DM. Therefore, weinitiated a multicenter randomized controlledtrial to investigate the preventive effects oftofogliflozin on the progression of atheroscle-rosis in subjects with T2DM but without a his-tory of apparent CV events, with patients nottreated with tofogliflozin as the control group.In this ongoing trial, an assessment will beperformed by chronologically observing thepreventive effects of tofogliflozin on the pro-gression of intima-media thickness (IMT) of thecarotid artery, a surrogate endpoint ofatherosclerosis [24, 25].

METHODS

Study Design

The Study of Using Tofogliflozin for Possiblebetter Intervention against Atherosclerosis fortype 2 diabetes patients (UTOPIA) trial is aprospective, randomized, open-label,blinded-endpoint, multicenter, and paral-lel-group comparative study. This study hasbeen registered on the University HospitalMedical Information Network Clinical TrialsRegistry (UMIN-CTR), a non-profit organizationin Japan, and meets the requirements of theInternational Committee of Medical JournalEditors (UMIN000017607).

Study Population

Japanese subjects with T2DM who periodicallyattended an outpatient diabetes clinic of one of24 institutions in Japan (see Electronic Supple-mentary Material Table) were recruited to thestudy. The inclusion and exclusion criteria wereas follows:

Inclusion Criteria1. Japanese patients with T2DM and inade-

quate glycemic control (HbA1c C6% but\9%) but with an inability to achieve the

blood glucose level stated in the DiabetesTreatment Guideline of 2014–2015 despitereceiving medication, but not SGLT2 inhi-bitors, combined with diet and physicaltherapy, those on a specific diet and physi-cal therapy only for at least 12 weeks, orthose who received SGLT2 inhibitors in thepast but who had not used SGLT2 inhibitorsfor at least 12 weeks before signing theconsent form.

2. No changes (including new prescriptions)in their antidiabetic, antithrombotic, anti-hypertensive medication or a therapeuticagent for dyslipidemia for at least 12 weeksbefore signing their consent form.

3. Age 30–74 years at the time of givingconsent.

4. Able to provide informed consent.

Exclusion Criteria1. Type 1 or secondary diabetes.2. In the perioperative period or with a

serious infection or injury.3. A history of myocardial infarction, angina,

stroke, or cerebral infarction.4. Severe renal dysfunction or end-stage

renal failure (estimated glomerular filtra-tion rate\30 mL/min/1.73 m2).

5. Serious liver functional impairment (as-partate aminotransferase C100 U/L).

6. Moderate to severe heart failure (class 3 orworse based on the New York Heart Asso-ciation Functional Classification).

7. Urinary tract or genital infection.8. Pregnant, possibly pregnant, nursing, or

planning to conceive a child.9. History of hypersensitivity to the study

drug.10. Present or past history of a malignant

tumor (exceptions: those not on medica-tion for malignant tumor and with norecurrence of the disease to date andwithout recurrence risks during this studywere allowed to participate).

11. Prohibited to use tofogliflozin.12. Other ineligibility determined by an

investigator.Screening of the study subjects was performedconsecutively, and the patients who met theeligibility criteria were asked whether they

1002 Diabetes Ther (2017) 8:999–1013

could participate. All of the patients who agreedto participate were registered.

Randomization and Study Intervention

Patient registration occurred via the Internetthrough the administration office of the UTO-PIA trial; once enrolled, the subjects were ran-domly and equally assigned to a tofogliflozintreatment group (group A) or a conventionaltreatment group (group B), with those in thelatter group using drugs other than SGLT2inhibitors. The randomization was performedusing a dynamic allocation method based oninsulin use/non-use, age, and sex.

Treatment is to be continued to achieve thetarget value specified in the treatment guide fordiabetes [26] (generally an HbA1c of\6.9%) inall patients. In the conventional treatmentgroup, either the dosage of current therapy is tobe increased or a concomitant oral glu-cose-lowering drug (excluding the other SGLT2inhibitors) is be added 12 weeks after random-ization. In the tofogliflozin group, tofogliflozin

20 mg is to be administered orally once daily.However, the addition of an alternativeanti-diabetic agent (excluding another SGLT2inhibitor) is be permitted 12 weeks after ran-domization. In the case of hypoglycemia, thedosage of the concomitant oral glucose-lower-ing drug will be titrated. Anti-hyperlipidemicand anti-hypertensive drugs may be used duringthe study (Fig. 1).

Observation Items and Schedule

The observation items and schedule are shownin Table 1 and Fig. 1. The study period will be2 years after subject registration (registrationperiod: January to November 2016; full studyduration March 2015 to September 2019). Allrandomized participants are to be followeduntil the scheduled study end regardless ofadherence to or discontinuation of study med-ication for any reason. Clinical outcomes,adherence, and AEs will be ascertained, andclinical and biochemical data are to be collected

Fig. 1 Flow chart showing the study schedules. SGLT2 Sodium-glucose cotransporter 2, IMT intima-media thickness,QOL quality of life, opt. optional

Diabetes Ther (2017) 8:999–1013 1003

at 0, 26, 52, 78, and 104 weeks afterrandomization.

