REVIEW

Individualizing Time-in-Range Goals in Managementof Diabetes Mellitus and Role of Insulin: ClinicalInsights From a Multinational Panel

Sanjay Kalra . Shehla Shaikh . Gagan Priya . Manas P. Baruah . Abhyudaya Verma . Ashok K. Das . Mona Shah .

Sambit Das . Deepak Khandelwal . Debmalya Sanyal . Sujoy Ghosh . Banshi Saboo . Ganapathi Bantwal .

Usha Ayyagari . Daphne Gardner . Cecilia Jimeno . Nancy E. Barbary . Khadijah A. Hafidh . Jyoti Bhattarai .

Tania T. Minulj . Hendra Zufry . Uditha Bulugahapitiya . Moosa Murad . Alexander Tan . Selim Shahjada .

Mijinyawa B. Bello . Prasad Katulanda . Gracjan Podgorski . Wajeeha I. AbuHelaiqa . Rima Tan . Ali Latheef .

Sedeshan Govender . Samir H. Assaad-Khalil . Cecilia Kootin-Sanwu . Ansumali Joshi . Faruque Pathan .

Diana A. Nkansah

Received: September 17, 2020 /Accepted: November 19, 2020 / Published online: December 26, 2020� The Author(s) 2020

ABSTRACT

Diabetes mellitus is a global health concernassociated with significant morbidity and

mortality. Inadequate control of diabetes leadsto chronic complications and higher mortalityrates, which emphasizes the importance ofachieving glycemic targets. Although glycatedhemoglobin (HbA1c) is the gold standard formeasuring glycemic control, it has several

S. Kalra (&)Department of Endocrinology, Bharti Hospital andBRIDE, Karnal, Haryana, Indiae-mail: brideknl@gmail.com

S. ShaikhDepartment of Endocrinology, KGN Institute ofDiabetes and Endocrinology, Mumbai, Maharashtra,India

G. PriyaDepartment of Endocrinology, Fortis Hospital,Chandigarh, Punjab, India

M. P. BaruahDepartment of Endocrinology, Excel Hospital,Guwahati, Assam, India

A. VermaEndocrine Division, Index Medical College, Indore,Madhya Pradesh, India

A. K. DasDepartment of Endocrinology and Medicine,Pondicherry Institute of Medical Sciences,Puducherry, India

M. ShahHARMONY Endocrine Diabetes and MetabolicClinic, Vadodara, Gujarat, India

S. DasDepartment of Endocrinology, Apollo Hospitals,Bhubaneswar, Odisha, India

D. KhandelwalDepartment of Endocrinology and Diabetes,Maharaja Agrasen Hospital, New Delhi, India

D. SanyalDepartment of Endocrinology, KPC MedicalCollege, Kolkata, West Bengal, India

S. GhoshDepartment of Endocrinology and Metabolism,IPGMER, Kolkata, West Bengal, India

B. SabooDia Care, Diabetes Care and Hormone Clinic,Ahmedabad, Gujarat, India

G. BantwalDepartment of Endocrinology, St. John’s MedicalCollege and Hospital, Bangalore, Karnataka, India

U. AyyagariDepartment of Endocrinology, Apollo Sugar Clinics,Chennai, Tamil Nadu, India

Diabetes Ther (2021) 12:465–485

https://doi.org/10.1007/s13300-020-00973-0

limitations. Therefore, in recent years, alongwith the emergence of continuous glucosemonitoring (CGM) technology, glycemic con-trol modalities have moved beyond HbA1c.They encompass modern glucometrics, such asglycemic variability (GV) and time-in-range(TIR). The key advantage of these newer metricsover HbA1c is that they allow personalized dia-betes management with person-centric gly-cemic control. Basal insulin analogues,especially second-generation basal insulins withproperties such as longer duration of action andlow risk of hypoglycemia, have demonstratedclinical benefits by reducing GV and improvingTIR. Therefore, for more effective and accuratediabetes management, the development of anintegrated approach with second-generationbasal insulin and glucometrics involving GVand TIR is the need of the hour. With thisobjective, a multinational group of

endocrinologists and diabetologists reviewedthe existing recommendations on TIR, providedtheir clinical insights into the individualizationof TIR targets, and elucidated on the role of thesecond-generation basal insulin analogues inaddressing TIR.

Keywords: Clinical insights; Continuousglucose monitoring; Diabetes; Glycemicvariability; Hypoglycemia; Insulin degludec;Insulin detemir; Insulin glargine 100 U/mL;Insulin glargine 300 U/mL; Insulin therapy;Second-generation basal insulin; Time-in-range

D. GardnerDepartment of Endocrinology, Singapore GeneralHospital, Singapore, Singapore

C. JimenoDepartment of Endocrinology, Philippine Society ofEndocrinology, Diabetes and Metabolism, Manila,Philippines

N. E. BarbaryDepartment of Endocrinology, Ain ShamsUniversity, Cairo, Egypt

K. A. HafidhDepartment of Endocrinology, Rashid Hospital-Dubai Health Authority, Dubai, UAE

J. BhattaraiDepartment of Endocrinology, Metro KathmanduHospital, Kathmandu, Nepal

T. T. MinuljDepartment of Endocrinology, General HospitalKaryadi, Semarang, Indonesia

H. ZufryDepartment of Endocrinology, General HospitalZainoel Abidin, Aceh, Indonesia

U. BulugahapitiyaDepartment of Endocrinology, Colombo SouthTeaching Hospital, Colombo, Sri Lanka

M. MuradDepartment of Internal Medicine, Indira GandhiMemorial Hospital, Male, Maldives

A. TanDepartment of Endocrinology, Sunway MedicalCentre, Kuala Lumpur, Malaysia

S. ShahjadaDepartment of Endocrinology, BSMMU(Bangabandhu Sheikh Mujib Medical UniversityHospital), Dhaka, Bangladesh

M. B. BelloDepartment of Endocrinology, Gwarinpa DistrictHospital, Abuja, Nigeria

P. KatulandaDepartment of Endocrinology, University ofColombo, Colombo, Sri Lanka

G. PodgorskiDepartment of Endocrinology, Greenacres Hospital,Port Elizabeth, South Africa

W. I. AbuHelaiqaDepartment of Endocrinology, Hamad GeneralHospital, Doha, Qatar

R. TanDepartment of Endocrinology, FEU-NRMF MedicalCenter, Quezon City, Philippines

A. LatheefDepartment of Endocrinology, Indira GandhiMemorial Hospital, Male, Maldives

S. GovenderUmhlanga Centre for Diabetes Endocrinology,Durban, South Africa

466 Diabetes Ther (2021) 12:465–485

Key Summary Points

Although glycated hemoglobin (HbA1c) isthe gold standard for measuring glycemiccontrol, it has several limitations.Glycemic control modalities have movedbeyond HbA1c and encompass modernglucometrics, such as glycemic variability(GV) and time-in-range (TIR).

