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Time in range: a new parameter to evaluate blood glucose control in patients with diabetes

Time in range: a new parameter to evaluate blood glucose control in patients with diabetes The International Consensus in Time in Range ( TIR) was recently released and defined the concept of the time spent in the target range between 70 and 180 mg/dL while reducing time in hypoglycemia, for patients using Continuous Glucose Monitoring (CGM). TIR was validated as an outcome measures for clinical Trials complementing other com- ponents of glycemic control like Blood glucose and HbA1c. The challenge is to implement this practice more widely in countries with a limited health public and private budget as it occurs in Brazil. Could CGM be used intermittently? Could self-monitoring blood glucose obtained at different times of the day, with the amount of data high enough be used? More studies should be done, especially cost-effective studies to help understand the possibility of having sen- sors and include TIR evaluation in clinical practice nationwide. Keywords: Time in range, Glycated hemoglobin, Continuous glucose monitoring, Hypoglycemia Background meaningful information. This technical review com - The International Consensus in Time in Range (IC- mentary expresses Brazilian experts’ opinion on this TIR) [1] was recently released and the purpose of this interesting metric obtained through continuous glucose manuscript is to critically discuss TIR and to offer dia - monitoring (CGM) and represents a demand requested betologists and endocrinologists concise and mean- by the Brazilian Diabetes Society to translate the IC-TIR ingful information. This technical review commentary to the national practice. expresses Brazilian experts’ opinion on this interesting The benefits of achieving normal or near-normal blood metric obtained through continuous glucose monitor- glucose levels are well known since the Diabetes Control ing (CGM) and represents a demand requested by the and Complications Trial (DCCT) [2]. Hemoglobin A1c Brazilian Diabetes Society to translate the IC-TIR to the test (HbA1c) has been used as a gold standard of gly- national practice. cemic control since DCCT, while the self- monitoring blood glucose (SMBG) has been a cornerstone of diabe- Main text tes care to verify glucose variability (GV) on daily basis The International Consensus in Time in Range (IC- [3]. TIR) [1] was recently released and the purpose of HbA1c reflects blood glucose concentrations over this manuscript is to critically discuss TIR and to three to four months and is the only parameter of gly- offer diabetologists and endocrinologists concise and cemic control that has strongly been associated with chronic diabetic vascular complications. “However, HbA1c may be influenced by several conditions that *Correspondence: monicagabbay@gmail.com affect the survival of red blood cell (RBC) independent of Diabetes Centre-UNIFESP, Federal University of São Paulo, São Paulo, glycemia, but also by glycation rates, uremia, pregnancy, Brazil Full list of author information is available at the end of the article smoking, and ethnicity. Higher HbA1C values have been © The Author(s) 2020. 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The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gabbay et al. Diabetol Metab Syndr (2020) 12:22 Page 2 of 8 described in minorities, mainly African Americans, for major clinical significance and must be reported. Level example. All these factors affect the interpersonal rela - 3 hypoglycemia is considered severe, whenever assis- tionships between HbA1c and mean glucose. The degree tance by third parties is necessary, without a specific of such impact is currently immeasurable and frequently value of blood glucose. Hypoglycemic event is consid- not fully appreciated. When these other conditions influ - ered if lasting at least 15 min. The cessation of a hypo - encing HbA1c levels are considered, it becomes clear that glycemic episode should be considered 15 min after the the relationship between HbA1c and complications may glycemia reaches values outside that range. Hypergly- not be the same as the relationship between mean blood cemic exposure is expressed as the percentage of time glucose and complications [4]”. with glucose values > 180 mg/dL. Hyperglycemia (Time HbA1c does not distinguish individuals with similar Above Range or TAR) is also divided into three levels average glycemia but with pronounced differences in level 1 (alert level, > 180 mg/dL to < 250 mg/dL), level 2 hypoglycemic events and/or hyperglycemic excursions (clinically significant, > 250  mg/dL) and level 3 (clinical [4, 5]. SMBG provides a “snapshot” of the glucose values diagnosis: ketoacidosis or hyperosmolar hyperglycemic and it is used both to titrate prandial insulin doses and to state). Splitting the time in hypo and hyperglycemia define correction bolus, but does not detect fluctuations into three levels allows a more assertive assessment of that might occur between each capillary glucose test severity and the most appropriate response. unless testing is done consecutively over short periods. “The recommended amount of data is 100% in at CGM provides a continuous measurement of the least 10  days or 70% of captured data in at least interstitial glucose over time and offers the opportunity 14 days of CGM. This metric, based on the ADAG to detect glucose variations, hypoglycemic events, and study has been called “estimated HbA1c” or just time in range (TIR) [4]. Both real-time CGM (rtCGM) or “eA1c”, and is present in some reports of CGM intermittent scan CGM (isCGM) are currently available devices. However, the use of this term started to [6]. The main benefit of CGM is observed in high-risk generate confusions when values of “real A1c”, patients with frequent or severe hypoglycemia, and those measured in the blood, were not similar to “eA1c”, with impaired awareness of hypoglycemia. CGM can be estimated by CGM data. Health care profession- effectively used in patients either in multiple daily injec - als and patients had difficulties in interpreting tions (MDI) treatment or in those with continuous sub- these differences, and the FDA (Food and Drug cutaneous insulin infusion (CSII). Administration) suggested that the name should be In 2017, an International Consensus on the Use of the changed [9]. Based on these arguments, Bergenstal Continuous Glucose Monitoring [7] standardized the use et  al. used data coming from novel CGM studies of CGM and recommended the analysis together with associated to the previous ADAG results to develop HbA1c to promote therapy adjustments in both type 1 a new index, the glucose management indicator (T1DM) and type 2 (T2DM) diabetes mellitus, especially (GMI) [10]. The FDA supported the use of the term for patients with frequent hypoglycemia. The