Study Outcomes

Primary study outcomes are the changes inmean IMT of the common carotid artery

(mean-IMT-CCA) and maximum IMT of theCCA (max-IMT-CCA) during the 104-weektreatment period measured by carotid arterialechography. The change in the mean left andright mean-IMT-CCA is preliminarily defined asthe most primary outcome in this study.Investigations will be performed at the start of

Table 1 Observation items and study schedule

Observationitems

Schedule

Registration Treatment period AtdiscontinuationVisit 1 (212

to 0 weeksVisit 2(0 weeks)

Visit 3(26 weeks)

Visit 4(52 weeks)

Visit 5(78 weeks)

Visit 6(104 weeks)

Patient

characteristics

s

Body weight,

BMI, and AC

s s s s s s

Blood pressure s s s s s s

Blood and urine

testsas s s s s s

Specific blood

chemistrybs s s s

Carotid IMTc s s s s

Vascular

function testds s s s

QOL scorese s s s s s

Adherence s s s s s

Adverse events s s s s s s

BMI Body mass index, AC abdominal circumference, IMT intima-media thickness, QOL quality of lifea HbA1c (glycated hemoglobin), red blood cells, white blood cells, hemoglobin, hematocrit, blood platelet count, aspartateaminotransferase, alanine aminotransferase, c-glutamyl transferase, serum creatinine, uric acid, total cholesterol, high-densitylipoprotein cholesterol, triglyceride, low-density lipoprotein cholesterol, fasting plasma glucose, amylase, spot urine, urinarymicroalbumin and urinary creatinine are measuredb C-peptide, fasting insulin, remnant-like particle cholesterol, high-sensitivity C-reactive protein, adiponectin, eicosapen-taenoic acid/arachidonic acid ratio, N terminal-pro B-type natriuretic peptide, glycosylphosphatidylinositol-specific phos-pholipase D, T-cadherin and adiponectin-C1q complex are measuredc Mean IMT, maximum IMT, and blood vessel diameter for both sides are measuredd Optional brachial-ankle pulse wave velocity (baPWV) and ankle brachial blood pressure index (ABI) are assessed inselected sitese Optional psychological attitudes of subjects with type 2 diabetes mellitus (T2DM) toward their diabetic therapy arequantified using the Diabetes Therapy-Related Quality of Life Questionnaire 7 (DTR-QOL7) scoress Examinations were scheduled

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the study, after 52 weeks, after 104 weeks, andat the time of any discontinuations or dosagechanges.

Secondary outcomes are the changes in (1)parameters related to glycemic control andb-cell function (HbA1c, fasting plasma glucose,serum C-peptide, immunoreactive insulin,homeostasis model assessment insulin resis-tance (HOMA-R) and beta-cell function(HOMA)-b, and intact proinsulin/insulin ratio;(2) parameters related to diabetic nephropathy,including serum creatinine levels, urinaryalbumin excretion, and estimated glomerularfiltration rate; (3) lipid parameters (totalcholesterol, HDL cholesterol, triglyceride,low-density lipoprotein cholesterol, rem-nant-like particle lipoprotein, and eicosapen-taenoic acid to arachidonic acid ratio); (4)biochemical measurements, includinghigh-sensitivity C-reactive protein, adipo-nectin, C1q–adiponectin complex, T-cadherin,glycosyl phosphatidyl inositol-specific phos-pholipase D, and N-terminal pro–brain natri-uretic peptide; (5) occurrence of CV events,including sudden death, ischemic heart dis-ease, cerebral vascular disease, and peripheralartery disease; (6) any AEs; and (7) changes intreatment-related mental status. In addition,(8) subsets of consenting individuals in selec-ted sites are enrolled in sub-studies assessingthe effect of the interventions on brachial-an-kle pulse wave velocity and ankle brachialblood pressure index.

Safety Evaluation

The details and incidence of adverse events areto be periodically ascertained. Based on theintention to treat the entire population, safetywill be checked by recording the AEs. When theinvestigators confirm AEs, the severity grade,procedures, outcomes, and relationship to thestudy agent will be assessed. A prompt report tothe study secretariat and to the data and safetymonitoring board (DSMB) will then be made bythe trial organizer. Any withdrawals from thestudy will be also reported promptly to theDSMB by the chief investigator. The DSMB will

then deliberate on the incident and report thedecision to the chief investigator.

Measurement of Carotid IMT

Ultrasonography scans of the carotid artery areto be performed by expert sonographers whoare specifically trained to perform the prescribedstudy examination. To avoid inter-sonographervariability, each participant will be examined bythe same sonographer with the same equipment[high-resolution B-mode ultrasound scannerequipped with a high-frequency ([7.5-MHz)linear transducer and a limit of detection of\0.1 mm] during all visits. Scanning of theextracranial CCA, the carotid bulb (Bul), andthe internal carotid artery (ICA) in the neck isperformed bilaterally in at least three differentlongitudinal projections (anterior, lateral, andposterior, which approximately correspond to60�, 90�, and 150� for the right carotid arteryand 210�, 270�, and 300� for the left carotidartery, marked on Meijer’s arc) as well as intransverse projections, and the site of greatestthickness, including plaque lesions, is soughtalong the arterial walls. In this study, localizedelevated lesions with a maximum thickness of[1 mm, having a point of inflection on thesurface of the intima-media complex, aredefined as ‘‘carotid plaque’’ based on theguideline of the Japan Society of Ultrasonics inMedicine [27]. The IMT is measured as the dis-tance between two parallel echogenic linescorresponding to the vascular lumen and theadventitial layer.

To avoid inter-reader variability, all scans areto be electronically stored, sent to the centraloffice (IMT Evaluation Committee, Osaka,Japan), and read by a single experienced readerblind to the subject’s clinical characteristics in arandom order using automated digital edge-de-tection software (Intimascope; MediaCross,Tokyo, Japan) [28]. The software system aver-ages about 200 points of IMT values in thesegment 2 cm proximal to the dilation of thecarotid Bul (mean-IMT-CCA). In addition, thegreatest thicknesses of the IMT, including pla-que lesions in the CCA (max-IMT-CCA), Bul

Diabetes Ther (2017) 8:999–1013 1005

(max-IMT-Bul), and ICA (max-IMT-ICA), aremeasured separately.

Sample Size

The mean [± standard deviation (SD)] progres-sion of carotid IMT in diabetic patients is con-sidered to be 0.034 ± 0.054 mm/year; a 1%improvement in the HbA1c value is consideredto achieves a 0.02 mm/year improvement inIMT [29]. Therefore, in a 2-year observationperiod, the registration of at least 310 patients isrequired to obtain 90% power to detect a dif-ference of 0.04 mm in IMT between the twotreatment groups, assuming an SD of 0.108 mmfor individual differences (which was presumedto be common to both groups), a 10% dropout,and a 0.05 level of significance. The dropoutrate during the 2-year observation period isassumed to be 10%. According to this calcula-tion, the target number of enrolled patients wasset at 340 (170 in each group) for the 2-yearregistration period.

