REVIEW

Optimizing Glycemic Control Through Titrationof Insulin Glargine 100 U/mL: A Review of Currentand Future Approaches with a Focus on AsianPopulations

Chaicharn Deerochanawong . Shailendra Bajpai . I. Made Pande Dwipayana .

Zanariah Hussein . Maria Aileen Mabunay . Reynaldo Rosales .

Shih-Tzer Tsai . Man Wo Tsang

Received: July 19, 2017 / Published online: November 1, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Various data have demonstrated inadequateglycemic control amongst Asians with type 2diabetes mellitus (T2DM), possibly on accountof suboptimal titration of basal insulin—anissue which needs to be further examined. Herewe review the available global and Asia-specificdata on titration of basal insulin, with a focuson the use of insulin glargine 100 U/mL(Gla-100). We also discuss clinical evidence onthe efficacy and safety of titrating Gla-100,

different approaches to titration, includingsome of the latest technological advancements,and guidance on the titration of basal insulinfrom international and local Asian guidelines.The authors also provide their recommenda-tions for the initiation and titration of basalinsulin for Asian populations. Discussion of thedata included in this review and in relation tothe authors’ clinical experience with treatingT2DM in Asian patients is also included. Briefly,clinical studies demonstrate the achievement ofadequate glycemic control in adults with T2DMthrough titration of Gla-100. However, studiesinvestigating approaches to titration, specifi-cally in Asian populations, are lacking and needto be conducted. Given that the management ofinsulin therapy is a multidisciplinary teameffort involving endocrinologists, primary carephysicians, nurse educators, and patients,greater resources and education targeted at

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Electronic supplementary material The onlineversion of this article (doi:10.1007/s13300-017-0322-z)contains supplementary material, which is available toauthorized users.

C. Deerochanawong (&)Rajavithi Hospital, College of Medicine, RangsitUniversity, Bangkok, Thailande-mail: chaichan@health.moph.go.th

S. Bajpai � M. A. MabunaySanofi, Singapore

I. M. P. DwipayanaFaculty of Medicine, Udayana University, Bali,Indonesia

Z. HusseinDepartment of Medicine, Putrajaya Hospital,Putrajaya, Malaysia

R. RosalesSt. Luke’s Medical Center, Manila, Philippines

S.-T. TsaiCheng Hsin General Hospital, Taipei, Taiwan

M. W. TsangUnited Medical Practice, Hong Kong SAR, China

Diabetes Ther (2017) 8:1197–1214

DOI 10.1007/s13300-017-0322-z

these groups are needed regarding the optimaltitration of basal insulin. Technologicaladvancements in the form of mobile or web-based applications for automated dose adjust-ment can aid different stakeholders in opti-mizing the dose of basal insulin, enabling alarger number of patients in Asia to reach theirtarget glycemic goals with improved outcomes.

Keywords: Asia; Basal insulin; Doseoptimization; Dose titration; Insulin glargine100 U/mL; Type 2 diabetes mellitus

INTRODUCTION

Asians show a strong ethnic association andgenetic predisposition for developing type 2diabetes mellitus (T2DM) at a younger age, anda lower body mass index than their Caucasiancounterparts [1–3]. Consequently, Asian popu-lations demonstrate higher rates of morbidityand early mortality [4, 5]. Only 37.3% of Asianpatients from the International Diabetes Man-agement Practice Study (IDMPS) [6] and 35.3%from the Joint Asia Diabetes Evaluation (JADE)program [7] had adequately controlled T2DM,with glycated hemoglobin (HbA1c) levels\7%,as recommended by the American DiabetesAssociation (ADA)/European Association for theStudy of Diabetes (EASD) [8, 9].

T2DM is a progressive disease, and earlytreatment intensification has been shown to aidin the achievement of glycemic targets[6, 7, 10–12]. Benefits of intensive glycemiccontrol include a reduction in the risk ofmicrovascular complications and the impact ofmacrovascular problems [13, 14]. Studies haveillustrated that patients on basal insulin areoften able to achieve HbA1c\7% [15–17], andearly intervention with basal insulin has beenshown to maintain glycemic control in the longterm [10]. Evidence, therefore, indicates thatearly initiation of basal insulin should be con-sidered for patients with T2DM.

However, data indicate that Asian patients arepoorly controlled for approximately 6–10 years,with average HbA1c levels of 8.7–9.8% at the

point of basal insulin initiation [11, 18–20]. Theprospective, observational First Basal InsulinEvaluation (FINE) study examined the initiationof basal insulin in insulin-naı̈ve patients withT2DM, uncontrolled (HbA1c C 8%) with oralantidiabetic drugs (OADs), in real-world clinicalpractice from 11 different Asian countries [19].The study showed that in countries where thedelay in initiation of basal insulin was[9 years,patients were less likely to reduce their HbA1c

levels and meet glycemic targets [21]. Also ofinterest is a pooled analysis of 724 Asian patientsfor whom data were extracted from seven ran-domized clinical trials (RCTs) that investigatedthe initiation and titration of insulin glargine100 U/mL (Gla-100). The pooled analysisdemonstrated, through multivariate analysis,that a higher baseline HbA1c at initiation oftreatment with Gla-100 is associated with asmaller reduction in HbA1c (p\0.0001) [22].This finding reinforces the importance of earlyinitiation of basal insulin in Asian patients.

Once basal insulin is initiated, dose titrationis an important factor affecting the patient’sability to achieve their target glycemic control[23]. Several studies have demonstrated theattainment of HbA1c levels\7% in patientswith T2DM titrating Gla-100 toward well-de-fined physiologic targets, known as thetreat-to-target (TTT) method [16, 17, 24–26].

There is a difference in insulin needsbetween Asian and Caucasian populations onaccount of ethnic and genetic differences, asdemonstrated by a pooled analysis of 16 RCTs[1]. In this analysis, at similar doses of Gla-100,non-Asian patients were able to achieve betterHbA1c control than Asian patients, indicatingthat higher daily basal insulin doses may berequired by Asian patients to achieve adequateglycemic control [1]. Differences in the patho-physiology of T2DM mean that the findingsfrom clinical trials in Caucasian populationscannot necessarily be extrapolated to Asianpopulations, as noted in a publication wherethis was cited to be one of the potential reasonsfor insufficient dose adjustments in Japanesepatients with T2DM [27]. Additionally, there isa lack of data on the titration of basal insulin in

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Asian populations compared with that availablefor Caucasian populations.

Asian patients with diabetes are generallyleaner than Caucasian patients and are there-fore perceived to have an increased risk ofhypoglycemia (although this has been demon-strated to be an incorrect assumption [1]),which leads to conservative treatment goals [28]and a cautious approach to the titration ofinsulin in Asia [19]. Real-world data from theObservational Registry of Basal Insulin Treat-ment (ORBIT) study conducted in Chinademonstrates suboptimal titration of basalinsulin [29]. In the study, titration of basalinsulin was in accordance with the provider’srecommendation and the patient’s willingness[20], and the dose of basal insulin was increasedby only 0.03 units/kg/day over a period of6 months [29].

These challenges demonstrate the difficultyof managing dose titration in Asian patients (apossible reason for the inadequate glycemiccontrol seen amongst Asians), and highlight theneed for further education and examination ofthe titration of basal insulin in Asia.

Of the several basal insulin analogs available,this review will focus on Gla-100 (Lantus�,Sanofi, France), a long-acting recombinanthuman insulin analog indicated for the treat-ment of adults and pediatric patients with type1 diabetes mellitus, and adults with T2DM [30].Newer basal insulin analogs, such as insulinglargine 300 U/mL (Gla-300), will not be dis-cussed in this review. Gla-100, by virtue ofhaving been available for more than 10 years[30, 31], has amassed a large volume of RCT andreal-world data that warrants standalone dis-cussion, especially since titration is still subop-timal in Asia [19, 29]. Despite the availability ofnewer basal insulins, in the opinion of theauthors Gla-100 remains an integral part of thediabetes treatment paradigm in Asia, and dis-cussion of approaches to the titration ofGla-100 is therefore still relevant. In this review,global and—where possible—Asian data on theefficacy and safety of titrating Gla-100 will beexplored, and opinion on these data from theauthors and their experiences with treatingT2DM in Asian patients are also included.Where possible, approaches specific to the

titration of Gla-100 have been reviewed; how-ever, due to the lack of data, approaches to thetitration of other basal insulins have also beenincluded. This article is based on previouslyconducted studies, and does not involve anynew studies of human or animal subjects per-formed by any of the authors.