The key advantage of these newer metricsover HbA1c is that they allow personalizeddiabetes management with person-centricglycemic control.

Basal insulin analogues, especially second-generation basal insulins with propertiessuch as longer duration of action and lowrisk of hypoglycemia, have demonstratedclinical benefits by reducing GV andimproving TIR.

A multinational group of endocrinologistsand diabetologists provided their clinicalinsights for guiding clinicians on theinitiation of insulin therapy in peoplewith diabetes, with emphasis on the roleof the second-generation basal insulinanalogues.

DIGITAL FEATURES

This article is published with digital features,including a summary slide, to facilitate under-standing of the article. To view digital featuresfor this article go to https://doi.org/10.6084/m9.figshare.13247288.

INTRODUCTION

Optimal management of diabetes necessitatesfrequent and precise measurement of bloodglucose levels [1]. Landmark trials in diabetes,including UKPDS (UK Prospective DiabetesStudy) and DCCT (Diabetes Control and Com-plications Trial), demonstrated that glycatedhemoglobin (HbA1c) is linked to vascular com-plications [2, 3]. Thereafter, HbA1c was widelyaccepted as a biomarker of glycemia andemerged as the benchmark for diabetes man-agement. Despite its importance as an indicatorfor the development for diabetes-related com-plications, many studies have also revealed thelimitations of this biomarker of glycemia [4].Apart from inaccurate test results in the pres-ence of several medical conditions, HbA1c nei-ther provides any information on glucosedynamics nor captures glucose fluctuations [4].

Self-monitoring of blood glucose (SMBG)serves as the primary technique to evaluate andmanage glycemic control [5]. Self-monitoring ofblood glucose provides immediate blood glu-cose values through intermittent finger-stickmeasurements [5]. The glucose values derivedfrom SMBG are useful in monitoring the gly-cemic effects of antidiabetic medications, food,and exercise [4]. However, the use of SMBG islimited as a result of physical discomfort,inconvenience, inaccuracy of results in a fewinstances, and errors in capillary blood glucosereadings and data recording [5]. Secondly, themost important drawback of capillary bloodglucose readings is the limited amount ofinformation retrieved on the basis of measure-ments at few specific time points per day (suchas before meals and at bedtime) compared to5–10-min sampling by a continuous glucosesensor [6].

S. H. Assaad-KhalilDepartment of Endocrinology, AlexandriaUniversity, Alexandria, Egypt

C. Kootin-SanwuDepartment of Endocrinology, Ridge Hospital Accra,Accra, Ghana

A. JoshiDepartment of Endocrinology, Kathmandu Diabetesand Thyroid Center, Kathmandu, Nepal

F. PathanDepartment of Endocrinology, Bangladesh Instituteof Research and Rehabilitation for Diabetes,Endocrine and Metabolic Disorders (BIRDEM),Dhaka, Bangladesh

D. A. NkansahDepartment of Endocrinology, 37 Military HospitalAccra, Accra, Ghana

Diabetes Ther (2021) 12:465–485 467

Clinical observations have revealed thatglucose profiles can greatly differ even in indi-viduals with well-controlled diabetes. Whilesome people with diabetes have small or mod-erate glucose excursions with rare hypo-glycemia events, others have significantly largeglucose fluctuations with frequent episodes ofhypoglycemia. Such fluctuations in glucoselevels over time within the same day, orbetween different days at the same time points,are reflected as GV. GV is one of the majorcomponents of dysglycemia in people withdiabetes [4]. Accumulating evidence indicatesthat apart from chronic hyperglycemia, thechronic complications of diabetes also resultfrom hypoglycemia and GV [1]. Besides, GV isalso a major determinant of hypoglycemia,which gives another reason to target GV forintervention [7, 8]. However, GV is not accu-rately reflected by both widely used tools formonitoring glycemia, namely HbA1c and SMBG[5, 9]. Therefore, apart from reducing the gly-cemic burden, as recorded by HbA1c, minimiz-ing GV is an appropriate treatment goal and theneed of the hour [10].

A reliable measurement of GV is provided bycontinuous glucose monitoring (CGM), whichallows for 24-h real-time measurement of glu-cose levels [10], and it can be performed in realtime or intermittently. Intermittently viewedmonitoring (I-CGM) shows continuous glucosenumbers retrospectively. This method of mon-itoring is an intermediate between a CGM sys-tem and a normal blood glucose meter. UnlikeI-CGM, real-time CGM (RT-CGM) offers real-time measurement of glucose trends, direction,and the rate of glycemic change. It must benoted that CGM provides results based onmeasurements of the interstitial fluid and not ofblood monitoring; therefore, ‘‘real-time’’ may bea misnomer and delays are a part of this processas well [11]. The development of CGM tech-nology has permitted the creation of new met-rics for monitoring glucose, such as GV and thepercentage of time spent in target glucoserange—called TIR (time-in-range). These met-rics provide clinical insights into short-termglycemic control. CGM also provides key inputsto allow algorithm-based insulin delivery [9].

As a result of the limitations of HbA1c inmonitoring short-term glycemic changes andthe emergence of new metrics for monitoringglucose, the term ‘‘beyond HbA1c’’ has emergedin the field of diabetes research over the pastfew years. The field of ‘‘beyond HbA1c’’ includesglucometrics, such as TIR, GV, and the per-centage of time in hyperglycemia and hypo-glycemia, and person-reported outcomes, i.e.,quality-of-life (QoL) assessments. With theincreasing accuracy of CGM, blood glucosemonitoring in people with diabetes is entering anew era [9].

Even though there is evidence favoring earlyinitiation of insulin therapy in individuals withpoorly controlled diabetes by oral antidiabeticdrugs (OADs), the optimal use of insulin ther-apy is delayed by several physician- and person-related barriers. The second-generation basalinsulin analogues glargine 300 U/mL (Gla-300)and insulin degludec evidently provide moretherapeutic benefits, have lower risk of hypo-glycemia, and also possess longer action profiles([24 h) compared to first-generation insulinanalogues [12]. As compared to first-generationinsulin analogues, second-generation analoguesoffer lower GV and comparable TIR [13].Further, emerging evidence indicates that thesesecond-generation basal insulin analogues helpovercome barriers associated with early insulinuse and effectively address parameters involvedin moving ‘‘beyond HbA1c’’ [12].

With this background, an effort was under-taken to develop clinical evidence-based expertopinions and views for delineating appropriatebasal insulin strategies for the treatment ofdiabetes, based on modern glucose metrics suchas GV and TIR. This document summarizes thebackground evidence-based discussion and keyopinions and views of multinational experts onbasal insulin strategies for better accuracy indiabetes management.