Analysis Population

All allocated participants except for those forwhom IMT values are not measured at all dur-ing the observation period will be analyzedregardless of adherence using an intent-to-treatapproach.

Statistical Analysis

Analyses of the primary and secondary end-points are to be performed in the full analysisset, which will include all participants whoreceived at least one treatment dose during thestudy period and who did not seriously violatethe study protocol, such as by not providinginformed consent or registering outside thestudy period. The primary analysis comparingtreatment effects and the baseline-adjustedmeans and their 95% confidence intervals esti-mated by analysis of covariance of the changesin mean and maximum IMT at 104 weeks willbe compared between the treatment groups.The results will be adjusted by allocation fac-tors. The primary analysis will not include

missing observations, with the mixed-effectsmodel for repeated measures (MMRM) beingused as a sensitivity analysis to examine theeffect of the missing data. In addition, MMRMwill be used as a sensitivity analysis to examinethe outcomes at baseline and 104 weeks mod-eled as a function of time, treatment, andtreatment-by-time interactions. The secondaryanalysis will be performed in the same manneras the primary analysis.

All comparisons are planned and all p valueswill be two-sided. P values of\0.05 will beconsidered to be statistically significant. Allstatistical analyses will be performed using SASsoftware version 9.4 (SAS Institute, Cary, NC).The statistical analysis plan will be developed bythe principal investigator and a biostatisticianbefore the completion of patient recruitmentand database locking.

Compliance with Ethics Guidelines

The protocol was approved by the institutionalreview board at each participating institution incompliance with the Declaration of Helsinkiand current legal regulations in Japan. Thestudy will be conducted in accordance with theEthical Guidelines for Medical and HealthResearch Involving Human Subjects publishedby the Ministry of Health, Labour and Welfareof Japan and the Helsinki Declaration of 1964,as revised in 2013. Written informed consentfor participation and publication was obtainedfrom all the participants after a full explanationof the study was provided.

Trial Organization

The UTOPIA trial was designed by the principalinvestigators (Iichiro Shimomura, OsakaUniversity Graduate School of Medicine, Osaka,Japan and Hirotaka Watada, Juntendo Univer-sity School of Medicine, Tokyo, Japan) throughthe UTOPIA Project Office based at the Depart-ment of Metabolic Medicine, Osaka UniversityGraduate School of Medicine, Osaka, Japan. Theprincipal investigators are responsible for allaspects of trial management, including collect-ing and cleaning all data, handling all

1006 Diabetes Ther (2017) 8:999–1013

protocol-related issues, monitoring and opti-mizing adherence to interventions, adjudicat-ing outcomes, auditing the study progress, anddetermining, executing, and publishing thefinal study analysis. We also have an IMT Eval-uation Committee and a Clinical Events Com-mittee, which are independent of this trial; theformer is as described in the ‘‘Measurement ofCarotid IMT’’ section, while the latter is com-posed of two cardiologists and one neurologist.

RESULTS

Between January 2016 and November 2016, 340participants were recruited at 24 clinical sitesand randomly allocated either to tofogliflozintreatment group (group A, 169 patients) or aconventional treatment group (group B, 171patients) using drugs other than SGLT2inhibitors.

CONCLUSION

Many clinical studies have shown that HbA1clevel is associated with the risk of CVD inpatients with T2DM [3]; consequently, themanagement of glucose levels represents one ofthe principal treatment goals of diabetes therapy.However, despite the legacy effect of long-termintensive glycemic intervention [30–32], recentstudies have cast doubt on the benefits of strictglycemic control on CVD in patients withestablished atherosclerosis or longstandingT2DM [4–6], with attenuation of the beneficialeffects of glycemic control likely due to theincreased incidence of hypoglycemic episodes[7, 8]. In addition, since early and comprehen-sive medical intervention for the accompanyingCV risk factors, such as obesity, hypertension,and dyslipidemia, has been shown to effectivelyprevent the development of diabetic CVD[9, 10], early medical intervention using a com-prehensive approach beyond glycemic controlalone would be an advantage.

SGLT2 inhibitors are oral anti-diabetic agentsthat have the potential to improve glycemiccontrol with a low risk of hypoglycemia. Thisclass of agents has also been demonstrated to

ameliorate a variety of CV risk factors via itsmetabolic, hemodynamic, renal, and neuro-hormonal effects [17, 33]. In addition, anincrease in blood ketone bodies is frequentlydetected in patients receiving SGLT2 inhibitortreatment, considered to be due to an increasein lipolysis and mobilization of lipids/free fattyacids to compensate for glucose loss via theurine. Although the effect of such an increase inblood ketone bodies on safety is unknown, theketone metabolite b-hydroxybutyrate may pre-vent the progression of atherosclerosis byblocking danger signaling in vascular cells. Theactivation of the NOD-like receptor family pyrindomain-containing 3 (NLRP3) inflammasome isrequired for caspase-1 to convert inactivepro-interleukin (IL)-1beta and pro-IL-18 intotheir bioactive and secreted forms as crucialmediators of inflammation in the vessel wall[34]. It has recently been reported that b-hy-droxybutyrate blocks NLRP3 inflamma-some-mediated inflammation [35]. Consideringthe pleiotropic anti-atherogenic effect of SGLT2inhibitors mentioned above, they are expectedto inhibit the progression of atherosclerosis.