TITRATING GLA-100

Meta-analyses published in 2014 by DeVrieset al. [32] and Owens et al. [33] examined effi-cacy and safety outcomes across 15 TTT trialswith once-daily Gla-100 added to differentcombinations of OADs at bedtime in insu-lin-naı̈ve individuals with T2DM uncontrolledon OADs. The analysis included data derivedfrom Sanofi-sponsored phase IIIb and IV TTTRCTs with protocol-driven titration algorithmsfor a duration C 24 weeks [32, 33]. Overall, 2837patients were analyzed, with efficacy assessed interms of reduction in HbA1c and fasting plasmaglucose (FPG) [32, 33]. Safety outcomes assessedincluded hypoglycemia, as well as change ininsulin dose and body weight [32, 33]. Safetyand efficacy outcomes were calculated for weeks0–12, referred to as the ‘‘titration period,’’ aswell as for weeks 12–24, referred to as the‘‘maintenance period’’ [33]. All outcomes wereassessed for each of the different treatmentcombinations, which included Gla-100 withmetformin, Gla-100 with sulfonylurea, as wellas Gla-100 in combination with metformin andsulfonylurea [32, 33].

Glycemic control improved following theinitiation and subsequent titration of Gla-100,with HbA1c and FPG decreasing from baseline toweek 12, and this decrease was sustained orfurther improved at week 24 in participantsreceiving all three treatment combinations[32, 33]. The combination of Gla-100 and met-formin demonstrated the greatest efficacy, witha mean reduction in HbA1c from 8.7% at base-line to 7% at week 24 [32]. Of the patientsreceiving Gla-100 and metformin, 56.8%achieved an HbA1c target of\7.0% at week 24,the largest proportion of patients amongst thethree treatment combinations [32]. Of the totalHbA1c reduction achieved at week 24,[80%

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was achieved by week 12, demonstrating thatGla-100 can aid in the achievement of early andsatisfactory treatment outcomes [33].

With regard to the safety outcomes, thecombination of Gla-100 and metformindemonstrated the lowest incidence of overall,daytime, and nocturnal hypoglycemia, as wellas the lowest weight gain compared with theother treatment groups [32, 33]. This wasdespite the greatest increase in the insulin dosetaken by those on Gla-100 and metformincompared with patients who received sulfony-lurea in their treatment regimen [32, 33]. Theincidence of hypoglycemia was similar duringthe titration and maintenance periods for all ofthe treatment groups [33].

Overall, the meta-analyses concluded thatinitiation and subsequent titration of Gla-100can lead to improved early ([80% reduction inHbA1c by week 12) and sustained glycemiccontrol, with a low incidence of hypoglycemicevents and minimal changes in weight [32, 33].Patients receiving Gla-100 and metformin had asignificantly shorter duration of diabetes atinitiation compared with patients who receivedsulfonylurea in their treatment regimen—apossible reason for the greater efficacy andsafety outcomes achieved by these individuals[32, 33].

In the past decade, several clinical trials haveapplied and investigated uniform titrationalgorithms, often referred to as TTT algorithms[34, 35]. TTT is a therapeutic concept that takesinto consideration and works toward well-de-fined and specific physiological targets for con-trolling the pathophysiology of a disease [35].The TTT approach is particularly suitable for thetreatment of diabetes, as it can be measured by‘‘gold-standard’’ quantitative measures such asHbA1c and fasting blood glucose (FBG), clinicalthresholds which have been determined bymultiple international and national diabetesorganizations [35]. Multiple TTT algorithmshave been investigated in clinical studies. Thesealgorithms are designed to produce equaldegrees of glycemic control and are thereforeable to reveal differences in safety, tolerability,and clinical utility between different treatmentregimens when insulin dosing and efficacy ismaximized [36]. An overview and the

intervention details of several key TTT clinicaltrials involving patients with T2DM with inad-equate glycemic control on OADs alone areshown in Table S1 in the Electronic supple-mentary material (ESM). The studies listed showconsistent and substantial improvements inglycemic control, as well as a low incidence ofhypoglycemic episodes with Gla-100.

APPROACHES TO THE TITRATIONOF BASAL INSULIN

It is often considered too difficult andtime-consuming for those in a primary careenvironment to initiate patients with T2DM onbasal insulin [34, 37]. A primary care physicianhas an average consultation time of 5–20 min tooversee and assess the large amount of clinicalinformation that must be reviewed before ini-tiating and titrating basal insulin for eachindividual patient [38]. Various approaches tothe titration of Gla-100 and other basal insulins,using TTT algorithms, have been investigated inorder to help improve this situation. Some ofthose that have been investigated in clinicalstudies are discussed below, and others will behighlighted in the section ‘‘Strategies for opti-mal titration of basal insulin in Asianpopulations.’’

Titration in Groups Versus Individuals

The Initiate Insulin by Aggressive Titration andEducation (INITIATE) study investigated theinitiation and self-titration of Gla-100 using aTTT algorithm in insulin-naı̈ve patients withT2DM [26]. Patients enrolled in the study wereeducated either individually or in groups ofbetween four to eight on a variety of factors inrelation to the treatment of T2DM, includingself-adjustment of the dose of Gla-100. Educa-tional sessions were held prior to, as well asthroughout, the 24-week treatment period.Over the 24 weeks, mean HbA1c levels decreasedfrom 8.7 ± 0.2 to 6.9 ± 0.1% (p\0.001) inthose educated individually, and from 8.8 ± 0.2to 6.8 ± 0.1% (p\0.001) in those educated ingroups, showing that providing support to

1200 Diabetes Ther (2017) 8:1197–1214

groups of patients who are initiating Gla-100treatment can be as effective at achieving gly-cemic control as providing support on an indi-vidual basis [26]. The frequency ofhypoglycemic events between both groups wassimilar, as was the dose of Gla-100. The totaltime spent on educating patients in groups onself-titration, monitoring, and injection ofGla-100 was 48% less than in those educatedindividually [26]. This study demonstrated thatproviding education on the dose titration ofGla-100 in groups is a viable option, and couldhelp to overcome the resource and time con-straints often faced by primary care physicians[34, 37, 38], enabling a higher number ofpatients to receive and optimize their insulintherapy [26].

Patient-Led Versus Physician-Led Titration

Greater awareness of the principle of patientself-titration has been aided by several TTT trialsof insulins [36]. One of these is the CanadianImplementing New Strategies with InsulinGlargine for Hyperglycemia Treatment(INSIGHT) study, which investigated self-titra-tion with Gla-100 using a TTT algorithm in 206patients with T2DM. The study found improvedglycemic control and greater increases in treat-ment satisfaction in those who self-titratedGla-100 compared with those who receivedphysician-adjusted conventional therapy withOADs [16].

Similarly, a study conducted by theAT.LANTUS (A Trial Comparing Lantus Algo-rithms to Achieve Normal Glucose Targets inSubjects with Uncontrolled Blood Sugar) studygroup compared two TTT treatment algorithmsfor the initiation and titration of Gla-100, thefirst being physician-led dose titration and thesecond self-management of dose adjustments[39]. The study concluded that a simplepatient-administered titration algorithm signif-icantly improves glycemic control with a lowincidence of severe hypoglycemia comparedwith physician-led titration. It should be noted,however, that Asian patients were underrepre-sented in the AT.LANTUS study [18, 39].

In order to address this, the randomizedmultinational Asian Treat to Target LantusStudy (ATLAS) compared the relative effective-ness of patient-led versus physician-led titrationof Gla-100 using TTT algorithms in insulin-na-ı̈ve Asian patients with T2DM [18]. A greaterdecrease in HbA1c values approaching the targetwas achieved by those who self-titrated theirinsulin dose compared with physician-ledtitration [18]. Severe hypoglycemia was rare inboth treatment groups. Thus, when guidance isprovided, Asian patients are able to effectivelyself-titrate their basal insulin to improve gly-cemic control [18].