consensus GMI, and probably it will be used in the reports of also recommended that all patients should be trained in different CGM devices from now on [11].” how to access, interpret, and answer questions regarding their glycemic control in the available devices and tools. Finally, the consensus defined the concept of the time Definitions of the minimum requirements for CGM per - spent in the target range, or simply “time in range” formance, such as meeting ISO (International Organiza- and standardizes the use of the primary glucose range tion for Standardization) standards, the relationship of between 70 and 180  mg/dL. Occasionally, glucose val- dependence of CGM calibration with glucometers, and ues between 70 and 140  mg/dL can be used as a sec- an acceptable mean absolute relative difference (MARD) ondary range, especially for regulatory issues and were provided. comparability studies. Before 2017 consensus, time in The consensus also considered hypoglycemia defi - target ranges were reported in various ways, and it was nitions as clinical trial standardization and divided impossible to compare one study with the others. The them into levels 1, 2, and 3, based on the joint posi- consensus agreement finished a discussion about what tion statement of the American Diabetes Association would be the best metric to be used. In 2019, the IC- (ADA) and the European Association for the Study of TIR recommended clinical targets for CGM data for Diabetes (EASD) following the recommendations of T1DM and T2DM, at-risk or “frail” patients with dia- the International Hypoglycaemia Study Group (IHSG) betes and established a specific recommendation for [8]. This Time Bellow Range (TBR) was divided into pregnancy. Moreover, percentages of time in hypogly- Level 1 (between 54 and 70  mg/dL) has minor impor- cemia and hyperglycemia were also a matter of the IC- tance in clinical studies. Level 2 (below 54  mg/dL) has TIR consensus (Table 1). G abbay et al. Diabetol Metab Syndr (2020) 12:22 Page 3 of 8 Table 1 Guidance on target for assessment of glycemic control in patients with diabetes TIR Time in hypoglycemia Time in hyperglycemia T1DM and T2DM > 70% (70–180 mg/dL) < 4% below 70 mg/dL < 1% below < 25% 54 mg/dL T1DM and T2DM “fragile” > 50% (70–180 mg/dL) < 1% below 70 mg/dL > 90% below 250 mg/dL T1DM pregnancy > 70% (63–140 mg/dL) < 4% below 63 mg/dL < 25% above 140 mg/dL Gestational DM and T2DM pregnancy > 85–90% (63–140 mg/dL) < 4% below 63 mg/dL < 10% above 140 mg/dL Gestational DM and T2DM pregnancy: there are no specific recommendations for these conditions given the limited evidence but that it is expected that it would be significantly higher than in type 1 diabetes pregnancy Evaluation of CGM metrics is essential to motivate, and usefulness of TIR. To validate TIR as an outcome educate and teach patients with diabetes in clinical prac- measure for clinical trials, Beck et  al. [15], reanalyzed tice. The aim is to reduce the time spent in hypoglyce - the dataset of DCCT study [2]. Using DCCT’s capil- mia (glucose levels < 70  mg/dL) to less than 1  h/day and lary measurements, the authors searched for associa- time below 54  mg/dL to less than 15  min/day, equiva- tions between TIR and the development or progression lent to < 4% and < 1%, respectively as the standard goal. of microalbuminuria or retinopathy. All 1440 DCCT Indeed, targets must be individualized and meet personal participants measured a 7-point glucose profile from needs and circumstances [1, 7, 12]. fingerstick samples for 1  day every 3  months. In total, The article published by ADA/EASD, entitled “Improv - blood glucose (BG) testing data were available for 32,528 ing the Clinical Value and Utility of CGM Systems: Issues quarterly data collections, with the 7-point profile com - and Recommendations” [13] motivated an editorial plete for 24,892. The correlation between mean TIR and by Riddle, Gerstein, and Cefalu highlighting thought- HbA1c was − 0,7913. TIR was higher in the intensively provoking points about CGM [14]. They supported treated group than in the conventionally treated group the definition of several terms and ways of reporting a (52 vs. 31%). Although the information coming from BG standardized CGM and the classification and report of measurements was not so complete as it would have been hypoglycemia. Additionally, they stressed the impor- with CGM, the massive amount of blood glucose tests tance of this standardization for a paradigm shift in reg- could be used as a good representation of the glucose ulatory affairs. Another important aspect to be pointed profile of DCCT population. Pitfalls are that the 7-point out is that monitoring the time in range can also offers profile represents only daytime measures and that this an opportunity for people with diabetes to improve the study was performed only in patients with T1DM. These management of their diabetes. results do not apply for patients with T2DM, although we In a recent publications IQVIA developed the CORE can speculate that in T2DM patients it is likely that the Diabetes Model, that simulates clinical outcomes and same associations would be present. That would possibly costs for cohorts of patients with diabetes. The authors imply a further correlation with the UKPDS [18] or any demonstrated that improvement in time in range to 80% other robust data with mainly T2DM. and reducing hypoglycemic events by up to 40% can, Lu et  al. have investigated the relationship between conservatively, lead to a reduction in costs of $6.7–9.7 retinopathy and TIR evaluated through CGM in patients billion over 10  years in USA. This publication, based on with T2DM. The prevalence of retinopathy was higher in recent studies by Beck et col [15] and Vigersky et col [16], patients with lower TIR. Moreover, patients with more also predicts that an increase in TIR reduces the cumula- advanced retinopathy had less TIR and higher measures tive incidence of developing complications such as myo- of glucose variability [19]. Similarly, Mayeda et  al. have cardial infarction, end stage renal disease, severe vision shown an association between TIR evaluated through loss and amputation [17]. CGM and symptoms of peripheral neuropathy in indi- Some questions are still not answered such as: who viduals with T2DM [20]. However, these studies evalu- should use CGM and when, and who should pay for it? It ated only short term CGM in patients with long-standing is described that there might be different definitions for disease and did not include TIR data during the course of specific ethnic groups and there are still open doors for the disease. a better understanding concerning CGM, cardiovascular Recently, a commentary by Hirsh et  al. has drawn risk and GV. attention to the fact that TIR was relatively low in the Following the publication of the CGM consensus DCCT data (52% vs. 31%, intensive vs. conventional