METHODS

A group of multinational clinical experts com-prising diabetologists and endocrinologistsfrom 15 countries, namely India, Nepal,Indonesia, Ghana, UAE, Bangladesh, Egypt,

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Malaysia, Philippines, Nigeria, Sri Lanka, Qatar,Maldives, South Africa, and Singapore, met vir-tually on 31 May 2020. The expert panel thor-oughly reviewed available literature evidenceand discussed the importance of TIR and basalinsulin strategies in diabetes management, withemphasis on the role of second-generation basalinsulin analogues. The clinical insights into TIRprovided were based on the review of theAdvanced Technologies and Treatments forDiabetes (ATTD) international consensus on theuse of CGM 2017 and TIR 2019. Additionally, areview of published literature comparing theTIR profiles of the basal insulins was conductedon the basis of databases searches from PubMedand Google Scholar using the terms ‘‘time inrange’’ in combination with ‘‘glargine,’’ ‘‘deglu-dec,’’ and ‘‘detemir.’’ Further, a gray literaturesearch was performed using the same searchterms. Articles published in journals resultingfrom these searches in the last 5 years and rel-evant references cited in those articles wereexamined. Only the relevant articles publishedin English were included.

On the basis of key opinions, review of sci-entific evidence, and clinical judgment, thepanel provided their clinical insights into indi-vidualizing TIR and basal insulin strategies indiabetes management, which are summarizedin this article. This article is based on previouslyconducted studies and does not contain anystudies with human participants or animalsperformed by any of the authors.

EMERGING GLUCOSE METRICSAND MEASURES: IMPACTON DIABETES OUTCOMES

Moving ‘‘Beyond HbA1c’’: Need of the Hour

Measurement of HbA1c is considered the goldstandard method for assessing chronic glycemiccontrol in people with diabetes. However, themeasurement of HbA1c has its limitations,including its inability to measure acute glucosefluctuations. Further HbA1c is an unreliablemeasure in patients with anemia, iron defi-ciency, hemoglobinopathies, and during

pregnancy; moreover, it does not provideinformation about hypoglycemia and on howto adjust the treatment regimen when HbA1c

levels are elevated. Therefore, although HbA1c isa valuable indicator of glycation, as well as anindicator of population health and diabeticcomplications, some limitations do exist forthis parameter as well [14].

Lack of Reliability of HbA1c in EstimatingPrevailing Glycemia: Concept of GlycationGap

Absolute dependence on HbA1c for assessmentof glycemic control in diabetes may lead to anerror in clinical assessment and managementowing to either under- or overestimation ofprevailing glycemia. The deviation of HbA1c

from serum fructosamine-predicted HbA1c isdefined as the glycation gap (GGap), anddepicts an individually consistent differencebetween other measures of mean glycemia andHbA1c [15]. A glycation gap is found in around40% of people with diabetes and is associatedwith diabetes-related complications and mor-tality [15]. Individuals with a positive GGapmay receive uptitration of glycemia treatment,putting them at undue risk for hypoglycemia.However, individuals with a negative GGapmay be falsely reassured with a measured HbA1c

level that is lower than actual glycemic status.This does not result in appropriate therapyintensification to improve glycemia, puttingsuch individuals at risk for diabetes-relatedcomplications [15]. Therefore, for therapeuticpurposes, using HbA1c levels alone is not com-pletely reliable for evaluating glycemic status[15].

SMBG: Limitations in Filling GlycationGap

Although SMBG has gained broad applicationwith the widespread availability of glucometers,this traditional method only measures singleglucose values at time points determined by theuser. Therefore, SMBG only provides a snapshotof the whole glucose picture—ignoring rapidglycemic changes occurring between SMBG

Diabetes Ther (2021) 12:465–485 469

measurements [4]. It does not provide anyindication of the rate or direction of glucoselevel changes [14]. As a result, even frequentSMBG does not adequately reflect the GV orGGap in people with diabetes, since it providesonly serial, single time-point measurements in24-h glucose dynamics [5].

Continuous Glucose Monitoring

The field of daily management of diabetes withglucose concentration monitoring was revolu-tionized with the introduction of minimallyinvasive needle CGM sensors in 1999 [16]. CGMsensors measure interstitial glucose concentra-tions. A transmitter is linked to the sensor,which sends signals to an insulin pump orhandheld receiver or smartphone supportedwith an appropriate application. CGM is com-monly used in two ways: real-time CGM bypatients and retrospective CGM by clinicians[17].

CGM sensors provide almost continuousglucose measurement, delivering readings every5 min. Additionally, the use of CGM revealshypo- and hyperglycemic events that are notdetected by SMBG. This system improves gly-cemic control and reduces GV [18, 19]. Besidesthe real-time availability of glucose concentra-tion, CGM also provides users with visual/acoustic hypoglycemic alerts, which help miti-gate or avoid hypoglycemia [16].

Unlike SMBG, which measures glucose levelsin the blood, CGM measures glucose changes ininterstitial fluid (ISF). There are differencesbetween blood glucose and ISF glucose: whileblood transfers glucose to all parts of the body,ISF transfers glucose to cells. Further, ISF glucoseis measured continuously every few minutes,while SMBG is performed a few times every day[20].

Compared to HbA1c, CGM is a more directand integrated method for estimating meanglucose levels [21]. This method helps in meanglucose calculations through a better reflectionof glycemic peaks and troughs along with pro-viding high-density data, thereby addressingthe GGap for individual patients. Therefore,

CGM potentially complements HbA1c for esti-mating glycemic control [15].

Systematic analyses of CGM data enablevisualization of glucose changes over time andalso help identify factors responsible for suchchanges, thereby providing indications foroptimizing diabetes therapy [20]. However,implantation of the CGM system is associatedwith some inconvenience and discomfort, aswell as requiring higher levels of medical inter-vention [22]. The advantages and disadvantagesof the CGM system are summarized in Table 1.

Improved Glycemic Outcomes with CGM:Clinical Evidence

In Type 1 Diabetes Mellitus: Although conven-tional intensive insulin therapy leads to goodglycemic control, it is associated with the risk ofhypoglycemia [29]. In an open-label, random-ized crossover trial (Glycaemic control & Opti-misation of Life quality in type 1 Diabetes[GOLD] study) conducted among adults withtype 1 diabetes mellitus (T1DM), it was observedthat intensive insulin therapy with multipledaily insulin injections (MDI) was more effec-tive using CGM as compared to conventionaltreatment (HbA1c, 7.92% vs. 8.35%) [18]. TheGOLD 3 study assessed the effects of CGM onnocturnal and daytime hypoglycemia in peoplewith T1DM treated with MDI. The time withnocturnal glucose levels below 70 mg/dLdecreased by 48%, while glucose levels below54 mg/dL reduced by 65% with CGM. Timewith daytime glucose levels below 70 mg/dLreduced by 40% and below 54 mg/dL by 54%.The study concluded that CGM reduced bothnocturnal and daytime hypoglycemia in peoplewith T1DM treated with MDI and improvedhypoglycemia-related confidence, therebyimproving the QoL [29].

In Type 2 Diabetes Mellitus: In people withtype 2 diabetes mellitus (T2DM) using insulin,CGM is a monitoring tool and influences thechoice of insulin regimen. This method can beused to motivate patients to choose earlierinsulin treatments, in case of oral antidiabeticdrug failure, and for selecting the most appro-priate insulin regimen [30].