Mobile and Web-Based Technologies

Advances in mobile and web-based technolo-gies provide the potential for new models ofcollaborative care between patients andhealthcare providers (HCPs) [40]. This includescapabilities for the real-time sharing of data, aswell as improved communication betweenHCPs and patients between medical visits [40].Whilst the outpatient-based face-to-face caremodel is suitable for managing acute illnesses,this approach may be inadequate for managingchronic diseases such as diabetes [40]. Patientswith diabetes often need continuous advice onmanaging their glucose levels and on the risk ofhypoglycemia (especially for patients on insu-lin) [40, 41], particularly as they are sensitive tomany factors such as change in diet, physicalactivity, and stress [40]. In particular, basalinsulin titration by way of face-to-face visitswith a clinician can be time-consuming as wellas logistically and financially burdensome forpatients, especially those of low socioeconomicstatus (SES), as it often requires multipleappointments with the physician before doseoptimization and adequate glycemic control areachieved [41, 42]. Research has consistentlyshown that diabetes management is an areawhere mobile and web-based technologies canimprove the glycemic control of patients andempower them with the confidence toself-manage their disease to a greater extent[40, 43]. Some of the mobile and web-basedtechnologies used for the titration of basal

Diabetes Ther (2017) 8:1197–1214 1201

insulin in patients with T2DM are reviewedbelow.

Mobile Technology ApplicationsSeveral studies have investigated the clinicalefficacy and safety of the titration of basalinsulin using an application, visualized via atablet or a smart phone, in patients with T2DM[40, 44, 45]. The applications are guided byestablished basal insulin titration algorithms,and work by providing patients with the dosageof basal insulin they need to administer toachieve optimum glycemic control, based ontheir blood glucose (BG) level, which is requiredto be inputted into the application [40, 44]. Theapplications offer several self-tracking andstreamlined communication tools. These toolsinclude text message and virtual visit capabili-ties (audio, video, and shared screen control),charts demonstrating a correlation betweenmedication adherence and glycemic level, BGreadings that can be automatically integratedinto the application via wireless glucometers,daily reminders for BG testing, alerts to warnpatients if their BG is low, and information ondiabetes medications. Both patients and theirclinicians can also have the application syn-chronized to allow HCPs to remotely monitortheir patients. These tools allow for in-depthco-exploration of data and collaborative deci-sion-making between patients and clinicians[40, 44]. In Singapore, doctors from the Singa-pore General Hospital (SGH) Department ofEndocrinology and Integrated Health Informa-tion Systems have developed a smart phoneapplication named SGH Diabetes Pal that canguide patients with T2DM to self-titrate theirbasal insulin by providing recommended dailydoses [46]. The application allows each patient’smaximum dose to be inputted into the appli-cation as a safety feature [44].

A 24-week study has been conducted inSingapore to determine the effectiveness of theSGH Diabetes Pal application. The study enrol-led insulin-naı̈ve patients with T2DM withsuboptimal glycemic control despite the use oftwo or more OADs. Patients either used theapplication (interventional group) or writteninstructions (control group) to self-titrate theirdoses of insulin detemir. Although not

statistically significant, the reduction in HbA1c

from the baseline was numerically greater in theintervention group than in the control group. Asteeper increase in the daily dose of basal insu-lin was observed in the intervention group.There were no episodes of severe hypoglycemiain either group [44].

A 14-week study by Hsu et al. consideredwhether a cloud-based diabetes managementprogram, implemented through a tablet com-puter application, could help poorly controlledindividuals with T2DM who were startingtreatment with basal insulin therapy achievebetter glycemic control (HbA1c) compared withstandard clinical practice involving interimface-to-face visits as well as telephone/faxcommunication between patients and HCPs[40]. At the end of the study, patients using theapplication achieved a statistically greater meanHbA1c decrease than those receiving standardcare. Additionally, an improvement in BG levelswas observed within only a few days post-initi-ation for some patients using the application.On average, the amount of time required toinstruct patients on use of the application wasgenerally less than 1 h, and patients using theapplication reported a higher satisfaction ofcare. The mean virtual visit time per patientusing the application was much lower than themean clinician visit time of patients receivingstandard care. Communication between thepatients and HCPs through the application alsodecreased over time as patients gained theconfidence to make their own clinical decisions.Overall, patients using the application reportedthat connectivity with their clinician throughthe application helped them feel more confi-dent and motivated, that the collaboration withthe HCP helped empower them to make theirown decisions, and that they could, through theapplication’s visualization capabilities, under-stand the connection between their BG levelsand insulin intake [40].

A study by Spat et al. demonstrated that atablet computer application aiding basal/bolusinsulin titration can reduce the risk of humanerror [45]. This was done through a simulationof HCP decisions made in a paper-based clinicaltrial with the application. The simulationincluded 1190 decisions made by HCPs during

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the paper-based clinical trial. From the simula-tion, four errors associated with the applicationwere identified regarding the calculation of thedaily insulin dose adjustment. However, thesimulation also detected 144 calculation errorsby physicians and nurses from the paper-basedclinical study. The most common errors iden-tified in the paper-based clinical trial wereassociated with basal/bolus insulin dose calcu-lation, daily insulin dose calculation, and dailyinsulin dose adjustment. This highlights thepotential of an electronic application toimprove the accuracy of the implementation ofa basal insulin titration protocol [45].

Although the above studies demonstrate theadvantages of mobile technologies, in a reviewof a diverse number of diabetes mobile appli-cations, Chomutare et al. noted that only 20%have educational content and fewer still havethe ability to provide personalized feedback,indicating that there are still unmet needs thatmobile technologies have not addressed [47].

Web-Based TechnologyThe internet provides a readily accessible plat-form for real-time communication betweenpatients and HCPs, exchange of information,and remote health monitoring [48–50]. Patientscan upload their BG readings to secure web-based platforms for the clinician to review andsubsequently send back suggested changes ininsulin dose and self-monitoring of blood glu-cose (SMBG) frequency, or even to providefeedback [41]. Alternatively, platforms can bebuilt to provide insulin titration advice directlyto the patient, based on a built-in titrationalgorithm [51]. Web-based platforms can reducethe need for appointments with a physiciansolely for the purpose of insulin titration, andcan be a more cost-effective method of fol-low-up, especially for patients who live in ruralareas [41].

A study showed significant improvements inglycemic control for patients with T2DM usingan internet-based glucose monitoring system(IBGMS) for insulin titration compared withstandard care (i.e., face-to-face appointmentswith the endocrinologist). Patients in the stan-dard care group were required to keep a recordof their SMBG readings in a diary between visits

to the endocrinologist. Patients in the IBGMSgroup had statistically significant HbA1c

improvements after 3 months that were sus-tained over 6 months, which was not observedin patients in the standard care group. Biweeklycommunication with the endocrinologistthrough the IBGMS system allowed patients tohave more accurate adjustments of their insulindose. In addition, SMBG testing reminders andease of data tracking and analysis through thesystem’s tables/graphs were all hypothesized toaid patients in the IBGMS group to achievegreater glycemic control than those receivingstandard care [41].

Cross-Platform Mobile and Web-BasedTechnologiesIn the past year, several basal insulin dose cal-culators have been approved by the US Foodand Drug Administration. These are Insulia(Gla-100, Gla-300, and insulin detemir) [52, 53],iSage Rx (Gla-100, Gla-300, insulin detemir, andinsulin degludec) [54, 55], and My Dose Coach(any once-daily long-acting basal insulin)[56, 57]. These systems utilize both mobile andweb-based platforms to automate the doseadjustment of basal insulin for patients withT2DM. While these systems are not replace-ments for HCPs, they do provide optimized andpersonalized suggestions for daily doses of basalinsulin in between patient–HCP visits. In gen-eral, the HCP registers a patient and creates anindividualized titration algorithm through awebsite portal, which can be accessed by thepatient via a smart phone application. Patientsinput their daily FPG values into the smartphone application which provides them withreal-time dose recommendations as per theHCP’s treatment plan. HCPs can remotely tracktheir patients’ progress and make changes to thetitration algorithm depending on treatmentresponse [52, 54, 56].