in 2017, new data were published on the importance treatment, respectively) [21]. The difference in TIR Gabbay et al. Diabetol Metab Syndr (2020) 12:22 Page 4 of 8 between the groups that developed retinopathy and non-linear correlation between TIR (70–140 mg/dL) and others was 12%, while for those with or without micro- HbA1c for 60 days (R = 0,69). albuminuria a difference of only 10% was reported. The The opinion of the SBD experts invited group, the difference in TIR between those that developed eye or strength of the study is that the authors collected sensor kidney disease and others was a decreasing of approx- data from CGM only when the sensor has been used for imately 2.5  h per day in the range, which emphasized more than 80% of the time. They found a strong relation - the critical role of TIR measurement. The authors con - ship between TIR, time above range and HbA1c, but only cluded that TIR is strongly associated with the risk of a modest association with hypoglycemia. The weakness is microvascular complications, and therefore could be that they used a stricter range for calculation of TIR (70– used as another endpoint for clinical investigations. 140  mg/dL). Although these data were obtained from a pediatric population, the study partially validated the “Recent studies have demonstrated the relationship concept of TIR in this population, since in previous stud- between TIR and complications in T2D patients. ies a linear relation between HbA1c and TIR has been Lu et  al. initially investigated the association shown in subjects with T1DM and T2DM. between the TIR, assessed by CGM, and diabetic retinopathy (DR) in 3262 patients. Patients with “In a multicentre international randomized con- more advanced DR had significantly less TIR and trolled trial (CONCEPTT) the continuous glucose higher measures of GV (p < 0.01) with significant monitoring in pregnant women with T1DM showed associations between TIR and all stages of DR [19]. strong correlation of TIR with better outcomes [24] Then, the same group analyzed  carotid intima- The same group recently used rt-CGM and isCGM media thickness (CIMT)  of 2215 T2D patients in 186 pregnant women to understand to what and found a correlation between TIR and macro- extent are CGM-derived measure of glucose con- vascular disease. Those with abnormal CIMT had trol associated with large for gestational age infant significantly lower TIR (p < 0.001) and each 10% (LGA) and neonatal outcome. Using either Dexcom increase in TIR was associated with 6,4% lower G4 or Freestyle Libre CGM device Kristensen et  al. risk of abnormal CIMT [22]. It should be noted calculated TIR, below or above pregnancy glucose that all subjects in these studies underwent 3 days target, CV%, SD of mean glucose, mean amplitude of of CGM, while previous ones demonstrated that glucose excursion (MAGE). They found no difference increasing the number of days of CGM improved in maternal or neonatal outcomes between women the correlation of CGM data with the glucose met- using rt-CGM and isCGM and demonstrated that rics over 3  months, and that 12–15  days of CGM 5–7% lower TIR during the second and third trimes- may be needed to optimally evaluate glycemic con- ters was associated with increased risk of LGA and trol”. neonatal outcome, including macrosomia, shoulder dystocia, neonatal hypoglycemia. Interestingly, they Articles that report paired HbA1c and TIR metrics or support the non-inferior use of isCGM as technology HbA1c and frequent self-monitoring of blood glucose ease of use, low cost, safe and accurate in pregnancy points out TIR as a new tool for determining the outcome [24]. In a commentary of this study, Helen Murphy of clinical studies. Vigersky and McMahon [16] analyzed suggests that for optimal obstetric and neonatal out- 18 studies including 2577 T1DM and T2DM subjects comes, women should aim to reach a TIR > 70% and and found a strong relationship between TIR and HbA1c a time above range < 25%, as early as possible dur- (R = − 0,84; R = 0,71). It was demonstrated that for every ing pregnancy. Those who can’t achieve this target 10% change in TIR, there was a 0.8% change in HbA1c. should be encouraged that any 5% increase in TIR is TIR and HbA1c are not efficient for estimating the time associated with clinically relevant improvements in in hypoglycemia (time below range), so composite met- neonatal health [25].” rics (TIR + time below range) are suggested to be com- plementary to HbA1c. A limitation of the study is that Relationship between CGM-derived glycemic variables most of the subjects were white and non-Hispanic. Since and the corresponding HbA1c levels were also found by the relationship between HbA1c and average glucose dif- analyzing individual-level data from four randomized fers by race/ethnicity, the findings of this study may be clinical trials [27]. Those lasted ≥ 24  weeks, had end-of- inaccurate for non-Caucasians. study HbA1c levels and at least 2  weeks of continuous Additionally, TIR could be a useful metric along HbA1c glucose monitoring data collected from 530 adults with to assess glycemic control in children. Petersson et  al. T1DM and insulin-requiring T2DM. Participants were [23] evaluated 133 children and adolescents from Swe- categorized based on end-of-study HbA1c levels ranging den that used rt-CGM or isCGM and demonstrated a from < 6.5 to ≥ 8.5% and were separated into categories G abbay et al. Diabetol Metab Syndr (2020) 12:22 Page 5 of 8 Future directions based on CGM-derived metrics. HbA1c was strongly Usage of CGM enabled diabetologists, endocrinologists correlated with mean glucose value (r = 0.80), TIR and diabetes educators to analyze more than one com- (r = − 0.75) and percentage of glucose values > 250 mg/dL ponent of glycemic control. One of the possibilities for (r = 0.729), but was weakly correlated with the percent- the future is the combination of various metrics trying to age of glucose values < 70  mg/dL (r = − 0.39) or < 54  mg/ better define glycemic control [31]. dL (r = − 0.21). More than 90% of participants with either Composite indices could have a numeric, visual or even mean glucose < 140  mg/dL or time in range > 80% had having both indices aligned together. Composite indices HbA1c levels ≤ 7.0%. For participants with HbA1c ≥ 8.0%, that have a numeric representation include the Index the median TIR was 44%, with 90% of participants having of Glycemic Control (IGC), Q-score, Composite Con- a TIR < 59%. tinuous Glucose Monitoring Index (COGI) and others. TIR has also evaluated in the intensive care unit (ICU) Moreover, those with a visual representation include the scenario. Omar et  al. [28] determined the whole time of graphical display of CGM [32, 33], and indices with both insulin infusion (A) and the time within the proposed a numeric and visual representation include the Hypo- target range (B) during insulin infusion and expressed Triad and the Comprehensive Glucose Pentagon (CGP) TIR as TIR = (B/A) × 100. They found that patients with [34]. more than 80% TIR, with or without diabetes, had better The Q-Score is a new metric suitable to screen for outcomes (wound infection, lengths of ventilation, and CGM profiles that require therapeutic action. It identi - ICU stay) than those with less than 80% TIR. Addition- fied five primary factors that determined CGM profiles ally, they had less hypoglycemia. Krinsley and Preiser [29] (central tendency, hyperglycemia, hypoglycemia, intra- had previously found that survival in critically ill patients and inter-daily variations) where one parameter from without diabetes is strongly associated with TIR (70 to each factor was selected for constructing the formula. 