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CGM may be useful in predicting hypo-glycemia in high-risk populations such aselderly people using insulin. Klimontov andMyakina used blinded CGM in 83 insulin-trea-ted elderly inpatients (65–80 years old) to assessthe risk of nocturnal hypoglycemia. The studyobserved nocturnal hypoglycemia in 39% of the24-h CGM recordings [31].

A prospective randomized trial by Ehrhardtet al. comparing SMBG and RT-CGM demon-strated a significant improvement in HbA1c

following RT-CGM in people with T2DM nottaking prandial insulin. While the mean declinein HbA1c at 12 weeks was 0.5 ± 0.8% in theSMBG group, it was 1.0 ± 1.1% in the RT-CGMgroup (p = 0.006) [32]. In the study by Zicket al., 72 h of CGM was used in people with

T2DM on MDI. It was reported that CGMdetected 56.9% of individuals with hypo-glycemia, compared to 26.4% detected by con-ventional SMBG. Moreover, in people withT2DM treated with a variety of insulin regi-mens, CGM revealed a more comprehensivepicture of hypoglycemia, even during a periodof stable therapy [33]. As per a study by Pazos-Couselo et al., significantly higher percentagesof hyperglycemic (p = 0.047) and hypoglycemicepisodes (p = 0.016) were detected by CGMcompared to SMBG. Further CGM detectednocturnal hypoglycemia in 33% of participants.It was also observed that 19% of participantswho reportedly had no hypoglycemia by SMBGmeasurements had hypoglycemia when asses-sed using CGM measurements [34].

Table 1 Advantages and limitations of CGM

Advantages [22, 23] Limitations

Detailed assessment of glycemic

control

Safety issues: Site reactions; rashes due to adhesives; falling off, pulling off, sweating (all

significantly improved with recent modifications); losing receiver or transmitter; various

transmission issues at night; sensors malfunctioning, and silencing of alarms if the

smartphone is in silent or vibration mode [24].

Provides comprehensive glucose

data

Technical issues: Adjustment of initial calibration and regular daily recalibrations required

for some of the currently available devices; episodic differences in the performance of

the sensor in the same individual; sensors can be used for only varying lengths of time,

with implantable sensors lasting the longest [24].

Sensor accuracy issues: In extreme glucose ranges, such as\60 mg/dL or[200 mg/dL,

observed during prolonged aerobic exercise, sensor accuracy may be compromised. This

disadvantage continues to be a challenge and calls for patient awareness [25].

Alerts for hypoglycemia and

hyperglycemia

Privacy and data concerns: There are risks to the privacy of data of patients and their

ownership and ability to control how their information is collected, stored, and used

[26]. However, privacy and patient-data-related concerns are associated with cloud data

storage and the risk for hacks, and not technically with the sensor per se.

No missed recordings User/patient-related issues: Burden of wearing a device continuously; a skin puncture is

done each time for insertion of the glucose sensor into the subcutaneous part of skin

tissue; complex and difficult to personalize the user interface [24]. However, the user

interface, displays, user-friendliness, data management, and data analysis software have

significantly improved over time [27].

Impact of sleep positions: ‘‘Compression lows’’—Specific sleep positions might result in

aberrant glucose readings, such as a sudden decrease in reported glucose values,

presumably due to decreased local blood flow caused by tissue compression. In some

cases, aberrant CGM readings display elevated values [28].

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Optimal utilization of CGM may also help inmotivating or avoiding diabetes burnout inpeople with T2DM. Evidence indicates thatimproved lifestyle and behavior changes, i.e.,reduced diabetes burnout associated withRT-CGM use, result in reduced HbA1c levels inthese people [35].

RECENT TECHNIQUESFOR MEASURING BLOOD GLUCOSEFLUCTUATIONS: TIME-IN-RANGEAND GLYCEMIC VARIABILITY

GV refers to fluctuations in blood glucoselevels. Fluctuations in blood glucose levels canlead to intraday and interday variations, whichcan increase both the risk of hypoglycemia andglycemic excursions to the hyperglycemicrange [36]. For people using CGM, TIR isdefined as the time spent in the target glucoserange (70–180 mg/dL) while aiming at reduc-ing the time spent in hypoglycemia. TIR servesas an outcome measure for glycemic control inclinical trials, for complementing other com-ponents such as HbA1c and blood glucoselevels [37].

GV and Its Implications in DiabetesMellitus

Several studies have elucidated the relationshipbetween GV and hypoglycemia. Hypoglycemiais more common in individuals with increasedGV [36]. A pooled analysis of six randomizedcontrolled trials (RCTs) conducted among peo-ple with T2DM treated with 24 weeks of Gla-100or comparators demonstrated that all measuresof GV were significantly associated with poorglycemic control and the development ofhypoglycemia during the trial [38]. Moreover,intraday GV is associated with a higher risk ofnocturnal and overall hypoglycemia, and adecrease in GV is strongly correlated with areduction in both hyperglycemic and hypo-glycemic episodes [36].

Studies have highlighted the key role playedby GV in T1DM as well. Besides reinforcing therelationship between GV and the risk of

hypoglycemia, these studies have also shown alink between GV and the development of car-diovascular autonomic dysfunction in adultswith T1DM. Further the increased inflamma-tion as a result of GV could lead to endothelialdamage and vascular complications in adultswith T1DM [39].

Analysis of data from the double-blind TrialComparing Cardiovascular Safety of InsulinDegludec versus Insulin Glargine (Gla-100) inPatients with Type 2 Diabetes at High Risk ofCardiovascular Events (DEVOTE) evaluated thelink between GV and the occurrence of severehypoglycemia and subsequent mortality. Anincreased risk of severe hypoglycemia (hazardratio [HR] 4.11, 95% confidence interval [CI]3.15, 5.35) and all-cause mortality (HR 1.58,95% CI 1.23, 2.03) was observed in individualswith interday fasting GV [40]. People experi-encing severe hypoglycemia have a greater thantwofold higher risk of cardiovascular death andall-cause mortality [41].

GV also has implications for diabetic com-plications. It is associated with markers of car-diovascular and endothelial damage. High GV isassociated with cognitive impairment in peoplewith T2DM [36]. GV has also been associatedwith the prediction of mortality: a higher risk ofmortality is observed in individuals with highervisit-to-visit GV [36]. Besides, it has beenobserved that GV has implications for patients’QoL and psychological well-being. In insulin-treated people, high GV is associated with poorQoL, as well as increased length of hospital stay.When diabetes treatment is associated with theperception of reduced GV, there is a simulta-neous improvement in QoL parameters, such astreatment satisfaction, work productivity, andabsenteeism [36].