Cell-Phone-Based SupportCell phones are a part of daily life for mostadults of all age groups and different culturaland socioeconomic backgrounds [43], and areincreasingly being used to deliver health ser-vices [58].

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A study by Levy et al. aimed to investigatewhether the remote titration of Gla-100 wasfeasible by using only the basic features of a cellphone, namely short message service (SMS) textmessaging and phone calls (including voice-mail) between patients and HCPs. This could beparticularly beneficial for patients of low SES,who find it challenging to attend multiple fol-low-ups with physicians and own a cell phonewithout advanced features (i.e., not a smartphone). The 12-week study aimed to investigatewhether SMS and phone calls could assistpatients to optimize their insulin dose, as wellas determine the feasibility of this type ofintervention, and whether there are cost savingsand improved patient satisfaction comparedwith standard care (control group). In the study,a web-based platform automatically sent textmessages to patients each weekday, to whichthey had to respond through SMS citing theirBG level. A diabetes nurse educator would inturn log on to the web platform daily to viewthe patients’ BG reading and flag any alarmingvalues with the patients by phone. Titration ofGla-100 was performed once weekly by thenurse through phone calls or voicemails. A sig-nificantly greater number of patients in theintervention group achieved their optimalinsulin dose in a median of just 3 weeks com-pared with patients receiving standard care, forwhom it took a median of 7.07 weeks. Thepatients in the intervention group were highlyinteractive, and the majority of SMS text mes-sages sent to the patients received a reply.Additionally, nurses were able to contactpatients on the first or second attempt, or byvoicemail, 91% of the time. The median dura-tion of titration-related interactions in theclinic was 30.0 min, whereas the median forphone/voicemail interactions was 6.0 min(p = 0.008). Patients in the intervention groupalso saved travel time to and from the clinic, aswell as time spent in the waiting room, andwere shown to be more satisfied with theirtreatment [42]. The findings of this study are inline with previous studies that have demon-strated the effectiveness of SMS text messagingin assisting general and low-SES patients withdiabetes to manage their disease [59–61].

Although the above studies indicate thatadvances in mobile and web-based technologieshave the potential to enable successful collab-oration between patients and HCPs for thetitration of basal insulin and management ofdiabetes as a whole, further research is stillneeded to assess patient acceptability, attitudestoward these platforms, and their cost-effec-tiveness [62].

INTERNATIONAL GUIDELINERECOMMENDATIONSFOR THE INITIATIONAND TITRATION OF BASAL INSULIN

Recommendations on the initiation and titrationof basal insulin can be found in several interna-tional clinical practice guidelines. The 2017American Association of Clinical Endocrinolo-gists (AACE)/American College of Endocrinology(ACE) comprehensive diabetes managementalgorithm specifies that basal insulin can be ini-tiated in patients with T2DM with an entry HbA1c

level\7.5% when either monotherapy withmetformin or other OADs, or dual therapy withmetformin and other agents, fails to achieve theglycemic target (HbA1c\7%) [63]. The guidelinesalso indicate that basal insulin can be initiated as apart of dual therapy with metformin in patientswith entry HbA1c C 7.5%, or when a patient pre-sents with a HbA1c level[9.0% (dual or tripletherapy with metformin) and symptomatichyperglycemia at entry [63]. The 2015 diabetesclinical practice guidelines from the AACE/ACEacknowledged that the traditional postponementof insulin therapy after prolonged failure of life-style management and OADs to achieve glycemiccontrol has been revised in the past decade, andrecommended that basal insulin therapy shouldbe initiated much sooner, and often in combina-tion with OADs [64]. The ADA’s updated Stan-dards of Medical Care in Diabetes 2017 states theimportance of dose titration of any insulin regi-men once initiated, and that dose adjustmentsshould be based on prevailing BG levels, togetherwith knowledge of the pharmacodynamic profileof the insulin used [23]. The ADA recommendsthat if theHbA1c target (\7%) isnotachievedafter

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3 months of monotherapy with metformin,combination therapy of basal insulin with met-formin, amongst other options, should be con-sidered [23]. The 2015 position statement fromthe ADA/EASD emphasizes that insulin has theadvantage of being effective where other agentsmay not be, and should beconsidered apartofanycombination regimen when hyperglycemia issevere, particularly if the patient is symptomatic[9]. The International Diabetes Federation (IDF)recommends the initiation of basal insulin afterthe failure of combination therapy with met-formin and other OADs, and the titration ofinsulin using a self-titration regimen, or with atleast biweekly contact with a HCP [65]. Table 1highlights key recommendations regarding theinitiation and titration of basal insulin from sev-eral international guidelines.

COUNTRY-SPECIFICRECOMMENDATIONSFOR THE INITIATIONAND TITRATION OF BASAL INSULININ ASIA

Most countries in Asia have developed diabetestreatment guidelines that closely reflect interna-tional guidelines. For example, recommendationsin the 2015 Indonesian Clinical Practice Guide-line of Insulin Therapy in Diabetes MellitusPatients reflect guidelines issued by the ADA/EASD and AACE/ACE, and contain guidance onthe initiation and titration of insulin [66]. Rec-ommendations from Hong Kong’s Department ofHealth regarding the treatment of hypergylcemiain primary care settings also closely follow guide-lines from the ADA/EASD, AACE/ACE and IDF,amongst others, with different treatment optionsfor different baseline HbA1c levels, as well asinformation on the titration of insulin [67]. ThePhilippine Practice Guidelines on the Diagnosisand Management of Diabetes Mellitus are aimedat educating all physicians involved in the man-agement of diabetes. The guidelines include rec-ommendations on the screening and diagnosis ofdiabetes mellitus, the screening and prevention ofcomplications associated with diabetes, as well asinformation on the management of diabetes,

particularly for special populations such as theelderly [68]. In Malaysia, the Ministry of Health’sendocrinologists developed a practical guide forinsulin therapy in 2010 that outlines a clear andconcise approach for all HCPs to initiate insulinsafely, optimize doses effectively, and intensifyinsulin regimens promptly [69]. The release of theguidelines was followed by nationwide educationon the guidelines for primary care physicians, theresult of which was an increase in the rates ofinsulin initiation in primary care practice. TheClinical Practice Guidelines for Diabetes Care2015 from the Diabetes Association of theRepublic of China (Taiwan) emphasizes thattreatment goals should be individualized based onthe patient’s condition, similar to recommenda-tions from the 2015 ADA/EASD position state-ment [70]. The 2014 Clinical Practice Guidelinefor Diabetes from Thailand was adapted from theIDF, ADA/EASD, and the National Institute forHealth and Care Excellence (NICE) guidelines,and recommends starting basal insulin in patientswith T2DM after the failure of dual or triple ther-apy with OADs [71]. Table 2 provides an overviewof key recommendations regarding the initiationand titration of basal insulin from severalAsian-country-specific guidelines.

In alignment with international guidelines,the majority of the recommended titrationalgorithms in Asia follow the TTT approach(Table 2), wherein basal insulin is initiated at alow dose to avoid hypoglycemia and subse-quently adjusted based on pre-defined physio-logic targets, meaning that patients mayeventually end up on different doses of insulin.The TTT approach has proven to be an effectiveapproach for initiating and adjusting the doseof basal insulin for non-Asian and Asianpatients with T2DM [16–18, 32, 33, 39].

AUTHOR RECOMMENDATIONSFOR THE INITIATIONAND TITRATION OF BASAL INSULININ ASIAN POPULATIONS

Based on their clinical experience, the authorshave provided recommendations for the

Diabetes Ther (2017) 8:1197–1214 1205

initiation and titration of basal insulin specificto the Asian population in Fig. 1 and Table 3,respectively.

The algorithm in Fig. 1 is in accordance withthose provided by the ADA, AACE/ACE, and IDF[23, 63, 65], and indicates the optimal time forinitiation of basal insulin; namely, followingfailure of treatment with metformin along withlifestyle modifications for a period of 3 months.However, the reality is that this algorithm isoften not followed in clinical practice in Asia. Inthe authors’ clinical experience, basal insulin isoften initiated following failure with dual ortriple OAD therapy (in addition to lifestylemodifications). Although patient-specific fac-tors must be taken into consideration, in gen-eral there needs to be a push for earlierinitiation of basal insulin in Asia, and theauthors hope to encourage this.