140 mg/dL) above 80%. Their findings are independent of The Q-Score should allow the categorization of glycemic the ICU length of stay and severity of the individual’s ill- control from very good to poor it also allows identifica - ness. The authors suggest that individualized algorithms tion of factor(s) underlying the profiles that are mainly for patients with and without diabetes could replace responsible for the quality of metabolic control in each published working guidelines that may be unnecessarily patient [35]. restrictive. Leelarathna et  al. created the COGI which consists of There are many methods described in the literature three key components of glucose control, as assessed to evaluate glycemic control. Rodbard evaluated vari- by CGM: TIR, TBR, and GV. It was evaluated in adults ous metrics of glycemic control, and compared TIR, with T1DM, using hybrid closed-loop (HCL) therapy and time in hypoglycemia (TBR) and Time in Hyperglycemia MDI therapy combined with rtCGM [36]. They weighted (TAR) with previously described risk indices, intend- each of the components differently, determined arbitrar - ing to validate metrics for quality of glycemic control, ily by their importance in 50% for TIR, 35% for TBR and hypoglycemia and hyperglycemia [30]. The analysis of 15% for GV. COGI ranges from 0 to 100; a one percent the mathematical properties of these methods were increase of time < 70  mg/dL is equivalent to almost 5% described in detail through linear regressions and corre- reduction of TIR while 9 mg/dL increase in SD is equiva- lations between conceptual groups. The report consisted lent to 3% reduction in TIR. They found that patients in of different “risk indices” of glycemic control (M100, CSII with HbA1c between 7.5 and 10%, COGI was sig- Blood Glucose Risk Index, Glycemic Risk Assessment nificantly higher in HCL compared to sensor-augmented Diabetes Equation, Index of Glycemic Control, J-Index, pump therapy, mean (SD) 60.3 (8.6) versus 69.5 (6.9), Low Blood Glucose Index (LBGI), percentage of GRADE (p < 0001), and those CSII users with HbA1c < 7.5% COGI attributable to hypoglycemia (GRADE % Hypoglycemia), improved from 59.9 (11.2) to 74.8 (6.6) (p < 0001). MDI Hypoglycemia Index, High Blood Glucose Index (HBGI), users had similar results. The authors concluded that percentage of GRADE attributable to hyperglycemia COGI is a concise metric that unifies three important (GRADE  %Hyperglycemia) and Hyperglycemia Index aspects of CGM data and it could be used to evaluate glu- and suggested that it is unlikely that those risk indices cose control and to demonstrate the differences between could provide additional information. Of interest, TIR different treatment modalities. was highly negatively correlated with   %TAR but poorly Finally, the CGP which includes five key metrics of correlated with   %TBR. Thus, for the SBD experts, TIR, glycemic control derived from CGM such as mean sen- TBR, and TAR are understandable and straightforward sor glucose, GV, severity of hypo- and hyperglycemia, criteria with high correlation to other glycemic metrics and time out of range (the inverse of TIR), but eliminates that are more complex to calculate and more challenging HbA1C, demonstrates glycemic control both numerically to understand. Gabbay et al. Diabetol Metab Syndr (2020) 12:22 Page 6 of 8 and visually [31]. It showed potential to enable health sensors, independently of other possible confounding care providers, investigators and patients to better under- factors. Although the seven-point SMBG has been used stand the components of glycemic control and the effect for TIR evaluation, there is recent evidence that results of several interventions on the individual elements of that with this method might significantly differ from those control. This can be done on a daily, weekly, or monthly obtained through CGM [40], with overestimation of % basis [31, 34]. of hypo and hyperglycemia. Gathering more than one metric is an attractive idea when analyzing diabetes control and might be used more frequently over the next years. Currently, however, we Conclusion have no strong evidence about composite indexes, so in After reviewing the available data, the Brazilian Dia- our opinion, we should get used to the concept of TIR betes Society recommends the use of TIR as a new and before moving to other combined metrics. very useful tool to evaluate glycemic control. Data should The big challenge is to implement this practice more be extracted from sensors, for at least 10  days, but pref- widely in countries with a limited health public and pri- erentially for 14  days. In the absence of sensors, more vate budget as it occurs in Brazil. Could CGM be used studies should be done to validate SMBG obtained at dif- intermittently, for example, 14  days every 3  months, ferent times of the day and with the amount of data high looking for patterns of GV, TIR, and percentage of hyper enough to simulate the time in specific ranges. and hypoglycemia, before the medical appointments? “It Nevertheless, the most comprehensive data available is important to note that there are differences between until now are in T1D, they are considered for T2D as the professional short-term blinded continuous glu- well. cose monitoring (pCGM) and the personal CGM (real- Strategies to implement the use of this new metric time- rtCGM). Personal rtCGM allows an individual to into medical practice in Brazil and other developing self-monitor how his blood glucose responds to various countries middle-income countries is still a challenge. lifestyle factors on a daily basis, while pCGM is masked Cost-effective studies are needed to help understand to the user at the time of wear. Some studies evidenced the possibility of having sensors and include TIR evalu- improvement in HbA1c with the blinded device in T1D ation in clinical practice nationwide. and T2D patients, others did not show any difference regarding metabolic control [37–39]. In a 3-day blinded Abbreviations CGM study using the iPRO device in 106 consecutive ADA: American Diabetes Association; BG: Blood