To avoid hypoglycemia, providing treatmentthat can control blood glucose levels and at thesame time minimize interday and intraday GVis important. Mori et al. conducted a study toassess the actual state of interday GV andidentify factors affecting GV in diabetic outpa-tients on insulin therapy. Interday GV was seenin 93% of outpatients, and 62% of patientsshowed inconsistent interday GV. Interdayvariability was associated with the followingfactors: gender (higher in women compared to

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men, p = 0.04), diabetes type (higher in peoplewith T1DM compared to those with T2DM, p\0.001), dose of insulin (mean of the daily dif-ferences [MODD] correlated positively withtotal insulin dose, bolus insulin dose, and basalinsulin but not with bolus dose to basal doseratio; p = 0.001, 0.016, 0.001, and 0.361,respectively), and treatment regimen (MODDvalue highest in individuals treated with basaland bolus insulin and lowest in those treatedwith mixed preparations). The study indicatedthat treatment and instructions based on indi-viduals’ characteristics, interday GV, and life-style are important for people receiving insulintherapy [42].

Connecting the Dots: Time-in-Rangeand Impact on Diabetes Outcomes

Advancements in CGM technology have pro-vided access to alternative indices and newmetrics of glucose control. Among these met-rics, TIR has emerged as a preferred measureamong individuals with diabetes. Also, emerg-ing evidence indicates that TIR can predictlong-term complications of diabetes and preg-nancy outcomes. However, in the case ofphysicians who are mostly familiar with HbA1c

and blood glucose measurements, it might bedifficult to understand and explain TIR goals topatients, position TIR in comparison to otherglucose metrics, and interpret TIR [43]. TheAdvanced Technologies & Treatments for Dia-betes (ATTD) international consensus on theuse of CGM 2017 standardized the use of CGMto promote therapy adjustments in people withboth type 1 and type 2 diabetes mellitus, espe-cially those with frequent hypoglycemia. Beforethe 2017 consensus, different studies used dif-ferent time-in-target ranges, and hence onestudy could not be compared with another. Toovercome such variations and discrepancies, theATTD consensus categorized hypoglycemia intothree levels:(i) Level 1 (54 to\ 70 mg/dL)(ii) Level 2 (\54 mg/dL)(iii) Level 3 (severe hypoglycemia causing cog-

nitive impairment, not defined by definiteglucose value)

Hyperglycemia was also categorized intothree levels:

(i) Level 1 (alert level, [ 180 mg/dL toB 250 mg/dL)

(ii) Level 2 (clinically significant,[250 mg/dL)(iii) Level 3 (clinical diagnosis: hyperosmolar

hyperglycemic or state ketoacidosis)

Categorization of the time spent in the threelevels of hypoglycemia and hyperglycemiaallows a more accurate assessment of severityand facilitates initiation of the most appropriateresponse [14, 37].

On the basis of the categorization of hypo-and hyperglycemia into different levels basedon glucose values, the ATTD consensus paneldefined TIR as the time spent in an individual’starget glucose range of 70–180 mg/dL (3.9–10 mmol/L) [14]. The TIR metric includes threeCGM measurements: percentage of readingsand time per day above target glucose range(TAR), within target glucose range (TIR), andtime below target glucose range (TBR). As perthe recent ATTD international consensus on TIR(2019), most people with T1DM and T2DMshould aim to spend more than 70% of time perday (approx. [17 h) in TIR (70–180 mg/dL),with TBR (\70 mg/dL) less than 4% and TAR([180 mg/dL) being less than 25% of time perday (Fig. 1) [44].

Petersson et al. evaluated the relationshipbetween time-in-target range (TIT) and HbA1c

through CGM in children and adolescents withT1DM. While TIR was defined as 70–180 mg/dL,TIT was defined as 70–140 mg/dL. Over 60 days,the mean TIR was 60.8% (± 13.1%), while themean TIT was 40.9% (± standard deviation[SD], 12.2%). Moreover, a significant nonlinearrelation was observed between TIT and HbA1c

during the study period. The study concludedthat in addition to HbA1c, time spent in TITcould be a useful metric to assess glycemiccontrol [45].

Beck et al. conducted analyses utilizingdatasets from four randomized trials including545 adults with type 1 diabetes who had centrallaboratory measurements of HbA1c at baselineand 6 months. TIR (70–180 mg/dL [3.9–10.0 mmol/L]) of 70% and 50% correspondedwith HbA1c values of approximately 7% and 8%,

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respectively. An increase in TIR of 10% (2.4 hper day) corresponded to a decrease in HbA1c ofapproximately 0.6%, establishing an inverserelationship between the two [46].

Vigersky and McMahon also analyzed therelationship between TIR and HbA1c acrossmultiple studies (n = 1137), including peoplewith T2DM. The study revealed that for targetHbA1c of B 7% and B 6.5%, the %TIR targetsshould be approximately 65% and 70%,respectively. The study reported that forachieving a target decrease in HbA1c of 0.8%(9 mmol/mol), there was a 10% change in %TIR[47].

Apart from measuring glycemic control inpatients, TIR may also be used as an appropriateclinical endpoint in diabetes research [48]. Forexample, TIR serves as a valid clinical outcomefor evaluating the risk of vascular complicationsof diabetes. Evidence suggests that TIR isinversely correlated with the risk of developingvascular complications in people with diabetes[48]. On the basis of the above discussion

points, the expert panel put forward recom-mendations for TIR management based onpopulation type and the phase of life. The rec-ommendations are captured herein and sum-marized in Fig. 2.

TIR Recommendations for DifferentPopulations and Life Phases

• TIR is a useful metric in OAD inadequacy inadults, as OAD inadequacy is usually seenwithin 5 years in two-thirds of cases.

• In T1DM, the lower cutoff may be 80 mg/dLto prevent hypoglycemia.

• Adults with T2DM without complicationsdeserve tight control: [80% in 70–160mg/dL, as this group is mostly on metforminand the risk of hypoglycemia is low; hence,70 mg/dL is the acceptable lower limit andTAR\ 15%, TBR\ 5%.

• The definition of TIR needs to be individu-alized particularly in organ dysfunction,pregnancy, and the elderly.

• TIR recommendations based on the fourphases of life can be adolescents T1DM/T2DM (10–18 years), adults ([18 years),pregnancy, and elderly.

• For adolescents: A target range of70–180 mg/dL is acceptable in T1DM andT2DM. Setting the lower limit to a valueabove 70 mg/dL will suspend insulin tooearly, which is not recommended. HigherTIR is recommended for T1DM, as they aremore prone to GV due to reduced endoge-nous insulin.

(i) In T1DM:[80% TIR in a target bloodglucose of 70–180 mg/dL;\15% TAR and\5% TBR(ii) In T2DM:[ 70% TIR in a target bloodglucose of 70–180 mg/dL;\25% TAR and\5% TBR

• For adults: As most people with diabetes fallinto this category, it is better to strive fortighter control in adults. Hence, two recom-mendations can be considered for TIR inadults and individualized as needed:

(i) Same as ATTD consensus recommenda-tions for T1DM and T2DM:[70% TIR in a

Fig. 1 Continuous glucose monitoring-based time-in-range targets for patients with diabetes [44]

474 Diabetes Ther (2021) 12:465–485

target blood glucose of 70–180 mg/dL;\25% TAR and\5% TBR, or(ii) Tighter control:[ 80% TIR in a targetblood glucose of 70–160 mg/dL; \ 15%TAR and \5% TBR. Tighter control isrecommended in people who are highlymotivated, newly diagnosed, have a long-life expectancy, and do not have co-morbidities.