The titration algorithm in Table 3 is closelyaligned with other algorithms given in

Asian-country-specific guidelines [66, 67, 69, 71],and involves a low dose of basal insulin for initi-ation to avoid hypoglycemia, and subsequentdose adjustments based on predefined physio-logic targets; that is, the TTT approach. Whenchoosing this algorithm, it is important that otherpatient- and disease-specific factors are also takeninto consideration, as well as any dose adjust-ments to OADs that might be required.

STRATEGIES FOR THE OPTIMALTITRATION OF BASAL INSULININ ASIAN POPULATIONS

Consistent and substantial improvements inglycemic control, as well as a low incidence ofhypoglycemic episodes, have been observed ininsulin-naı̈ve patients with T2DM titratingGla-100 using a TTT algorithm. Of these studies,

Table 1 Recommendations from international guidelines for the initiation and titration of basal insulin for the treatmentof T2DM

Guidelines Starting dose(U/kg/day)

Dose titration Glycemictargets

Controllinghypoglycemia

IDF 2012

[65]

For safety reasons,

starting doses of

insulin should be

low

Self-titration regimen: insulin dose increase

of 2 units every 3 days

Physician-led: biweekly or more frequent

contact with a healthcare professional

HbA1c:\7.0%

FPG:

\6.5 mmol/L

NR

ADA 2017

[23]

0.1–0.2 Increase dose by 2–4 units once or twice

weekly

HbA1c:\7.0%

FPG:

4.4–7.2 mmol/L

Decrease dose by 4

units

AACE/

ACE

2017

[63]

HbA1c\8%: 0.1–0.2

HbA1c[8%: 0.2–0.3

Fixed regimen: increase TDD of basal

insulin by 2 units every 2–3 days

Adjustable regimen: titrate insulin every

2–3 days according to: FBG

6.1–7.7 mmol/L: increase dose by 1 unit

FBG 7.8–10 mmol/L: add 10% of TDD

FBG[10 mmol/L: add 20% of TDD

HbA1c:\7.0%

FPG:

\6.1 mmol/L

BG\3.9 mmol/L:

decrease TDD by

10–20%

BG\2.2 mmol/L:

decrease TDD by

20–40%

AACE American Association of Clinical Endocrinologists, ACE American College of Endocrinology, ADA AmericanDiabetes Association, BG blood glucose, FBG fasting blood glucose, FPG fasting plasma glucose, HbA1c glycated hemo-globin, IDF International Diabetes Federation, NR not reported, T2DM type 2 diabetes mellitus, TDD total daily dose

1206 Diabetes Ther (2017) 8:1197–1214

only a handful have been conducted specificallyin Asian populations [18, 28]. Thus, there is alack of information and guidance on theappropriate frequency of titration, safe doseincrements, and the maximal dose of basalinsulin for Asian populations. Studies need tobe conducted to enable an adequate under-standing of the pathophysiology of Asianpatients and therefore how insulin

requirements, treatment goals, and the risk ofhypoglycemia differ from those for Caucasianpatients.

In order to provide some guidance, based ontheir own clinical experience, the authors rec-ommend that with careful monitoring, thepresence of hypoglycemia may be taken as anindication that the basal insulin dose is toohigh. Consideration should be given to any

Table 2 Recommendations from Asian-country-specific guidelines for the initiation and titration of basal insulin

Country Startingdose(U/kg/day)

Dose titration Glycemic targets Controllinghypoglycemia

Hong Kong [67] 0.1–0.2 According to latest average of 3

or more FBG values taken at

specific times:

FBG 4.0–7.0 mmol/L:

maintain current dose

FBG 7.1–10 mmol/L: increase

insulin dose by 2 units

FBG[10 mmol/L: increase

insulin dose by 4 units

HbA1c:\7.0%

FPG: 4–6 mmol/L

FBG\4.0 mmol/L:

decrease insulin dose

by 2 units

Malaysia [69] 0.1–0.2 Based on 3 consecutive BG values

obtained every 3–7 days:

BG 4–6 mmol/L: maintain

current dose

BG[6 mmol/L: increase insulin

dose by 2 units

HbA1c:\6.5%

FPG: 4.4–6.1 mmol/L

BG\4 mmol/L:

Reduce dose by 2 units

Indonesia [66] 0.1–0.2 FBG 5–7.2 mmol/L: maintain

current dose

FBG[7.2 mmol/L: increase dose

by 2–4 units, once–twice weekly

HbA1c:\7%

FPG: 4.4–6.1 mmol/L

FBG\5 mmol/L:

decrease insulin dose

by 4 units or 10–20%

Philippines [68] 0.2 NR HbA1c:\7%

FPG: 4–7 mmol/L

NR

Thailand [71] 0.1–0.2 FBG[6.7 mmol/L: increase

insulin dose by 2–4 units per

injection every 3–7 days

HbA1c:\7% NR

Singapore [72] NR NR HbA1c: B 7.0% NR

Taiwan [70] 0.1–0.2 NR HbA1c:\7% NR

BG blood glucose, FBG fasting blood glucose, FPG fasting plasma glucose, HbA1c glycated hemoglobin, NR not reported

Diabetes Ther (2017) 8:1197–1214 1207

dose adjustments to OADs that might berequired with basal insulin initiation and titra-tion. The authors recommend, despite currentreal-world practices in Asia, that the optimaltime for initiation of basal insulin should followapproximately 3 months of failure of met-formin monotherapy and lifestyle modifica-tions, as summarized in Fig. 1. Therecommended titration algorithm given inTable 3 involves a low dose of basal insulin forinitiation to avoid hypoglycemia, and subse-quent dose adjustments based on predefinedphysiologic targets. When choosing this algo-rithm, it is important that other patient- anddisease-specific factors are also taken intoconsideration.

The management of insulin therapy is amultidisciplinary team effort that involves

specialists, primary care physicians, nurse edu-cators, and patients. Due to the high prevalenceof T2DM in Asia [5], it is vital that primary careproviders, patients, and other HCPs are able toadequately manage insulin therapy; to achievethis, greater education and resources on theoptimal titration of basal insulin need to betargeted at these groups.

The time and resource constraints that pri-mary care physicians face [34, 37, 38] couldpotentially be relieved through the use ofmodern technology, including web-based tools,mobile applications, cell-phone-based support,glucometers capable of uploading data to theweb, and telephone hotlines[40–42, 44, 45, 48, 49, 73]. As an example, oneof the authors of this paper has implementedthe titration of insulin through the medium of

Fig. 1 Author recommendations for the initiation of basalinsulin for the treatment of T2DM in Asian populations.GLP-1 RA glucagon-like peptide-1 receptor agonist, HbA1c

glycated hemoglobin, mos months, OAD oral antidiabeticdrug, T2DM type 2 diabetes mellitus

1208 Diabetes Ther (2017) 8:1197–1214

SMS in his clinical practice in Indonesia.Patients send their SMBG readings by SMS every3–7 days to their clinician (author) and receiveadvice via a return SMS regarding changes intheir insulin dose. The author has reported thatpatients are satisfied with this method of com-munication because of its efficiency and theamount of attention from the physician that itaffords. In another author’s clinical practice inthe Philippines, patients relay their SMBGreadings through SMS or by phone call andaccordingly receive advice on their readingsthrough phone calls. Patients have reportedsatisfaction with this method as it saves ontravel time to the clinic and circumvents theneed to take time off work to attend clinicappointments.

With regard to technology-based methods,care should be taken to implement these in theright settings. Other approaches to titration, forexample group titration and education, may beeffective for elderly patients who may not becomfortable with the use of technology. Titrat-ing and providing education in groups not onlyreduces the amount of time needed with eachpatient but also creates an environment thatallows patients to discuss and share their prob-lems as well as support each other [26].

To reduce the burden on primary carephysicians, diabetes nurse educators should beempowered to provide patients with guidanceon titration. Nurse-led care is a practical andcost-effective model, and is effective in main-taining optimal glycemic control of patients aswell as enhancing their adherence to treatment[74]. One example of facilitating nurse-led carecould be to set up nurse-led titration clinics.