glucose; CIMT: Carotid intima: individuals, the authors concluded that the procedure media thickness; CGM: Continuous glucose monitoring; COGI: Composite con- tinuous glucose monitoring index; CSII: Continuous subcutaneous insulin infu- was ineffective for improving HbA1c levels in adults with sion; DCCT : Diabetes Control and Complications Trial; eA1c: estimated HbA1c; type 1 and 2 diabetes [38]. Nevertheless, the real effect of EASD: European Association for the Study of Diabetes; GV: Glucose variability; the pCGM is still controversial and need more evidence, HBGI: High Blood Glucose Index; HCL: hybrid closed: loop; IC-TIR: The Interna- tional Consensus in Time in Range; ICU: Intensive care unit; IHSG: International as the studies were conducted in a small number of sub- Hypoglycaemia Study Group; isCGM: Intermittent scan CGM; LBGI: Low Blood jects and heterogeneous populations, with limited data Glucose Index; MARD: Mean absolute relative difference; MDI: Multiple daily in T1DM children < 7  years and no cost-effectiveness injections; RBC: Red blood cell; rt- CGM: Real-time CGM; SBD: Brazilian Society of Diabetes; SMBG: Self- monitoring blood glucose; TIR: Time in Range; TAR: evaluation.” Time Above Range; TBR: Time Bellow Range; T1DM: Type 1; T2DM: Type 2. Alternatively, CGM could be indicated for those on multiple doses of insulin analogues who still have severe Acknowledgements None. hypo or nocturnal hypoglycemia, before witching to CSII? Should physicians prescribe a sensor-augmented Authors’ contributions pump for all young children and for those who already All authors were involved in the concept of the commentary and provided critical opinion of the data and gave approval of the final draft. All authors use CSII and persist with nocturnal or severe hypoglyce- participated in all steps of the manuscript. MG wrote all the suggestions down mia? Is the seven-point SMBG enough for TIR determi- in the end. All authors read and approved the final manuscript. nation or periodic use of CGM is essential in the clinical Funding practice? Clinical trials are urgently needed to elucidate Not applicable. these questions and establish adequate cost-effective clinical guidelines for middle-income countries. Availability of data and materials Not applicable. It is critical to emphasize that it has already been proven, even in developing countries, that increase in Ethics approval and consent to participate number of scans/days is related to increase in TIR and Not applicable. reduction in time in hypo and eA1c. These results sug - Consent for publication gested that better glucose control can be achieved with Not applicable. G abbay et al. Diabetol Metab Syndr (2020) 12:22 Page 7 of 8 Competing interests the Study of Diabetes and the American Diabetes Association Diabetes The authors declare that they have no competing interests. Technology Working Group. Diab Care. 2017;40:1614–21. 14. Riddle MC, Gerstein HC, Cefalu W. Maturation of CGM and glycemic Author details measurements beyond HbA1c. A turning point in research and clinical Diabetes Centre-UNIFESP, Federal University of São Paulo, São Paulo, Brazil. decisions. Diab Care. 2017;40:1611–3. 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Translating glycated 2019;1(42):1593–603. hemoglobin A1c into time spent in glucose target range: a multicenter 2. Nathan DM and for the DCCT/EDIC Research group. The diabetes control study. Ped Diab. 2019;20:339–44. and complications trial/epidemiology of diabetes interventions and 24. Feig DS, Donovan LE, Corcoy R, et al. Continuous glucose monitoring in complications study at 30 years: overview. Diab Care. 2014;37:9–16. pregnant women with type 1 diabetes (CONCEPTT ):a multicentre inter- 3. El-Laboudi AH, Godsland IF, Johnston DG, Oliver NS. Measures of glyce- national randomised controlled trial. Lancet. 2017;390(10110):2347–59. mic variability in type 1 diabetes and the effect of real-time continuous 25. Kristensen, et al. Continuous glucose monitoring in pregnant women glucose monitoring. Diab Technol Ther. 2016;18:806–12. with type 1 diabetes: an observational cohort study of 186 pregnancies. 4. Wright LA, Hirsch IB. Metrics beyond hemoglobin A1C in diabetes Diabetologia. 2019;62:1143–53. management: time in range, hypoglycemia, and other parameters. Diab 26. Murphy HR. Continuous glucose monitoring targets in type 1 dia- Technol Ther. 2017;19:S16–26. betes pregnancy: every 5% time in range matters. Diabetologia. 5. Beck RW, Connor CG, Mullen DM, Wesley DM, Bergenstal RM. The fallacy 2019;62:1123–8. of average: how using hba1c alone to assess glycemic control can be 27. Hirsch IB, Welsh JB, Calhoun P, Puhr S, Walker TC, Price DA. Associations misleading. Diab Care. 2017;40:994–9. between HbA1c and continuous glucose monitoring-derived glycaemic 6. Rodbard D. Continuous glucose monitoring: a review of recent stud- variables. Diabet Med. 2019;36:1637–42. ies demonstrating improved glycemic outcomes. Diab Technol Ther. 28. Omar AS, Salama A, Allam M, Elgohary Y, Mohammed S, Tuli AK, et al. 2017;19:S25–37. Association of time in blood glucose range with outcomes following 7. Danne T, Nimri R, Battelino T, Bergenstal RM, Kl Close, DeVries H, et al. cardiac surgery. BMC Anesthesiol. 2015;15:14. International consensus on use of continuous glucose monitoring. Diab 29. Krinsley JS, Preiser JC. Time in blood glucose range 70–140 mg/dL > 80% Care. 2017;40:1631–40. is strongly associated with increased survival in non-diabetic critically ill 8. Hypoglycaemia Study Group. International. Glucose concentrations adults. Crit Care. 2015;19:179. https ://doi.org/10.1186/s1305 4-015-0908-7. of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical tri- 30. Rodbard D. Metrics to evaluate quality of glycemic control: comparison als: a joint position statement of the American Diabetes Association of time in target, hypoglycemic, and hyperglycemic ranges with ‘‘Risk and the European Association for the Study of Diabetes. Diab Care. Indices’’. Diab Techn Ther. 2018;20:325–34. 2017;40:155–7. 31. Vigersky RA, Shin J, Jiang B, Siegmund T, McMahon C, Thomas A. The 9. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ. A1c- comprehensive glucose pentagon: a glucose-centric control in persons derived average glucose study group translating the A1C assay into with diabetes. J Diab Sci Technol. 2018;12(1):114–23. estimated average glucose values. Diab Care. 2008;31:1473–8. 32. Russell SJ, El-Khatib FH, Sinha M, Magyar KL, McKeon K, et al. Outpatient 10. Bergenstal RM, Beck RW, Close KL, Grumberger G, Sacks DB, Kowalski A, glycemic control with a bionic pancreas in type 1 diabetes. N Engl J Med. et al. Glucose management indicator (GMI): a new term for estimating 2014;371(4):313–25. A1C from continuous glucose monitoring. Diab Care. 2018;41:2275–80. 