We projected their results of several clinicalCV outcome trials of SGLT2 inhibitors indesigning our study to address the clinicallyimportant question of whether SGLT2 inhibi-tors can accomplish the elusive goal of ananti-diabetic agent, such as reducing the inci-dence of CVD [18, 36]. Among these, the resultsof the EMPA-REG OUTCOME trial, which wasdesigned to clarify the effects of the SGLT2inhibitor empagliflozin on clinical CV safety inpatients with T2DM and established CV mani-festations, have been published. This trialshowed that empagliflozin markedly reducedthe risk of CV mortality compared to placebo,but there was no significant risk reduction ofmacrovascular complications, such as non-fatalmyocardial infarction and stroke, suggestingthat possible mechanisms may be largelyhemodynamic effects induced by glycosuriaand natriuresis rather than a directanti-atherothrombotic effect [18, 37–39]. Thus,at this point in time, no study has demonstratedthat SGLT2 inhibitors prevent the developmentof atherosclerosis in patients with T2DM. Inaddition, to the best of our knowledge, very few

Diabetes Ther (2017) 8:999–1013 1007

clinical trials have investigated whether SGLT2inhibitors can prevent the development ofatherosclerosis in subjects with T2DM but noapparent CVD.

The UTOPIA trial is a multicenter, prospec-tive, randomized, investigator-initiated clinicaltrial with the aim to investigate the preventiveeffects of tofogliflozin, a potent and selectiveSGLT2 inhibitor, on the progression ofatherosclerosis in subjects with T2DM butwithout a history of apparent atheroscleroticdisease, using common carotid IMT, a widelyused surrogate marker of atherosclerosis, as theprimary endpoint. We use surrogate endpointsfor this trial due to many practical constraints,including trial costs and concern regarding thefeasibility of performing long-term interven-tion. Carotid ultrasound measurements of IMThave been validated against pathologic speci-mens and demonstrated to be strong predictorsof CV events in subjects with and withoutT2DM [40, 41]. It has also been shown thatchanges in carotid IMT over time correlate withrates of future CV events [42]. Therefore, severalclinical studies have assessed the inhibitoryeffects of a variety class of anti-diabetic agents(e.g. biguanides, thiazolidinediones, alpha-glu-cosidase inhibitors, and DPP-4 inhibitors) oncarotid IMT progression [43–48]. Although theUTOPIA study has a multicenter open-labeldesign, repeated IMT measurements are plan-ned in a blinded manner, and the analyses willbe performed at a core laboratory to avoid biasand measurement errors between institutions:all scans will be electronically stored and sent tothe core laboratory (IMT Evaluation Commit-tee, Osaka, Japan) and read by a single experi-enced reader unaware of the patients’ clinicalcharacteristics, in a random order using auto-mated digital edge-detection software (Intimas-cope; MediaCross) [28]. The same systematicprocedures for analyzing carotid IMT were usedin our previous studies [47, 48]. The reliabilityand reproducibility of measurements of carotidIMT has been certified in the current study.

To the best of our knowledge, no study todate has investigated the effects of SGLT2 inhi-bitors on changes in carotid IMT in diabeticsubjects. Tanaka et al. recently published theprotocol of the PROTECT study [49], the only

ongoing study to assess the preventive effect ofSGLT2 inhibitors on the progression of carotidatherosclerosis using carotid IMT as a surrogatemarker. The PROTECT study is a 24-monthprospective study in 480 Japanese subjects withT2DM, with the aim to assess the preventiveeffect of ipragliflozin, another SGLT2 inhibitor,on the progression of carotid IMT. Although theUTOPIA study design looks much like that ofthe PROTECT study, there are several differ-ences. First, the SGLT2 inhibitor used as testdrug in each study is different, with tofogli-flozin to be tested in the UTOPIA study butipragliflozin in the PROTECT study. Next, thereare several differences in the eligibility criteriabetween two studies, which could lead to thedifferences in the clinical characteristics of thestudy subjects. In particular, the UTOPIA studyexcludes patients with a history of CVD, whilethe PROTECT study does not exclude patientswith a history of CVD, although patients with ahistory of coronary artery disease, coronaryvascularization, open-heart surgery, stroke, ortransient ischemic attack B3 months prior toeligibility are excluded.

Several limitations of our study should bediscussed. First, it is not a double-blind,placebo-controlled trial but rather a prospec-tive, randomized, open blinded, endpointstudy. Although the determination of end-points is blinded and conducted by expertcommittees, medications are open-label, whichmay still induce unexpected bias. Second, it ispossible that the additional anti-diabetic agentsadministered when glycemic control becomesworse, especially in the control group, mayinfluence the outcomes. Previous studies haveshown that several classes of hypoglycemicagents, including DDP-4 inhibitors, suppressthe progression of carotid IMT [43–48]. Third,the subjects of this study are Japanese patientswith T2DM, a cohort with a relatively low CVrisk. Therefore, it would be premature to gen-eralize our findings to other racial or ethnicgroups. It should be also noted that anti-dia-betic agent prescribing in patients with T2DMin Japan is somewhat different from that inWestern countries. In treatment algorithms ofT2DM in Western countries, biguanides arerecommended as first-line agents. In contrast,

1008 Diabetes Ther (2017) 8:999–1013

the treatment guideline of the Japan DiabetesSociety does not specify first-line drugs andleaves the selection of anti-diabetic agents tothe treating physicians. The guideline recom-mends selecting ‘‘glucose-lowering agents basedon the disease condition of each particularpatient with consideration given to the phar-macological and safety profile of each glu-cose-lowering agent’’.

Notwithstanding these limitations, our studyis expected to provide clinical data that will behelpful in the prevention of diabeticatherosclerosis and subsequent cardiovascularand cerebrovascular disease. This is a veryimportant objective because the worldwideincidences of diabetes and diabetic atheroscle-rosis are increasing at staggering rates, and theeconomic and social costs to the individualsand countries will grow enormously in the nearfuture. Results from this important clinical trialare planned to be published in 2019.

ACKNOWLEDGEMENTS

The authors thank all of the staff and patientparticipants of this study. The authors gratefullyacknowledge the assistance of H Yamada (Soi-ken Holdings Inc., Tokyo Japan) and Editage byCactus Communications Inc. (Tokyo Japan) forproviding editorial assistance and proofreadingthe manuscript. This assistance was funded byKowa Co., Ltd., Tokyo, Japan.