• For pregnancy: Considering the target rangesimilar to ATTD consensus recommenda-tions, the time spent in the target rangeshould be increased by 10%, as it has thepotential to lead to better outcomes:[ 80%TIR in a target blood glucose of 63–140 mg/dL;\15% TAR and\5% TBR.

• For elderly: Targets need to be relaxed withmore time spent in the relaxed range, as thisgroup is more susceptible to hypoglycemia;[80% TIR in a target blood glucose of90–200 mg/dL; \ 15% TAR, \5% TBR(\90 mg/dL)\ 1% (\70 mg/dL).

• 80–90% children aged\ 10 years have hypo-glycemia unawareness. Thus, the lower limitof TIR should be relaxed.

• CGM reading differences with increase intemperature should be taken in accountboth during physiological (e.g., during sum-mer) and pathological (medication intake

such as antipyretic, e.g., acetaminophen)conditions.

• The variation between CGM and SMBG ismost evident during times when blood glu-cose levels are rapidly changing.

Relationship Between Time-in-Rangeand Microvascular Outcomes

A strong association between HbA1c levels andthe risk of diabetes-associated chronic vascularcomplications was first established in the land-mark DCCT trial [2]. Using the dataset of theDCCT trial, Beck et al. evaluated the associationbetween TIR and development and/or progres-sion of microalbuminuria, and diabeticretinopathy. For every 10 percentage-pointdecrease in TIR, the hazard rate for the devel-opment of microalbuminuria was increased by40% (95% CI 25–56), while a 64% (95% CI51–78) increase in retinopathy progression wasobserved (Fig. 3). This indicates a strong associ-ation between TIR and the risk of microvascularcomplications [48]. Another study investigatedthe association between diabetic retinopathyand TIR assessed by CGM in people with T2DM.Persons with more advanced diabetic retinopa-thy had significantly lower TIR and higher

Fig. 2 Panel recommendations for TIR based on age group

Diabetes Ther (2021) 12:465–485 475

measures of GV. Moreover, with increasing TIR,the prevalence of diabetic retinopathydecreased, based on severity. TIR was negativelyassociated with diabetic retinopathy; peoplewith T2DMwith vision-threatening retinopathyhad the lowest TIR [49].

Another common microvascular complica-tion is diabetic peripheral neuropathy (DPN).In a study on the association between TIR andDPN, Mayeda et al. demonstrated that DPNprevalence was 43% and 74% among partici-pants who were within the target range[ 70%and\70% of the time, respectively. For every10% decrease in TIR, there was a 25% increasein the risk of DPN. However, there was no sig-nificant association between HbA1c and DPNsymptoms. Therefore, the study concluded thatthe prevalence of DPN is inversely correlatedwith TIR [50].

Effect of Time-in-Range on MacrovascularOutcomes

Carotid intima-media thickness (CIMT) servesas a biomarker of subclinical atherosclerosis andcan be used to predict incident cardiovascularevents. A recent study investigated the use of

TIR, measured by CGM and CIMT, as a surro-gate marker of cardiovascular disease. It wasobserved that people with T2DM and abnormalCIMT had significantly lower TIR compared tothose with normal CIMT (p\0.001). Thesefindings suggest a link between TIR andmacrovascular disease [51].

Daily Life Measures Based on Time-in-Range

An online survey was conducted to understandpatients’ perspectives regarding the success ofdiabetes therapies, factors having the greatestimpact on their daily lives, and the drivers ofdiabetes and mindset improvement. The studyrevealed TIR as the most common factor thathad a great impact on daily life across all threestudy groups (people with T1DM [T1], peoplewith T2DM on insulin therapy [T2I], and peoplewith T2DM not on insulin therapy [T2NI]).Further, 36% of T2I respondents, 54% of T1respondents, and 22% of T2NI respondentsreported TIR as the key factor for a positivemindset [52].

Fig. 3 Impact of TIR on microvascular outcomes [46]

476 Diabetes Ther (2021) 12:465–485

Individualizing TIR Goals for ImprovingOutcomes

In patients undergoing cardiac surgery, poorperioperative control of blood glucose levels isassociated with poor outcomes. Various gly-cemic targets have been prescribed to reducewound infection and overall mortality rates.A prospective study by Omar et al. evaluatedglucose control in patients with or withoutdiabetes, after cardiac surgery. The glycemictarget of the patients was 6.0–8.1 mmol/L, asdetermined by TIR. The patients with [ 80%TIR had better outcomes in terms of woundinfection (p = 0.05), length of hospital andintensive care unit (ICU) stay (p = 0.03 andp = 0.04, respectively), and length of ventila-tion (p = 0.03) as compared to those with\80% TIR [53].

Randomized trial data confirm that CGMleads to improvement in both neonatal healthoutcomes and maternal glucose control.The common target throughout pregnancy is toincrease TIR while reducing TAR and TBR.During the second and third trimesters, 5%lower TIR and 5% higher TAR is associated withan increased risk of neonatal hypoglycemia,large-for-gestational age infants, and neonatalICU admission. Therefore, a TIR of[ 70% (16 h,48 min) and a TAR of \25% (6 h) should beaimed for optimal neonatal outcomes as early aspossible during pregnancy [54].

The proposed clinical insights for TIR man-agement in the presence of complications arepresented herein and in Fig. 4.

Clinical Insights on TIRRecommendations for DifferentComplications

• CGM should be considered in pregnancy,renal failure, discordance between HbA1c,and clinical features/SMBG.

• TIR is an ‘‘additional’’ measure (along withother glycemic parameters), mainly if moreaccessible parameters are inconclusive.

• There is a need for more longitudinal studies(cross-sectional) to establish TIR as a surro-gate marker of complications.

• For individuals at high risk of hypo-glycemia (renal/hepatic disease): A relaxedtarget range with a high lower limit isrecommended;[ 70% TIR in a target bloodglucose of 90–180 mg/dL; \ 25% TAR and\5% TBR.

• With micro-/macrovascular complica-tions:(i) Microvascular: Same as adults;[70% TIRin a target blood glucose of 70–180mg/dL;\25% TAR and\5% TBR or[80% TIR in atarget blood glucose of 70–160mg/dL;\15%TAR and\5% TBR.(ii) Macrovascular: Same target as microvas-cular complications or relaxed as followingC 70% TIR in a target blood glucose of80–180mg/dL; \25% TAR and \5% TBR.While stringent control has shownmicrovascu-lar benefits, people withmacrovascular compli-cationsmaybe at ahigher riskofhypoglycemia,and hence relaxed targets are recommended.