33. Rodbard D. Evaluating quality of quality of glycemic control: graphical 11. Pluchino KM, Wu Y, Silk AD, Yi J, Lias CH. Comment on Bergenstal et al. displays of hypo- and hyperglycemia, time in target range, and mean glucose management indicator (GMI): a new term for estimating a1c glucose. J Diab Sci technol. 2015;9(1):56–61. from continuous glucose monitoring. Diab Care. 2019;42:28. https ://doi. 34. Rama Chandran S, Vigersky RA, Thomas A, Lim LL, Ratnasingam J, Tan A, org/10.2337/dc18-2366. et al. Role of composite glycemic indices: a comparison of the compre- 12. The Consensus Report of the American Association of Clinical Endocri- hensive glucose pentagon across diabetes types and hba1c levels. Diab nologists, the American Association of Diabetes Educators, the American Tech Ther. 2019. https ://doi.org/10.1089/dia.2019.0277. Diabetes Association, the Endocrine Society, JDRF International, Leona M, 35. Augstein P, Heinke P, Vogt L, Vogt R, Rackow C, Kohnert KD, et al. Q-Score: Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and development of a new metric for continuous glucose monitoring that the T1D exchange. Diab Care. 2017;40:1622–30. enables stratification of antihyperglycaemic therapies. BMC Endocr 13. Petrie JR, Peters AL, Bergenstal RM, Holl RW, Fleming GA, Heinemann Disord. 2015;15:22. L. Improving the clinical value and utility of CGM systems: issues and recommendations: a joint statement of the European Association for Gabbay et al. Diabetol Metab Syndr (2020) 12:22 Page 8 of 8 36. Leelarathna L, Thabit H, Wilinska ME, Bally L, Mader JK, Pieber TR, Benesch 40. Avari P, Uduku C, George D, Herrero P, Reddy M, Oliver N. Differences C, Arnolds S, Johnson T, Heinemann L, Hermanns N, Evans ML, Hovorka R. for percentage times in glycemic range between continuous glucose Evaluating glucose control with a novel composite continuous glucose monitoring and capillary blood glucose monitoring in adults with type monitoring index. J Diab Sci Techn. 2019. https ://doi.org/10.1177/19322 1 diabetes: analysis of the REPLACE-BG dataset. Diab Technol Ther. 2019. 96819 83852 5.https ://doi.org/10.1089/dia.2019.0276. 37. Hoeks L, Greven W, De Valk H. Real-time continuous glucose monitor- ing system for treatment of diabetes: a systematic review. Diab Med. Publisher’s Note 2011;28:386–94. Springer Nature remains neutral with regard to jurisdictional claims in pub- 38. Pepper GM, Steinsapir J, Reynolds K. Eec ff t of short-term iPRO continuous lished maps and institutional affiliations. glucose monitoring on hemoglobin A1c levels in clinical practice. Diab Technol Ther. 2012;14(8):654–7. 39. Vigersky R, Fonda SJ, Chellappa M, Walker SM, Ehrhardt NM. Short- and long-term effects of real-time continuous glucose monitoring in patients with type 2 diabetes. Diab Care. 2012;35:32–380. Ready to submit your research ? 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Abstract

The International Consensus in Time in Range ( TIR) was recently released and defined the concept of the time spent in the target range between 70 and 180 mg/dL while reducing time in hypoglycemia, for patients using Continuous Glucose Monitoring (CGM). TIR was validated as an outcome measures for clinical Trials complementing other com- ponents of glycemic control like Blood glucose and HbA1c. The challenge is to implement this practice more widely in countries with a limited health public and private budget as it occurs in Brazil. Could CGM be used intermittently? Could self-monitoring blood glucose obtained at different times of the day, with the amount of data high enough be used? More studies should be done, especially cost-effective studies to help understand the possibility of having sen- sors and include TIR evaluation in clinical practice nationwide. Keywords: Time in range, Glycated hemoglobin, Continuous glucose monitoring, Hypoglycemia Background meaningful information. This technical review com - The International Consensus in Time in Range (IC- mentary expresses Brazilian experts’ opinion on this TIR) [1] was recently released and the purpose of this interesting metric obtained through continuous glucose manuscript is to critically discuss TIR and to offer dia - monitoring (CGM) and represents a demand requested betologists and endocrinologists concise and mean- by the Brazilian Diabetes Society to translate the IC-TIR ingful information. This technical review commentary to the national practice. expresses Brazilian experts’ opinion on this interesting The benefits of achieving normal or near-normal blood metric obtained through continuous glucose monitor- glucose levels are well known since the Diabetes Control ing (CGM) and represents a demand requested by the and Complications Trial (DCCT) [2]. Hemoglobin A1c Brazilian Diabetes Society to translate the IC-TIR to the test (HbA1c) has been used as a gold standard of gly- national practice. cemic control since DCCT, while the self- monitoring blood glucose (SMBG) has been a cornerstone of diabe- Main text tes care to verify glucose variability (GV) on daily basis The International Consensus in Time in Range (IC- [3]. TIR) [1] was recently released and the purpose of HbA1c reflects blood glucose concentrations over this manuscript is to critically discuss TIR and to three to four months and is the only parameter of gly- offer diabetologists and endocrinologists concise and cemic control that has strongly been associated with chronic diabetic vascular complications. “However, HbA1c may be influenced by several conditions that *Correspondence: monicagabbay@gmail.com affect the survival of red blood cell (RBC) independent of Diabetes Centre-UNIFESP, Federal University of São Paulo, São Paulo, glycemia, but also by glycation rates, uremia, pregnancy, Brazil Full list of author information is available at the end of the article smoking, and ethnicity. Higher HbA1C values have been © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gabbay et al. Diabetol Metab Syndr (2020) 12:22 Page 2 of 8 described in minorities, mainly African Americans, for major clinical significance and must be reported. Level example. All these factors affect the interpersonal rela - 3 hypoglycemia is considered severe, whenever assis- tionships between HbA1c and mean glucose. The degree tance by third parties is necessary, without a specific of such impact is currently immeasurable and frequently value of blood glucose. Hypoglycemic event is consid- not fully appreciated. When these other conditions influ - ered if lasting at least 15 min. The cessation of a hypo - encing HbA1c levels are considered, it becomes clear that glycemic episode should be considered 15 min after the the relationship between HbA1c and complications may glycemia reaches values outside that range. Hypergly- not be the same as the relationship between mean blood cemic exposure is expressed as the percentage of time glucose and complications [4]”. with glucose values > 180 mg/dL. Hyperglycemia (Time HbA1c does not distinguish