Funding information. Financial support forthis study including journal’s article processingcharges was provided by Kowa Co., Ltd., Tokyo,Japan.

Authors’ contributions. All named authorsmeet the International Committee of MedicalJournal Editors (ICMJE) criteria for authorshipfor this manuscript. All authors had full accessto all of the data in this study and take completeresponsibility for the integrity of the data andaccuracy of the data analysis, as well as for theintegrity of the work as a whole. All authorshave given final approval to the version to bepublished.

Disclosures. Naoto Katakami is a staffmember of the endowed chair (Department ofMetabolism and Atherosclerosis) established byfunds from Kowa Co., Ltd., and has receivedresearch funds from MSD and lecture fees fromAstellas Pharma Inc., AstraZeneca K.K., Boeh-ringer Ingelheim, Daiichi Sankyo Inc., Dainip-pon Sumitomo Pharma Co., Eisai Co., Eli Lilly,Kowa Pharmaceutical Co., Kyowa Hakko KirinCo. Ltd., Mitsubishi Tanabe Pharma Co.,Novartis Pharmaceuticals, Novo NordiskPharma, Ono Pharmaceutical Co., TakedaPharmaceutical Co., Sanofi-Aventis, and Shio-nogi & Co. Tomoya Mita has received lecturefees from Ono Pharmaceutical Co., Ltd., TakedaPharmaceutical Company Limited, scholarshipdonations from MSD K.K., Astellas Pharma Inc.,AstraZeneca K.K., Ono Pharmaceutical Co., Ltd.,Kyowa Hakko Kirin Co. Ltd., Sanofi-AventisK.K., Daiichi Sankyo Company, Limited,Sumitomo Dainippon Pharma Co., Ltd., TakedaPharmaceutical Company Limited, MitsubishiTanabe Pharma Corporation, Terumo Corpora-tion, Nippon Boehringer Ingelheim Co., Ltd.,Novo Nordisk Pharma Ltd., Pfizer Japan Inc.,Benefit One Health Care Inc., Mochida Phar-maceutical Co., Ltd., and Nitto Boseki Co., Ltd.as well as funds of endowed chair from MSDK.K., Takeda Pharmaceutical Company Limited.Toshihiko Shiraiwa has received lecture feesfrom Sanofi-Aventis K.K. and Takeda Pharma-ceutical Company Limited and research fund-ing from Novo Nordisk Pharma Ltd.,Sanofi-Aventis K.K., Takeda PharmaceuticalCompany Limited, AstraZeneca K.K., NipponBoehringer Ingelheim Co., Ltd., and MitsubishiTanabe Pharma Corporation. Tetsuyuki Yasudahas received lecture fees from Nippon Boehrin-ger Ingelheim Co., Ltd. and Sanofi-Aventis K.K.Yosuke Okada has received lecture fees fromAstellas Pharma Inc., MSD K.K., Ono Pharma-ceutical Co., Ltd., Mitsubishi Tanabe PharmaCorporation, Bayer Holding Ltd., NovartisPharmaceuticals Corp., Novo Nordisk PharmaLtd., Eli Lilly Japan K.K., and Kissei Pharma-ceutical Co., Ltd. as well as research fundingfrom Kowa Pharmaceutical Co. Ltd. and Mit-subishi Tanabe Pharma Corporation. HideakiKaneto has received lecture fees from NipponBoehringer Ingelheim Co., Ltd., Sanofi-Aventis

Diabetes Ther (2017) 8:999–1013 1009

K.K., Novo Nordisk Pharma Ltd., Eli Lilly JapanK.K., MSD K.K., Ono Pharmaceutical Co., Ltd.,Takeda Pharmaceutical Company Limited, Dai-ichi Sankyo Company, Limited, MitsubishiTanabe Pharma Corporation, AstraZeneca K.K.,Astellas Pharma Inc., Novartis PharmaceuticalsCorp., and Sumitomo Dainippon Pharma Co.;scholarship donations from Novo NordiskPharma Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Sumitomo Dainippon Pharma Co., Ltd.,Ono Pharmaceutical Co., Ltd., Sanofi-AventisK.K., Eli Lilly Japan K.K., Astellas Pharma Inc.,Daiichi Sankyo Company, Limited, MitsubishiTanabe Pharma Corporation, MSD K.K., TakedaPharmaceutical Company Limited, AstraZenecaK.K., Mochida Pharmaceutical Co., Ltd., TaishoToyama Pharmaceutical Co., Kissei Pharmaceu-tical Co., Ltd., and Kyowa Hakko Kirin Co. Ltd.Takeshi Osonoi has received lecture fees fromTakeda Pharmaceutical Company Limited,Astellas Pharma Inc., Novo Nordisk PharmaLtd., and Sanwa Kagaku Kenkyusho Co., Ltd.;manuscript fees from Sanwa Kagaku KenkyushoCo., Ltd.; and research funding from TakedaPharmaceutical Company Limited, Novo Nor-disk Pharma Ltd., Astellas Pharma Inc., SanwaKagaku Kenkyusho Co., Ltd., Mitsubishi TanabePharma Corporation, Nippon BoehringerIngelheim Co., Ltd., Taisho Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Com-pany, Limited, Bayer Holding Ltd., Kowa Phar-maceutical Co. Ltd., and AbbVie Inc. NobuichiKuribayashi has received lecture fees fromTakeda Pharmaceutical Company Limited,Sanofi-Aventis K.K., Novo Nordisk Pharma Ltd.,MSD K.K., and Mitsubishi Tanabe Pharma Cor-poration. Satoru Sumitani has received lecturefees from Sumitomo Dainippon Pharma Co.,Ltd. Yasunori Sato has received lecture fees fromSiemens K.K. Hirotaka Watada has receivedlecture fees from Sanofi-Aventis K.K., MSD K.K.,Astellas Pharma Inc., Takeda PharmaceuticalCompany Limited, Mitsubishi Tanabe PharmaCorporation, AstraZeneca K.K., Nippon Boeh-ringer Ingelheim Co., Ltd., Eli Lilly Japan K.K.,Novo Nordisk Pharma Ltd., Sanwa KagakuKenkyusho Co., Ltd., Kowa Co., Ltd., NovartisPharmaceuticals Corp., Daiichi Sankyo Com-pany, Limited, Kyowa Hakko Kirin Co. Ltd.,Ono Pharmaceutical Co., Ltd., and Kissei