Technology could also be taken advantage of tosupport nurse-led titration. A study hasdemonstrated that patients can effectivelytitrate their doses of Gla-100 and improve theirglycemic control through SMS/phone call con-tact with their diabetes nurse educators. Thismethod also reduced travel time, time spent inthe waiting room, and the overall cost of treat-ment for patients [42].

Despite an increasing drive for patients to bemore involved in the management of theirdisease [9, 75, 76], physicians often are of theopinion that patients are unable or unpreparedto effectively self-titrate and manage theirinsulin dose. The ATLAS study has demon-strated that patients in Asia are able to effec-tively titrate their dose of Gla-100 whenprovided with guidance [18]; however, only afew clinical studies investigating the self-titra-tion of basal insulin amongst patients withT2DM have been conducted [18, 39]. Toincrease awareness of self-titration, as well asprovide specialists and primary care physicianswith evidence that patients are able to effec-tively self-titrate their insulin, further studiesinvestigating patient-led titration specifically inAsian populations should be conducted. Sup-porting patients is also vital, and can beachieved through various measures, such as bysetting up insulin titration clinics as well asenrolling patients into patient support pro-grams that encourage self-titration. Mobile andweb-based technologies can also empowerpatients with the confidence to self-managetheir disease to a greater extent, and variousstudies have demonstrated that by using thesetechnologies, patients are able to effectively

Table 3 Author recommendations for the titration of basal insulin for the treatment of T2DM in Asian populations

Starting dose(U/kg/day)

Dose titration Glycemic targets Controllinghypoglycemia

0.1–0.2 Based on the lowest FPG reading of the previous 3 days,

adjust the dose of basal insulin weekly:

FPG 4.0–6.0 mmol/L: maintain current dose

FPG 6.1–8.9 mmol/L: increase dose by 2 units

FPG[8.9 mmol/L: increase dose by 4 units

HbA1c\7%

FPG

4.0–6.0 mmol/L

FPG\4.0 mmol/L:

reduce dose by 2 units

FPG fasting plasma glucose, HbA1c glycated hemoglobin, T2DM type 2 diabetes mellitus

Diabetes Ther (2017) 8:1197–1214 1209

titrate their basal insulin for improved glycemiccontrol. Patients are often frustrated with thetime it takes to attain adequate glycemic control[77], and involving them in their own treat-ment can potentially help to resolve this.

The ultimate goal of the research and recom-mendations outlined in this article is to enablepatients with T2DM to achieve optimal glycemiccontrol. The authors acknowledge that achievingthis requires patients to control their postpran-dial BG in addition to their FPG, possiblyrequiring a prandial insulin. Dose optimizationof basal and prandial insulin analogs together istherefore a subject for future consideration.

CONCLUSIONS

We have reviewed the efficacy and safety oftitrating Gla-100, and highlighted the impor-tance of optimal dose titration in supportingAsian patients with T2DM to achieve glycemiccontrol. Specific challenges exist within Asiathat impact basal insulin titration and thereforeaffect treatment outcomes. These include thestrong ethnic association with and genetic pre-disposition to diabetes among Asians [4, 78], aswell as the relatively long delays incurred beforeinsulin initiation and suboptimal dose titration,which have been reported in several countries[11, 18–21]. Current treatment guidelines rec-ommend early initiation of basal insulin ther-apy, and subsequent effective patient- orphysician-led dose titration regimens to facili-tate dose optimization [9, 63, 65–67, 69, 71]. Inthe past decade, various studies have illustratedthat titration of Gla-100 using the TTT methodhas been able to aid patients in achievingHbA1c\7% [32, 33], and early interventionwith basal insulin has been shown to maintainglycemic control in the long term [10]. Earlyinitiation and optimal titration of basal insulinis therefore key to improving patient outcomes.Given the success with patient-led dose titrationobserved in several studies [16, 18, 39], thismethod could prove to be an effective means ofoptimizing treatment. Thus, future initiatives inAsia should embrace educational support topromote patient-led approaches so as toempower individuals with T2DM to take

control of their treatment [18]. Additionally,the use of mobile and web-based technologieshas the potential to facilitate successful collab-oration between patients and HCPs [40–44] andtherefore improve the titration of basal insulinand the management of diabetes as a whole,and should be further used and encouraged.

ACKNOWLEDGEMENTS

The authors did not receive funding to partici-pate in the development of this article. Editorialassistance in the preparation of this manuscriptwas provided by Priya Shreedhar of MediTechMedia Singapore, funded by Sanofi Singapore.In addition to medical writing support, articleprocessing charges were funded by Sanofi Sin-gapore. All named authors meet the Interna-tional Committee of Medical Journal Editors(ICMJE) criteria for authorship for this manu-script, take responsibility for the integrity of thework as a whole, and have given final approvalfor the version to be published. Dr. Tran QuangKhanh, an endocrinologist at Nguyen TriPhuong Hospital in Ho Chi Minh City, Viet-nam, contributed to the initial discussion ofthis review paper. Information from theIndonesian Clinical Practice Guideline of Insu-lin Therapy in Diabetes Mellitus Patients wasverified by Pratidina Paramita and Ratna IndahWidyasari, employees of Sanofi. Informationfrom the 2014 Clinical Practice Guideline forDiabetes from Thailand was verified by Soam-rutai Boonsuepsakul, an employee of Sanofi.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studies,and does not involve any new studies of humanor animal subjects performed by any of theauthors.

Disclosures. Maria Aileen Mabunay isan employee of Sanofi and contributed in theircapacity as diabetes subject matter experts.Shailendra Bajpai is an employees of Sanofi andcontributed in their capacity as diabetes subjectmatter experts. They did not exercise selectiveinfluence over the opinions expressed by other

1210 Diabetes Ther (2017) 8:1197–1214

authors in this article. Chaicharn Deerochana-wong has been a consultant and speaker forSanofi, Takeda, Novo Nordisk, Eli Lilly, Boeh-ringer Ingelheim, Astra Zeneca, and Abbott.I. Made Pande Dwipayana has served on anadvisory board for Sanofi. Reynaldo Rosales is amember of the Medical Advisory Board of SanofiPhilippines, and has received honoraria forspeaker services from Sanofi and Novo Nordisk.Man Wo Tsang has received honoraria forspeaker services from Sanofi, served on advisoryboards for Eli Lilly, MSD, Astra Zeneca, andAbbott Nutrition, and received a research grantfrom Johnson & Johnson. Shih-Tzer Tsai hasbeen a consultant and has received honorariafor speaker services from Sanofi, Novo Nordisk,Eli Lilly, Astra Zeneca, and Boehringer Ingel-heim. Zanariah Hussein has received honorariafor speaker services from Sanofi, Eli Lilly, andNovo Nordisk.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

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. Chan JCN, Bunnag B, Chan SP, Isip-Tan IT. Clinicaloutcomes in Asian and non-Asian people with type2 diabetes (T2D) initiating glargine 100 units/mL(Gla-100) therapy: results of a pooled analysis from16 RCTs. Presented at American Diabetes Associa-tion 76th Scientific Sessions; 2016 June 10–14; NewOrleans, LA, USA. Poster 980-P.

2. Chiu M, Austin PC, Manuel DG, Shah BR, Tu JV.Deriving ethnic-specific BMI cutoff points forassessing diabetes risk. Diabetes Care.2011;34:1741–8.

3. Ma RC, Chan JC. Type 2 diabetes in East Asians:similarities and differences with populations inEurope and the United States. Ann N Y Acad Sci.2013;1281:64–91.

4. Ramachandran A, Snehalatha C, Shetty AS, Nan-ditha A. Trends in prevalence of diabetes in Asiancountries. World J Diabetes. 2012;3:110–7.

5. International Diabetes Federation. IDF diabetesatlas. 7th edn. Brussels, Belgium; 2015. https://www.idf.org/e-library/welcome.html. AccessedSeptember 2017.

6. Chan JC, Gagliardino JJ, Baik SH, et al. Multifaceteddeterminants for achieving glycemic control: theInternational Diabetes Management Practice Study(IDMPS). Diabetes Care. 2009;32:227–33.