• With concomitant acute infections:(i) Non-hospitalized: C 75% TIR in a targetblood glucose of 80–180 mg/dL;\20% TARand\5% TBR.(ii) Hospitalized: [ 80% TIR in a targetblood glucose of 140–180 mg/dL; \ 15%TAR and\ 5% TBR. The cutoffs are kept inthis range, assuming that use of antipyreticssuch as acetaminophen in acute infectionscan have an effect on CGM readings, giving afalse higher value.

• Those with fever taking antipyretics and onCGM should undergo cross-check with fin-ger stick method.

• In patients with sepsis in ICU: TAR([180 mg/dL) should be minimized to\5% and the lower limit of 70 mg/dLshould be pushed to 80 mg/dL to minimizemortality.

Diabetes Ther (2021) 12:465–485 477

BASAL INSULIN STRATEGIESFOR TIME-IN-RANGE AND GV:EMERGING POSITION OF SECOND-GENERATION BASAL INSULINS

Management of GV as the Stepping-Stonein Diabetes Management

As intraday and interday GV are risk factors inpeople with diabetes [55], several factors havebeen proposed to help reduce GV in such indi-viduals who are on insulin treatment, such as[55-60]:

• Timely insulinization• Choice of insulin• Initiation dose• Proper timing of injection of prandial insu-

lin (for regular or rapid-acting analogue)• Systematic and adequate titration• Prompt intensification (using prandial insu-

lin) when indicated• Stepwise intensification• Simple regimen• Dosing flexibility

Role of Basal Insulin Analoguesin Controlling GV in People with Diabetes

Different basal insulin analogues with variedtime–action profiles have been developed overthe years. These include first-generation basalinsulin analogues, viz. Gla-100 and insulindetemir, second-generation basal insulin ana-logues, viz. Gla-300 and insulin degludec.Understanding the differences between first-and second-generation basal insulin analogueshelps healthcare providers in making the mostappropriate treatment decisions according toindividual needs of people with diabetes [58].

Advantages of Second-Generation OverFirst-Generation Basal Insulin Analogues

Both first-generation and second-generationbasal insulin analogues have similar efficacy interms of reducing HbA1c. However, compared tofirst-generation analogues, newer analogueshave longer and more stable pharmacokinetics(PK) and pharmacodynamics (PD) profiles. Sec-ond-generation basal insulin analogues areassociated with low variability, with pre-dictable and stable glycemic control beyond24 h, thus, providing clinically meaningfulbenefits compared to first-generation basal

Fig. 4 Panel recommendations for TIR based on complications profile

478 Diabetes Ther (2021) 12:465–485

insulin analogues, including longer duration ofaction ([ 24-h coverage), reduced GV due to amore stable PK profile, and better injection timeflexibility [12]. Furthermore, the second-gener-ation basal insulin analogues have a lower riskof all-day hypoglycemia and nocturnal hypo-glycemia compared to first-generation basalinsulin analogues [12]. These analogues areassociated with a greater improvement intreatment satisfaction, patient-related out-comes, and QoL [61, 62]. Taken together, sec-ond-generation basal insulin analogues providenew treatment options to physicians forachieving target glycemic levels [12].

Improved Control Over GlucoseVariability: Comparing First-Generationand Second-Generation Basal InsulinAnalogues in T1DM and T2DM

A study by Yu evaluated the real-world benefitsof Gla-300 in lowering nocturnal fluctuations inblood glucose levels and nocturnal hypo-glycemia in people with T2DM. The meannocturnal glucose level achieved during theGla-300 (121 ± 31.23 mg/dL) treatment phasewas similar to that achieved during the Gla-100(126.1 ± 35.11 mg/dL) treatment phase. Vari-ability in mean nocturnal glucose levels (SD andCV) and the mean amplitude of glucose excur-sions between nights were lower during theGla-300 treatment period compared to theGla-100 treatment period. The study concludedthat Gla-300 is comparable to Gla-100 in pro-viding tight glycemic control. Besides, it wasobserved that Gla-300 had a greater potential toreduce the frequency of nocturnal hypo-glycemia vs. Gla-100 [63].

A two-period crossover study compared glu-cose control with Gla-300 and Gla-100 in peo-ple with T1DM. Both Gla-300 and Gla-100 had acomparable percentage of time within the tar-get glucose range. For Gla-300, a significantlylower increase in CGM-based glucose measure-ment was observed during the last 4 h of the24-h injection interval as compared to Gla-100(least-squares mean difference - 14.7 mg/dL[95% CI - 26.9 to - 2.5]; p = 0.0192). Irrespec-tive of morning or evening injection, mean

24-h glucose curves for the Gla-300 group weresmoother than for the Gla-100 group—indicat-ing lower glycemic excursions. Compared toGla-100, the nocturnal hypoglycemia rate waslower with Gla-300 (4.0 vs. 9.0 events per par-ticipant-year: rate ratio 0.45 [95% CI 0.24–0.82])[13].

An open-label, multicenter, prospective,observational study by Yamamoto et al. enrol-led 21 participants with T1DM to investigatethe differences in GV between Gla-100 and IDegusing CGM. The results showed that the meanamplitude of glycemic excursions was signifi-cantly reduced with degludec (p = 0.028), as wasthe area under the curve for daily blood glucoselevel\ 70 mg/dL (p = 0.046). The authors con-cluded that degludec confers reduced hypo-glycemia and daily blood glucose variability inparticipants with T1DM as compared to Gla-100[64].

Another study by Iga et al. involving 20patients with T1DM reported that fastinginterstitial GV on the CGM curves was signifi-cantly less with IDeg than Gla-100 (25.9 ± 22.0vs. 43.8 ± 30.1 mg/dL, p = 0.04). The authorsconcluded that while the hypoglycemic epi-sodes were similar with both IDeg and Gla-100,treatment with IDeg was associated with lowerGV [65].

Second-Generation Basal Insulins: Gla-300vs. Insulin Degludec

Studies have compared the safety and efficacy ofthe second-generation basal insulin analoguesGla-300 and insulin degludec in adults withT1DM or T2DM. A study comparing the PK/PDprofiles of Gla-300 vs. IDeg-100 demonstratedan evenly distributed PK profile and bettersteady-state PD profile with Gla-300 (20%lower within-day variability) in people withT1DM, with a once-daily dosing regimen of0.4 U/kg/day [66]. However, an earlier studyreported IDeg-200 to have lower intraday vari-ability (37% lower) and interday variability (ca.four times lower) compared to Gla-300 [67]. TheBRIGHT study was the first head-to-head clini-cal trial evaluating the efficacy and safety of twosecond-generation basal insulin analogues