Pharmaceutical Co., Ltd.; research funding fromNovartis Pharmaceuticals Corp., Eli Lilly JapanK.K., scholarship donations from MSD K.K.,Astellas Pharma Inc., AstraZeneca K.K., AbbotJapan Co., Ltd., Ono Pharmaceutical Co., Ltd.,Kissei Pharmaceutical Co., Ltd., Kyowa HakkoKirin Co. Ltd., Kowa Pharmaceutical Co. Ltd.,Sanofi-Aventis K.K., Sanwa Kagaku KenkyushoCo., Ltd., Johnson & Johnson K.K., DaiichiSankyo Company, Limited, Sumitomo Dainip-pon Pharma Co., Ltd., Terumo Corporation,Taisho Toyama Pharmaceutical Co., Ltd.,Takeda Pharmaceutical Company Limited,Mitsubishi Tanabe Pharma Corporation, NittoBoseki Co., Ltd., Nippon Boehringer IngelheimCo., Ltd., Novartis Pharmaceuticals Corp., NovoNordisk Pharma Ltd., Bayer Holding Ltd., PfizerJapan Inc., Bristol-Myers Squibb K.K., Benefitone Health care Inc., and Mochida Pharmaceu-tical Co., Ltd.; and funds of endowed chair fromMSD K.K. and Takeda Pharmaceutical CompanyLimited. Iichiro Shimomura has received lecturefees from Astellas Pharma Inc., AstraZenecaK.K., MSD K.K., Ono Pharmaceutical Co.,Kyowa Hakko Kirin Co., Kowa PharmaceuticalCo., Sanofi K.K., Sanwa Kagaku Kenkyusho Co.,Daiichi Sankyo Co., Takeda Pharma K.K., Mit-subishi Tanabe Pharma Co., Teijin Pharma, EliLilly Japan K.K., Nippon Boehringer IngelheimCo., Novartis Pharma K.K., Novo NordiskPharma, Bayer Yakuhin, Pfizer Japan Inc., Bris-tol-Myers K.K., Mochida Pharmaceutical Co.,Shionogi & Co., Taisho Toyama PharmaceuticalCo., and Shionogi & Co.; and research fundsfrom Astellas Pharma Inc., AstraZeneca K.K.,Eisai Co., MSD K.K, Otsuka Pharmaceutical Co.,Ono Pharmaceutical Co., Kaken PharmaceuticalCo., Kissei Pharmaceutical Co., Kyowa HakkoKirin Co., Sanofi K.K., Shionogi & Co., DaiichiSankyo Co., Dainippon Sumitomo Pharma Co.,Takeda Pharma K.K., Mitsubishi Tanabe PharmaCo., Teijin Pharma, Nippon Boehringer Ingel-heim Co., Novartis Pharma K.K., Novo NordiskPharma, Pfizer Japan Inc., Bristol-Myers K.K.,Mochida Pharmaceutical Co., Eli Lilly JapanK.K, Kowa Co., Ltd., Kowa Pharmaceutical Co.,and Taisho Toyama Pharmaceutical Co. Hide-nori Yoshii, Yutaka Umayahara, TsunehikoYamamoto, Kazuhisa Maeda, Hiroki Yokoyama,Keisuke Kosugi, Kentaro Ohtoshi, Isao Hayashi,

1010 Diabetes Ther (2017) 8:999–1013

Mamiko Tsugawa, Makoto Ohashi, Hideki Taki,Tadashi Nakamura, and Satoshi Kawashimadeclare that they have no conflict of interest.

Compliance with Ethical Guidelines. Allprocedures followed were in accordance withthe ethical standards of the responsible com-mittee on human experimentation (institu-tional and national) and with the HelsinkiDeclaration of 1964, as revised in 2013.Informed consent was obtained from allpatients for being included in the study.

Data Availability. The datasets generatedduring and/or analyzed during the currentstudy will be available from the correspondingauthor on reasonable request.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

REFERENCES

1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K,Laakso M. Mortality from coronary heart disease insubjects with type 2 diabetes and in nondiabeticsubjects with and without prior myocardial infarc-tion. N Engl J Med. 1998;339:229–34.

2. Stamler J, Vaccaro O, Neaton JD, Wentworth D.Diabetes, other risk factors, and 12-year cardiovas-cular mortality for men screened in the multiplerisk factor interventional trial. Diabetes Care.1993;16:434–44.

3. Laakso M. Glycemic control and the risk for coro-nary heart disease in patients with non-insulin-de-pendent diabetes mellitus. The finnish studies. AnnIntern Med. 1996;124:127–30.

4. Patel A, MacMahon S, Chalmers J, Neal B, Billot L,Woodward M, et al. Intensive blood glucose controland vascular outcomes in patients with type 2 dia-betes. N Engl J Med. 2008;358:2560–72.

5. Duckworth W, Abraira C, Moritz T, Reda D, Ema-nuele N, Reaven PD, et al. Glucose control andvascular complications in veterans with type 2diabetes. N Engl J Med. 2009;360:129–39.

6. Gerstein HC, Miller ME, Byington RP, Goff DC Jr,Bigger JT, Buse JB, et al. Effects of intensive glucoselowering in type 2 diabetes. N Engl J Med.2008;358:2545–59.

7. Frier BM, Schernthaner G, Heller SR. Hypoglycemiaand cardiovascular risks. Diabetes Care.2011;34[Suppl 2]:S132–7.

8. Khunti K, Davies M, Majeed A, Thorsted BL, Wol-den ML, Paul SK. Hypoglycemia and risk of car-diovascular disease and all-cause mortality ininsulin-treated people with type 1 and type 2 dia-betes: a cohort study. Diabetes Care.2015;38:316–22.