7. So WY, Raboca J, Sobrepena L, et al. Comprehensiverisk assessments of diabetic patients from sevenAsian countries: The Joint Asia Diabetes Evaluation(JADE) program. J Diabetes. 2011;3:109–18.

8. Inzucchi SE, Bergenstal RM, Buse JB, et al. Man-agement of hyperglycemia in type 2 diabetes: apatient-centered approach: position statement ofthe American Diabetes Association (ADA) and theEuropean Association for the Study of Diabetes(EASD). Diabetes Care. 2012;35:1364–79.

9. Inzucchi SE, Bergenstal RM, Buse JB, et al. Man-agement of hyperglycemia in type 2 diabetes, 2015:a patient-centered approach: update to a positionstatement of the American Diabetes Associationand the European Association for the Study ofDiabetes. Diabetes Care. 2015;38:140–9.

10. Owens DR. Clinical evidence for the earlier initia-tion of insulin therapy in type 2 diabetes. DiabetesTechnol Ther. 2013;15:776–85.

11. Balkau B, Calvi-Gries F, Freemantle N, et al. Pre-dictors of HbA1c over 4 years in people with type 2diabetes starting insulin therapies: the CREDITstudy. Diabetes Res Clin Pract. 2015;108:432–40.

12. Fonseca V, Gill J, Zhou R, Leahy J. An analysis ofearly insulin glargine added to metformin with orwithout sulfonylurea: impact on glycaemic controland hypoglycaemia. Diabetes Obes Metab.2011;13:814–22.

13. 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.

14. Stratton IM, Adler AI, Neil HA, et al. Association ofglycaemia with macrovascular and microvascularcomplications of type 2 diabetes (UKPDS 35):prospective observational study. BMJ.2000;321:405–12.

Diabetes Ther (2017) 8:1197–1214 1211

15. Banerji MA, Baron MA, Gao L, Blonde L. Influenceof baseline glycemia on outcomes with insulinglargine use in patients uncontrolled on oralagents. Postgrad Med. 2014;126:111–25.

16. Gerstein HC, Yale JF, Harris SB, et al. A randomizedtrial of adding insulin glargine vs. avoidance ofinsulin in people with type 2 diabetes on either nooral glucose-lowering agents or submaximal dosesof metformin and/or sulphonylureas. The CanadianINSIGHT (Implementing New Strategies with Insu-lin Glargine for Hyperglycaemia Treatment) Study.Diabet Med. 2006;23:736–42.

17. Riddle MC, Rosenstock J, Gerich J. Thetreat-to-target trial: randomized addition of glar-gine or human NPH insulin to oral therapy of type2 diabetic patients. Diabetes Care. 2003;26:3080–6.

18. Garg SK, Admane K, Freemantle N, et al. Patient-ledversus physician-led titration of insulin glargine inpatients with uncontrolled type 2 diabetes: a ran-domized multinational ATLAS study. Endocr Pract.2015;21:143–57.

19. Tsai ST, Pathan F, Ji L, et al. First insulinization withbasal insulin in patients with type 2 diabetes in areal-world setting in Asia. J Diabetes. 2011;3:208–16.

20. Ji L, Zhang P, Weng J, et al. Observational Registryof Basal Insulin Treatment (ORBIT) in patients withtype 2 diabetes uncontrolled by oral hypoglycemicagents in China—study design and baseline char-acteristics. Diabetes Technol Ther. 2015;17:735–44.

21. Ji L, Tsai ST, Lin J, Bhambani S. National variationsin comorbidities, glycosylated hemoglobin reduc-tion, and insulin dosage in Asian patients with type2 diabetes: the FINE-Asia registry. Diabetes Ther.2015;6:519–30.

22. Bi Y, Zhu D, Hong T, et al. Insulin glargine as anadjunct to oral antidiabetic drugs for Asians withtype 2 diabetes: a pooled analysis to identify pre-dictors of dose and treatment response. Presented at52nd Annual Meeting of the European Associationfor the Study of Diabetes; September 2016 10–16;Munich, Germany. ePoster 840.

23. American Diabetes Association. Standards of medi-cal care in diabetes—2017. Diabetes Care.2017;40(Suppl 1):S4–135.

24. Bretzel RG, Nuber U, Landgraf W, et al. Once-dailybasal insulin glargine versus thrice-daily prandialinsulin lispro in people with type 2 diabetes on oralhypoglycaemic agents (APOLLO): an open ran-domised controlled trial. Lancet. 2008;371:1073–84.

25. Schreiber SA, Haak T. Insulin glargine benefitspatients with type 2 diabetes inadequately

controlled on oral antidiabetic treatment: anobservational study of everyday practice in 12,216patients. Diabetes Obes Metab. 2007;9:31–8.

26. Yki-Jarvinen H, Juurinen L, Alvarsson M, et al. Ini-tiate Insulin by Aggressive Titration and Education(INITIATE): a randomized study to compare initia-tion of insulin combination therapy in type 2 dia-betic patients individually and in groups. DiabetesCare. 2007;30:1364–9.

27. Kadowaki T, Ohtani T, Naito Y, Odawara M.Potential formula for the calculation of starting andincremental insulin glargine doses: ALOHA sub-analysis. PLoS One. 2012;7:e41358. doi:10.1371/journal.pone.0041358.

28. Pan CY, Sinnassamy P, Chung KD, Kim KW. Insulinglargine versus NPH insulin therapy in Asian type 2diabetes patients. Diabetes Res Clin Pract.2007;76:111–8.

29. Ji L, Zhang P, Zhu D, et al. Observational Registry ofBasal Insulin Treatment (ORBIT) in patients withtype 2 diabetes uncontrolled with oral antihyper-glycaemic drugs: real-life use of basal insulin inChina. Diabetes Obes Metab. 2017;19:822–30.

30. Sanofi. LANTUS� (insulin glargine) prescribinginformation. Paris: Sanofi; 2015.

31. European Medicines Agency. EPAR summary for thepublic. Lantus (insulin glargine). 2012. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000284/WC500036073.pdf. Accessed September 2017.

32. Devries JH, Meneghini L, Barnett A, et al. Apatient-level analysis of efficacy and hypoglycaemiaoutcomes across treat-to-target trials with insulinglargine added to oral antidiabetes agents in peoplewith type 2 diabetes. Eur Endocrinol. 2014;10:23–30.

33. Owens DR, Traylor L, Dain MP, Landgraf W. Effi-cacy and safety of basal insulin glargine 12 and24 weeks after initiation in persons with type 2diabetes: a pooled analysis of data from treatmentarms of 15 treat-to-target randomized controlledtrials. Diab Res Clin Prac. 2014;106:264–74.

34. Arnolds S, Heise T, Flacke F, Sieber J. Commonstandards of basal insulin titration in type 2 dia-betes. J Diabetes Sci Technol. 2013;7:771–88.

35. Wangnoo SK, Sethi B, Sahay RK, et al. Treat-to-tar-get trials in diabetes. Indian J Endocrinol Metab.2014;18:166–74.

36. Garber AJ. Treat-to-target trials: uses, interpretationand review of concepts. Diabetes Obes Metab.2014;16:193–205.

1212 Diabetes Ther (2017) 8:1197–1214

37. Tan AM, Muthusamy L, Ng CC, et al. Initiation ofinsulin for type 2 diabetes mellitus patients: whatare the issues? A qualitative study. Singapore Med J.2011;52:801–9.

38. Chan JC, So W, Ma RC, et al. The complexity ofvascular and non-vascular complications of dia-betes: the Hong Kong Diabetes Registry. Curr Car-diovasc Risk Rep. 2011;5:230–9.

39. Davies M, Storms F, Shutler S, Bianchi-Biscay M,Gomis R. Improvement of glycemic control insubjects with poorly controlled type 2 diabetes:comparison of two treatment algorithms usinginsulin glargine. Diabetes Care. 2005;28:1282–8.

40. Hsu WC, Lau KH, Huang R, et al. Utilization of acloud-based diabetes management program forinsulin initiation and titration enables collabora-tive decision making between healthcare providersand patients. Diabetes Technol Ther.2016;18:59–67.