individuals with similar Above Range or TAR) is also divided into three levels average glycemia but with pronounced differences in level 1 (alert level, > 180 mg/dL to < 250 mg/dL), level 2 hypoglycemic events and/or hyperglycemic excursions (clinically significant, > 250  mg/dL) and level 3 (clinical [4, 5]. SMBG provides a “snapshot” of the glucose values diagnosis: ketoacidosis or hyperosmolar hyperglycemic and it is used both to titrate prandial insulin doses and to state). Splitting the time in hypo and hyperglycemia define correction bolus, but does not detect fluctuations into three levels allows a more assertive assessment of that might occur between each capillary glucose test severity and the most appropriate response. unless testing is done consecutively over short periods. “The recommended amount of data is 100% in at CGM provides a continuous measurement of the least 10  days or 70% of captured data in at least interstitial glucose over time and offers the opportunity 14 days of CGM. This metric, based on the ADAG to detect glucose variations, hypoglycemic events, and study has been called “estimated HbA1c” or just time in range (TIR) [4]. Both real-time CGM (rtCGM) or “eA1c”, and is present in some reports of CGM intermittent scan CGM (isCGM) are currently available devices. However, the use of this term started to [6]. The main benefit of CGM is observed in high-risk generate confusions when values of “real A1c”, patients with frequent or severe hypoglycemia, and those measured in the blood, were not similar to “eA1c”, with impaired awareness of hypoglycemia. CGM can be estimated by CGM data. Health care profession- effectively used in patients either in multiple daily injec - als and patients had difficulties in interpreting tions (MDI) treatment or in those with continuous sub- these differences, and the FDA (Food and Drug cutaneous insulin infusion (CSII). Administration) suggested that the name should be In 2017, an International Consensus on the Use of the changed [9]. Based on these arguments, Bergenstal Continuous Glucose Monitoring [7] standardized the use et  al. used data coming from novel CGM studies of CGM and recommended the analysis together with associated to the previous ADAG results to develop HbA1c to promote therapy adjustments in both type 1 a new index, the glucose management indicator (T1DM) and type 2 (T2DM) diabetes mellitus, especially (GMI) [10]. The FDA supported the use of the term for patients with frequent hypoglycemia. The consensus GMI, and probably it will be used in the reports of also recommended that all patients should be trained in different CGM devices from now on [11].” how to access, interpret, and answer questions regarding their glycemic control in the available devices and tools. Finally, the consensus defined the concept of the time Definitions of the minimum requirements for CGM per - spent in the target range, or simply “time in range” formance, such as meeting ISO (International Organiza- and standardizes the use of the primary glucose range tion for Standardization) standards, the relationship of between 70 and 180  mg/dL. Occasionally, glucose val- dependence of CGM calibration with glucometers, and ues between 70 and 140  mg/dL can be used as a sec- an acceptable mean absolute relative difference (MARD) ondary range, especially for regulatory issues and were provided. comparability studies. Before 2017 consensus, time in The consensus also considered hypoglycemia defi - target ranges were reported in various ways, and it was nitions as clinical trial standardization and divided impossible to compare one study with the others. The them into levels 1, 2, and 3, based on the joint posi- consensus agreement finished a discussion about what tion statement of the American Diabetes Association would be the best metric to be used. In 2019, the IC- (ADA) and the European Association for the Study of TIR recommended clinical targets for CGM data for Diabetes (EASD) following the recommendations of T1DM and T2DM, at-risk or “frail” patients with dia- the International Hypoglycaemia Study Group (IHSG) betes and established a specific recommendation for [8]. This Time Bellow Range (TBR) was divided into pregnancy. Moreover, percentages of time in hypogly- Level 1 (between 54 and 70  mg/dL) has minor impor- cemia and hyperglycemia were also a matter of the IC- tance in clinical studies. Level 2 (below 54  mg/dL) has TIR consensus (Table 1). G abbay et al. Diabetol Metab Syndr (2020) 12:22 Page 3 of 8 Table 1 Guidance on target for assessment of glycemic control in patients with diabetes TIR Time in hypoglycemia Time in hyperglycemia T1DM and T2DM > 70% (70–180 mg/dL) < 4% below 70 mg/dL < 1% below < 25% 54 mg/dL T1DM and T2DM “fragile” > 50% (70–180 mg/dL) < 1% below 70 mg/dL > 90% below 250 mg/dL T1DM pregnancy > 70% (63–140 mg/dL) < 4% below 63 mg/dL < 25% above 140 mg/dL Gestational DM and T2DM pregnancy > 85–90% (63–140 mg/dL) < 4% below 63 mg/dL < 10% above 140 mg/dL Gestational DM and T2DM pregnancy: there are no specific recommendations for these conditions given the limited evidence but that it is expected that it would be significantly higher than in type 1 diabetes pregnancy Evaluation of CGM metrics is essential to motivate, and usefulness of TIR. To validate TIR as an outcome educate and teach patients with diabetes in clinical prac- measure for clinical trials, Beck et  al. [15], reanalyzed tice. The aim is to reduce the time spent in hypoglyce - the dataset of DCCT study [2]. Using DCCT’s capil- mia (glucose levels < 70  mg/dL) to less than 1  h/day and lary measurements, the authors searched for associa- time below 54  mg/dL to less than 15  min/day, equiva- tions between TIR and the development or progression lent to < 4% and < 1%, respectively as the standard goal. of microalbuminuria or retinopathy. All 1440 DCCT Indeed, targets must be individualized and meet personal participants measured a 7-point glucose profile from needs and circumstances [1, 7, 12]. fingerstick samples for 1  day every 3  months. In total, The article published by ADA/EASD, entitled “Improv - blood glucose (BG) testing data were available for 32,528 ing the Clinical Value and Utility of CGM Systems: Issues quarterly data collections, with the 7-point profile com - and Recommendations” [13] motivated an editorial plete for 24,892. The correlation between mean TIR and by Riddle, Gerstein, and Cefalu highlighting thought- HbA1c was − 0,7913. TIR was higher in the intensively provoking points about CGM [14]. They supported treated group than in the conventionally treated group the definition of several terms and ways of reporting a (52 vs. 31%). Although the information coming from BG standardized CGM and the classification and report of measurements was not so complete as it would have been hypoglycemia. Additionally, they stressed the impor- with CGM, the massive