9. Gaede P, Lund-Andersen H, Parving HH, PedersenO. Effect of a multifactorial intervention on mor-tality in type 2 diabetes. N Engl J Med.2008;358:580–91.

10. Dailey G. Early and intensive therapy for manage-ment of hyperglycemia and cardiovascular riskfactors in patients with type 2 diabetes. Clin Ther.2011;33:665–78.

11. Gerich JE. Role of the kidney in normal glucosehomeostasis and in the hyperglycaemia of diabetesmellitus: therapeutic implications. Diabet Med.2010;27:136–42.

12. Jurczak MJ, Lee HY, Birkenfeld AL, Jornayvaz FR,Frederick DW, Ponqratz RL, Zhao X. SGLT2 deletionimproves glucose homeostasis and preserves pan-creatic beta-cell function. Diabetes. 2011;60:890–8.

13. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A,et al. Metabolic response to sodium-glucosecotransporter 2 inhibition in type 2 diabeticpatients. J Clin Invest. 2014;124:499–508.

14. Merovci A, Solis-Herrera C, Daniele G, Eldor R,Fiorentino TV, et al. Dapagliflozin improves muscleinsulin sensitivity but enhances endogenous glu-cose production. J Clin Invest. 2014;124:509–14.

15. Takahara M, Shiraiwa T, Matsuoka TA, Katakami N,Shimomura I. Ameliorated pancreatic b cell dys-function in type 2 diabetic patients treated with asodium-glucose cotransporter 2 inhibitor ipragli-flozin. Endocr J. 2015;62:77–86.

16. Hsu PF, Sung SH, Cheng HM, Yeh JS, Liu WL, ChanWL, et al. Association of clinical symptomatichypoglycemia with cardiovascular events and totalmortality in type 2 diabetes. Diabetes Care.2013;36:894–900.

Diabetes Ther (2017) 8:999–1013 1011

17. Vasilakou D, Karagiannis T, Athanasiadou E, et al.Sodium glucose cotransporter 2 inhibitors for type2 diabetes: a systematic review and meta-analysis.Ann Intern Med. 2013;159:262–74.

18. Zinman B, Wanner C, Lachin JM, Fitchett D,Bluhmki E, Hantel S, et al. Empagliflozin, cardio-vascular outcomes, and mortality in type 2 dia-betes. N Engl J Med. 2015;373:2117–28.

19. Suzuki M, Honda K, Fukazawa M, Ozawa K, HagitaH, Kawai T, et al. Tofogliflozin, a potent and highlyspecific sodium/glucose cotransporter 2 inhibitor,improves glycemic control in diabetic rats andmice. J Pharmacol Exp Ther. 2012;341:692–701.

20. Nagata T, Fukazawa M, Honda K, Yata T, Kawai M,Yamane M, et al. Selective SGLT2 inhibition bytofogliflozin reduces renal glucose reabsorptionunder hyperglycemic but not under hypo—or eug-lycemic conditions in rats. Am J Physiol EndocrinolMetab. 2013;304:E414–23.

21. Kaku K, Watada H, Iwamoto Y, Utsunomiya K,Terauchi Y, Tobe K, for The Tofogliflozin 003 StudyGroup, et al. Efficacy and safety of monotherapywith the novel sodium/glucose cotransporter-2inhibitor tofogliflozin in Japanese patients withtype 2 diabetes mellitus: a combined Phase 2 and 3randomized, placebo-controlled, double-blind,parallel-group comparative study. Cardiovasc Dia-betol. 2014;13:65.

22. Kleta R, Stuart C, Gill FA, Gahl WA. Renal gluco-suria due to SGLT2 mutations. Mol Genet Metab.2004;82:56–8.

23. Tanizawa Y, Kaku K, Araki E, Tobe K, Terauchi Y,Utsunomiya K, for the Tofogliflozin 004 and 005Study group, et al. Long-term safety and efficacy oftofogliflozin, a selective inhibitor of sodium-glu-cose cotransporter 2, as monotherapy or in combi-nation with other oral antidiabetic agents inJapanese patients with type 2 diabetes mellitus:multicenter, open-label, randomized controlledtrials. Expert Opin Pharmacother. 2014;15:749–66.

24. Yamasaki Y, Kodama M, Nishizawa H, Sakamoto K,Matsuhisa M, Kajimoto Y, et al. Carotid intimame-dia thickness in Japanese type 2 diabetic subjects:predictors of progression and relationship withincident coronary heart disease. Diabetes Care.2000;23:1310–5.

25. Mitsuhashi N, Onuma T, Kubo S, Takayanagi N,Honda M, Kawamori R. Coronary artery disease andcarotid artery intima-media thickness in Japanesetype 2 diabetic patients. Diabetes Care.2002;25:1308–12.

26. The Japan Diabetes Society. Treatment guide fordiabetes 2014–2015, Editorial Committee members

of ‘‘Treatment guide for diabetes’’ (Araki E, InagakiN, Inoguchi T, Utsunomiya K, Tanizawa Y, Naka-mura J, Noda M, Watada H, Imamura S), editors.Tokyo: Bunkodo Co., Ltd., 2014.

27. Terminology and Diagnostic Criteria Committee,Japan Society of Ultrasonics in Medicine. Subcom-mittee for preparing guidelines for ultrasounddiagnosis of carotid artery: standard method forultrasound evaluation of carotid artery lesions. JpnJ Med Ultrasonics. 2009;36:501–18.

28. Yanase T, Nasu S, Mukuta Y, Shimizu Y, NishiharaT, Okabe T, et al. Evaluation of a new carotidintima-media thickness measurement by B-modeultrasonography using an innovative measurementsoftware, Intimascope. Am J Hypertens.2006;19:1206–12.