41. Tildesley HD, Mazanderani AB, Ross SA. Effect ofinternet therapeutic intervention on A1C levels inpatients with type 2 diabetes treated with insulin.Diabetes Care. 2010;33:1738–40.

42. Levy N, Moynihan V, Nilo A, et al. The MobileInsulin Titration Intervention (MITI) for insulinadjustment in an urban, low-income population:randomized controlled trial. J Med Internet Res.2015;17:e180. doi:10.2196/jmir.4716.

43. Liang X, Wang Q, Yang X, et al. Effect of mobilephone intervention for diabetes on glycaemic con-trol: a meta-analysis. Diabet Med. 2011;28:455–63.

44. Bee YM, Batcagan-Abueg AP, Chei CL, et al. Asmartphone application to deliver a treat-to-targetinsulin titration algorithm in insulin-naive patientswith type 2 diabetes: a pilot randomized controlledtrial. Diabetes Care. 2016;39:e174–6. doi:10.2337/dc16-0419.

45. Spat S, Holl B, Petritsch G, et al. Automatic systemtesting of a decision support system for insulindosing using Google Android. Stud Health TechnolInform. 2013;186:187–91.

46. Singapore General Hospital. SGH and Duke-NUS tostudy effectiveness of mobile app in helping type 2diabetes patients new to insulin therapy. 2013.https://www.sgh.com.sg/about-us/newsroom/news-release/Pages/SGHandDuke-NUStostudyeffectivenessofmobileappinhelpingtype2diabetespatientsnewtoinsulintherapy.aspx. Accessed September 2017.

47. Chomutare T, Fernandez-Luque L, Arsand E, Hart-vigsen G. Features of mobile diabetes applications:review of the literature and analysis of current

applications compared against evidence-basedguidelines. J Med Internet Res. 2011;13:e65.

48. Kim HS, Jeong HS. A nurse short message service bycellular phone in type-2 diabetic patients for sixmonths. J Clin Nurs. 2007;16:1082–7. doi:10.2196/jmir.1874.

49. Kim HS, Song MS. Technological intervention forobese patients with type 2 diabetes. Appl Nurs Res.2008;21:84–9.

50. Yoon KH, Kim HS. A short message service by cel-lular phone in type 2 diabetic patients for 12months. Diabetes Res Clin Pract. 2008;79:256–61.

51. Bajaj HS, Venn K, Ye C, Aronson R. Randomizedtrial of long-acting insulin glargine titration webtool (LTHome) versus enhanced usual therapy ofglargine titration (INNOVATE trial). DiabetesTechnol Ther. 2016;18:610–5.

52. Insulia. Homepage. 2017. http://www.insulia.com/#!home. Accessed September 2017.

53. US Food and Drug Administration. Insulia approvalletter. 2017. https://www.accessdata.fda.gov/cdrh_docs/pdf17/K170669.pdf. Accessed September2017.

54. iSage Rx. Homepage. 2017. https://isageapp.com/.Accessed September 2017.

55. US Food and Drug Administration. iSage Rxapproval letter. 2017. https://www.accessdata.fda.gov/cdrh_docs/pdf16/K161865.pdf. AccessedSeptember 2017.

56. My Dose Coach. Homepage. 2017. https://www.mydosecoach.com/. Accessed September 2017.

57. US Food and Drug Administration. My Dose Coachapproval letter. https://www.accessdata.fda.gov/cdrh_docs/pdf16/K163099.pdf. Accessed Septem-ber 2017.

58. Free C, Phillips G, Watson L, et al. The effectivenessof mobile-health technologies to improve healthcare service delivery processes: a systematic reviewand meta-analysis. PLoS Med. 2013;10:e1001363.doi:10.1371/journal.pmed.1001363.

59. Arora S, Peters AL, Agy C, Menchine M. A mobilehealth intervention for inner city patients withpoorly controlled diabetes: proof-of-concept of theTExT-MED program. Diabetes Technol Ther.2012;14:492–6.

60. Fischer HH, Moore SL, Ginosar D, et al. Care by cellphone: text messaging for chronic disease man-agement. Am J Manag Care. 2012;18:e42–7.

Diabetes Ther (2017) 8:1197–1214 1213

61. Osborn CY, Mulvaney SA. Development and feasi-bility of a text messaging and interactive voiceresponse intervention for low-income, diverseadults with type 2 diabetes mellitus. J Diabetes SciTechnol. 2013;7:612–22.

62. Farmer A, Gibson OJ, Tarassenko L, Neil A. A sys-tematic review of telemedicine interventions tosupport blood glucose self-monitoring in diabetes.Diabet Med. 2005;22:1372–8.

63. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Con-sensus statement by the American Association ofClinical Endocrinologists and American College ofEndocrinology on the basis of type 2 diabetesmanagement algorithm—2017 executive summary.Endocr Pract. 2017;23:207–38.

64. Handelsman Y, Bloomgarden ZT, Grunberger G,et al. American Association of Clinical Endocrinol-ogists and American College of Endocrinology—clinical practice guidelines for developing a dia-betes mellitus comprehensive care plan—2015.Endocr Pract. 2015;21(Suppl 1):S1–87.

65. International Diabetes Federation. Global guidelinefor type 2 diabetes. 2012. https://www.idf.org/our-activities/advocacy-awareness/resources-and-tools/79:global-guideline-for-type-2-diabetes.html. Acces-sed September 2017.

66. Perkumpulan Endokrinologi Indonesia. Clinicalpractice guideline of insulin therapy in diabetesmellitus patients (in Indonesian). 2015. http://pbperkeni.or.id/newperkeni/wp-content/plugins/download-attachments/includes/download.php?id=102. Accessed September 2017.

67. Department of Health of the Government of theHong Kong Special Administrative Region. HongKong reference framework for diabetes care foradults in primary care settings: revised edition2017. 2017. http://www.pco.gov.hk/english/resource/files/RF_DM_full.pdf. Accessed September2017.

68. Philippine Society of Endocrinology Diabetes andMetabolism. Philippine practice guidelines on thediagnosis and management of diabetes mellitus.

2014. http://endo-society.org.ph/v5/wp-content/uploads/2013/06/Diabetes-United-for-Diabetes-Phil.pdf. Accessed September 2017.

69. Ministry of Health Malaysia. Practical guide toinsulin therapy in type 2 diabetes mellitus. 2011.http://www.mems.my/file_dir/3308086634dc0e0f9e1c72.pdf. Accessed September 2017.

70. Diabetes Association of the Republic of China.(Taiwan). Executive summary: clinical practiceguidelines for diabetes care. Formos. J EndocrinolMetab. 2015;6:1–8.

71. Diabetes Association of Thailand. Clinical practiceguideline for diabetes. 2014. http://203.157.39.7/imrta/images/cpg20141120.pdf. Accessed Septem-ber 2017.

72. Goh SY, Ang SB, Bee YM, et al. Ministry of Healthclinical practice guidelines: diabetes mellitus. Sin-gapore Med J. 2014;55:334–47.

73. Shultz EK, Bauman A, Hayward M, Holzman R.Improved care of patients with diabetes throughtelecommunications. Ann N Y Acad Sci.1992;670:141–5.

74. Wong FK, Mok MP, Chan T, Tsang MW. Nursefollow-up of patients with diabetes: randomizedcontrolled trial. J Adv Nurs. 2005;50:391–402.

75. Serrano V, Rodriguez-Gutierrez R, Hargraves I, et al.Shared decision-making in the care of individualswith diabetes. Diabet Med. 2016;33:742–51.

76. Shah ND, Mullan RJ, Breslin M, et al. Translatingcomparative effectiveness into practice: the case ofdiabetes medications. Med Care. 2010;48:S153–8.

77. Berard L, Bonnemaire M, Mical M, Edelman S.Insights into optimal basal insulin titration in type2 diabetes: results of a quantitative survey. DiabetesObes Metab. 2017;. doi:10.1111/dom.13064.

78. Yoon KH, Lee JH, Kim JW, et al. Epidemic obesityand type 2 diabetes in Asia. Lancet.2006;368:1681–8.

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