Diabetes Ther (2021) 12:465–485 479

(Gla-300 and IDed-100) in insulin-naıve adultswith T2DM inadequately controlled with OADs(± GLP-1RA). Both insulins provided similarglycemic control, with relatively low and com-parable hypoglycemia incidence and rates dur-ing the overall study period. However, duringthe titration period, hypoglycemia was lowerwith Gla-300 as compared to IDeg [68]. Anotherhead-to-head trial, the Trial Comparing theEfficacy and Safety of Insulin Degludec200 units/mL and Insulin Glargine 300 units/mLin Subjects with Type 2 Diabetes Mellitus Inad-equately Treated with Basal Insulin and OralAntidiabetic Drugs (CONCLUDE), reported thatincidence of overall symptomatic hypoglycemiawas not significantly different between Gla-300and IDeg-200 during the maintenance period inindividuals with T2DM. Since the study couldnot meet its primary endpoint, the secondaryendpoints were considered exploratory and notconclusive [69]. A small-scale study used CGMfor comparing the safety and efficacy of Gla-300and insulin degludec. The mean percentage ofTIR was similar with both insulin types(p = 0.848), but the percentage of time inhypoglycemia was significantly lower withGla-300 as compared to insulin degludec(p = 0.002). The percentage of time spent withnocturnal or severe hypoglycemia was also sig-nificantly lower with Gla-300 than with insulindegludec (1.1 ± 2.4 vs. 4.2 ± 5.8 and0.04 ± 0.18 and 1.8 ± 3.0, respectively). Thestudy showed that during insulin degludectreatment, the mean percentage of time withhypoglycemia, especially nocturnal hypo-glycemia, significantly correlated negativelywith albumin level, possibly as a result of thereversible binding of insulin degludec to albu-min [70]. Another study by Yamabe et al.showed that although both these insulins werecomparable in terms of efficacy, nocturnalhypoglycemia was significantly lower withGla-300 compared to insulin degludec(p = 0.021). The study indicated that althoughboth these long-acting insulin analogues arecomparable in terms of efficacy, Gla-300 haslesser risk of nocturnal hypoglycemia thaninsulin degludec [71].

Although the use of CGM allows betterassessment of glycemic control taking TIR into

consideration, large-scale studies based on CGMto compare the safety and efficacy of Gla-300and IDeg are lacking. The InRange is an ongoingmulticenter phase IV study that will collectCGM data over 20 days in adults with T1DMreceiving either Gla-300 or IDeg-100. Althoughthe study is aimed at showing the noninferior-ity of Gla-300 to IDeg-100 in terms of glycemiccontrol and TIR, upon completion, it is alsoexpected to provide valuable insights into theutility of CGM in clinical practice [72].

With this background, the experts delineatedrecommendations for the management of TIRin different patient populations. The use ofsecond-generation basal insulins was empha-sized by the expert members. The clinicalinsights regarding the choice of treatmentmodality for TIR management are summarizedbelow.

Clinical Insights on TIRRecommendations, Based on Modalityof Treatment

• Second-generation basal insulin scores betterthan insulin regimens in terms of increasedduration of action, lesser GV, improvedquality of life, reduction of diabetes distress,better adherence, prevention of cognitivedysfunction, and long-term complications.

• In practice, second-generation basal insulinbrings down blood glucose with lower hypo-glycemia compared to first-generation insu-lin for equivalent glucose levels.

• TIR recommendations remain the sameregardless of the modality of treatment.The treatment should be directed at achiev-ing TIR. This can be achieved with basalinsulins, especially second-generation basalinsulins.

• TIR targets remain the same regardless ofwhether the patient was on insulin or OADs(taking into consideration specific popula-tion, age group, and associatedcomplications).

480 Diabetes Ther (2021) 12:465–485

CONCLUSION AND FUTUREPERSPECTIVES

On the basis of clinical evidence, the expertpanel suggests the use of CGM-based glucosemetrics, such as TIR and GV, in addition toHbA1c for effective diabetes management anddecreasing the risk of both micro- andmacrovascular complications. In this review,the panel individualized TIR for specific popu-lations and complications in the context ofdiabetes. As personalized diabetes managementmoves from theory to practice, it is hoped thatthese recommendations can help practitionerseffectively refine patient care models. Finally,person-centric glycemic control with CGM andsecond-generation basal insulin analogues is anoption for more effective and accurate diabetesmanagement, along with improved adherenceand QoL measures.

ACKNOWLEDGEMENTS

The topic of using a patient-centric (with regardto time-in-range) approach to manage type 2diabetes was discussed at a multi-region, virtualexpert committee meeting held in June 2020which was logistically supported by Sanofi.This article was subsequently developed as anentirely separate exercise, based on the experts’identified need for literature conveying theregional perspective on this topic. The authorshave not received any funding from Sanofi forwriting and reviewing this manuscript. Sanofiand/or its affiliates did not exercise any selectiveinfluence over the opinions expressed by otherauthors in this article. The contents of thisarticle and the opinions expressed within arethose of the authors, and it is the decision of theauthors to submit the manuscript as a clinicalinsight for publication. All authors had fullaccess to the articles reviewed in this manu-script, take responsibility for the writing of thismanuscript, including critical review and edit-ing of each draft, approval of the submittedversion, and take complete responsibility forthe integrity and accuracy of this manuscript.Before submission to the journal, Sanofi was

given the opportunity to review the manu-script. However, the authors remain responsiblefor all content and editorial decisions.The content published herein solely representsthe views and opinions of the authors and doesnot necessarily represent the views or opinionsof sponsor Sanofi and/or its affiliates. Thedetails published herein are intended for infor-mational, educational, academic and/orresearch purposes and are not intended to sub-stitute for professional medical advice, diagno-sis or treatment.

Funding. Medical writing and the journal’sRapid Service fee were paid for by Sanofi India.The authors received no honoraria from Sanofidirectly or indirectly related to the developmentof this publication.

Medical Writing and Editorial Assistance.Medical writing and editorial support wereprovided by Dr. Rajshri Mallabadi andDr. Dhanya Mukundan of BioQuest SolutionsPvt. Ltd. and was paid for by Sanofi India.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work, and have given their approval for thisversion to be published.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Disclosures. Sanjay Kalra is on the EditorialBoard of Diabetes Therapy. The remainingauthors Shehla Shaikh, Gagan Priya, Manas P.Baruah, Abhyudaya Verma, Ashok K. Das, MonaShah, Sambit Das, Deepak Khandelwal, Deb-malya Sanyal, Sujoy Ghosh, Banshi Saboo,Ganapathi Bantwal, Usha Ayyagari, DaphneGardner, Cecilia Jimeno, Nancy E. Barbary,Khadijah A. Hafidh, Jyoti Bhattarai, Tania T.Minulj, Hendra Zufry, Uditha Bulugahapitiya,Moosa Murad, Alexander Tan, Selim Shahjada,Mijinyawa B. Bello, Prasad Katulanda, Gracjan

Diabetes Ther (2021) 12:465–485 481

Podgorski, Wajeeha I. AbuHelaiqa, Rima Tan,Ali Latheef, Sedeshan Govender, Samir H.Assaad-Khalil, Cecilia Kootin-Sanwu, AnsumaliJoshi, Faruque Pathan, and Diana A. Nkansahhave nothing to disclose.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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