29. Yokoyama H, Katakami N, Yamasaki Y. Recentadvances of intervention to inhibit progression ofcarotid intima-media thickness in patients withtype 2 diabetes mellitus. Stroke. 2006;37:2420–7.

30. Skyler JS, Bergenstal R, Bonow RO, Buse J, DeedwaniaP, Gale EA, et al. Intensive glycemic control and theprevention of cardiovascular events: implications ofthe ACCORD, ADVANCE, and VA diabetes trials: aposition statement of the American Diabetes Associ-ation and a scientific statement of the AmericanCollege of Cardiology Foundation and the AmericanHeart Association. Diabetes Care. 2009;32:187–92.

31. Zarich SW. Antidiabetic agents and cardiovascularrisk in type 2 diabetes. Nat Rev Endocrinol.2009;5:500–6.

32. Holman RR, Paul SK, Bethel MA, Matthews DR, NeilHA. 10-year follow-up of intensive glucose controlin type 2 diabetes. N Engl J Med. 2008;359:1577–89.

33. Inzucchi SE, Zinman B, Wanner C, Ferrari R,Fitchett D, Hantel S, et al. SGLT-2 inhibitors andcardiovascular risk: proposed pathways and reviewof ongoing outcome trials. Diabetes Vasc Dis Res.2015;12:90–100.

34. Zimmer S, Grebe A, Latz E. Danger signaling inatherosclerosis. Circ Res. 2015;116:323–40.

35. Youm YH, Nguyen KY, Grant RW, Goldberg EL,Bodogai M, Kim D, et al. The ketone metaboliteb-hydroxybutyrate blocks NLRP3 inflamma-some-mediated inflammatory disease. Nat Med.2015;21:263–9.

36. Neal B, Perkovic V, de Zeeuw D, Mahaffey KW,Fulcher G, Stein P, et al. Rationale, design, andbaseline characteristics of the canagliflozin cardio-vascular assessment study (CANVAS)—a random-ized placebo-controlled trial. Am Heart J.2013;166:217–223.e11.

1012 Diabetes Ther (2017) 8:999–1013

37. Sattar N, McLaren J, Kristensen SL, Preiss D,McMurray JJ. SGLT2 inhibition and cardiovascularevents: why did EMPA-REG outcomes surprise andwhat were the likely mechanisms? Diabetologia.2016;59:1333–9.

38. Abdul-Ghani M, Del Prato S, Chilton R, DeFronzoRA. SGLT2 inhibitors and cardiovascular risk: les-sons learned from the EMPA-REG OUTCOME study.Diabetes Care. 2016;39:717–25.

39. Heerspink HJ, Perkins BA, Fitchett DH, Husain M,Cherney DZ. Sodium glucose cotransporter 2 inhi-bitors in the treatment of diabetes mellitus: car-diovascular and kidney effects, potentialmechanisms, and clinical applications. Circulation.2016;134:752–72.

40. O’Leary DH, Polak JF, Kronmal RA, Manolio TA,Burke GL, Wolfson SK Jr, Cardiovascular HealthStudy Collaborative Research Group. Carotid-arteryintima and media thickness as a risk factor formyocardial infarction and stroke in older adults.N Engl J Med. 1999;340:14–22.

41. Lorenz MW, Markus HS, Bots ML, Rosvall M, SitzerM. Prediction of clinical cardiovascular events withcarotid intima-media thickness: a systematic reviewand meta-analysis. Circulation. 2007;115:459–67.

42. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu CR,Liu CH, et al. The role of carotid arterialintima-media thickness in predicting clinical coro-nary events. Ann Intern Med. 1998;128:262–9.

43. Katakami N, Yamasaki Y, Hayaishi-Okano R,Ohtoshi K, Kaneto H, Matsuhisa M, et al. Met-formin or gliclazide, rather than glibenclamide,attenuate progression of carotid intima-mediathickness in subjects with type 2 diabetes. Dia-betologia. 2004;47:1906–13.

44. Mazzone T, Meyer PM, Feinstein SB, Davidson MH,Kondos GT, D’Agostino RB Sr, et al. Effect of

pioglitazone compared with glimepiride on carotidintima-media thickness in type 2 diabetes: a ran-domized trial. JAMA. 2006;296:2572–81.

45. Yamasaki Y, Katakami N, Furukado S, Kitagawa K,Nagatsuka K, Kashiwagi A, et al. Long term effectsof pioglitazone on carotid atherosclerosis in Japa-nese patients with type 2 diabetes without a recenthistory of macrovascular morbidity. J AtherosclerThromb. 2010;17:1132–40.

46. Yamasaki Y, Katakami N, Hayaishi-Okano R, Mat-suhisa M, Kajimoto Y, Kosugi K, et al. Alpha-glu-cosidase inhibitor reduces the progression ofcarotid intima-media thickness. Diabetes Res ClinPract. 2005;67:204–10.

47. Mita T, Katakami N, Shiraiwa T, Yoshii H, Onuma T,Kuribayashi N, et al. Sitagliptin attenuates the pro-gression of carotid intima-media thickening ininsulin-treated patients with type 2 diabetes: thesitagliptin preventive study of intima-media thick-ness evaluation (SPIKE): a randomized controlledtrial. Diabetes Care. 2016;39:455–64.

48. Mita T, Katakami N, Yoshii H, Onuma T, Kaneto H,Osonoi T, et al. Alogliptin, a dipeptidyl peptidase 4inhibitor, prevents the progression of carotidatherosclerosis in patients with type 2 diabetes: thestudy of preventive effects of alogliptin on diabeticatherosclerosis (SPEAD-A). Diabetes Care.2016;39:139–48.

49. Tanaka A, Murohara R, Taguchi T, Eguchi K, SuzukiM, Kitakaze M, on behalf of the PROTECT StudyInvestigators, et al. Rationale and design of a mul-ticenter randomized controlled study to evaluatethe preventive effect of ipragliflozin on carotidatherosclerosis: the PROTECT study. CardiovascDiabetol. 2016;15:133.

Diabetes Ther (2017) 8:999–1013 1013