amount of blood glucose tests tance of this standardization for a paradigm shift in reg- could be used as a good representation of the glucose ulatory affairs. Another important aspect to be pointed profile of DCCT population. Pitfalls are that the 7-point out is that monitoring the time in range can also offers profile represents only daytime measures and that this an opportunity for people with diabetes to improve the study was performed only in patients with T1DM. These management of their diabetes. results do not apply for patients with T2DM, although we In a recent publications IQVIA developed the CORE can speculate that in T2DM patients it is likely that the Diabetes Model, that simulates clinical outcomes and same associations would be present. That would possibly costs for cohorts of patients with diabetes. The authors imply a further correlation with the UKPDS [18] or any demonstrated that improvement in time in range to 80% other robust data with mainly T2DM. and reducing hypoglycemic events by up to 40% can, Lu et  al. have investigated the relationship between conservatively, lead to a reduction in costs of $6.7–9.7 retinopathy and TIR evaluated through CGM in patients billion over 10  years in USA. This publication, based on with T2DM. The prevalence of retinopathy was higher in recent studies by Beck et col [15] and Vigersky et col [16], patients with lower TIR. Moreover, patients with more also predicts that an increase in TIR reduces the cumula- advanced retinopathy had less TIR and higher measures tive incidence of developing complications such as myo- of glucose variability [19]. Similarly, Mayeda et  al. have cardial infarction, end stage renal disease, severe vision shown an association between TIR evaluated through loss and amputation [17]. CGM and symptoms of peripheral neuropathy in indi- Some questions are still not answered such as: who viduals with T2DM [20]. However, these studies evalu- should use CGM and when, and who should pay for it? It ated only short term CGM in patients with long-standing is described that there might be different definitions for disease and did not include TIR data during the course of specific ethnic groups and there are still open doors for the disease. a better understanding concerning CGM, cardiovascular Recently, a commentary by Hirsh et  al. has drawn risk and GV. attention to the fact that TIR was relatively low in the Following the publication of the CGM consensus DCCT data (52% vs. 31%, intensive vs. conventional in 2017, new data were published on the importance treatment, respectively) [21]. The difference in TIR Gabbay et al. Diabetol Metab Syndr (2020) 12:22 Page 4 of 8 between the groups that developed retinopathy and non-linear correlation between TIR (70–140 mg/dL) and others was 12%, while for those with or without micro- HbA1c for 60 days (R = 0,69). albuminuria a difference of only 10% was reported. The The opinion of the SBD experts invited group, the difference in TIR between those that developed eye or strength of the study is that the authors collected sensor kidney disease and others was a decreasing of approx- data from CGM only when the sensor has been used for imately 2.5  h per day in the range, which emphasized more than 80% of the time. They found a strong relation - the critical role of TIR measurement. The authors con - ship between TIR, time above range and HbA1c, but only cluded that TIR is strongly associated with the risk of a modest association with hypoglycemia. The weakness is microvascular complications, and therefore could be that they used a stricter range for calculation of TIR (70– used as another endpoint for clinical investigations. 140  mg/dL). Although these data were obtained from a pediatric population, the study partially validated the “Recent studies have demonstrated the relationship concept of TIR in this population, since in previous stud- between TIR and complications in T2D patients. ies a linear relation between HbA1c and TIR has been Lu et  al. initially investigated the association shown in subjects with T1DM and T2DM. between the TIR, assessed by CGM, and diabetic retinopathy (DR) in 3262 patients. Patients with “In a multicentre international randomized con- more advanced DR had significantly less TIR and trolled trial (CONCEPTT) the continuous glucose higher measures of GV (p < 0.01) with significant monitoring in pregnant women with T1DM showed associations between TIR and all stages of DR [19]. strong correlation of TIR with better outcomes [24] Then, the same group analyzed  carotid intima- The same group recently used rt-CGM and isCGM media thickness (CIMT)  of 2215 T2D patients in 186 pregnant women to understand to what and found a correlation between TIR and macro- extent are CGM-derived measure of glucose con- vascular disease. Those with abnormal CIMT had trol associated with large for gestational age infant significantly lower TIR (p < 0.001) and each 10% (LGA) and neonatal outcome. Using either Dexcom increase in TIR was associated with 6,4% lower G4 or Freestyle Libre CGM device Kristensen et  al. risk of abnormal CIMT [22]. It should be noted calculated TIR, below or above pregnancy glucose that all subjects in these studies underwent 3 days target, CV%, SD of mean glucose, mean amplitude of of CGM, while previous ones demonstrated that glucose excursion (MAGE). They found no difference increasing the number of days of CGM improved in maternal or neonatal outcomes between women the correlation of CGM data with the glucose met- using rt-CGM and isCGM and demonstrated that rics over 3  months, and that 12–15  days of CGM 5–7% lower TIR during the second and third trimes- may be needed to optimally evaluate glycemic con- ters was associated with increased risk of LGA and trol”. neonatal outcome, including macrosomia, shoulder dystocia, neonatal hypoglycemia. Interestingly, they Articles that report paired HbA1c and TIR metrics or support the non-inferior use of isCGM as technology HbA1c and frequent self-monitoring of blood glucose ease of use, low cost, safe and accurate in pregnancy points out TIR as a new tool for determining the outcome [24]. In a commentary of this study, Helen Murphy of clinical studies. Vigersky and McMahon [16] analyzed suggests that for optimal obstetric and neonatal out- 18 studies including 2577 T1DM and T2DM subjects comes, women should aim to reach a TIR > 70% and and found a strong relationship between TIR and HbA1c a time above range < 25%, as early as possible dur- (R = − 0,84; R = 0,71). It was demonstrated that for every ing pregnancy. Those who can’t achieve this target 10% change in TIR, there was a 0.8% change in HbA1c. should be encouraged that any 5% increase in TIR is TIR and HbA1c are not efficient for estimating the time associated with clinically relevant improvements in in hypoglycemia (time below range), so composite met- neonatal health [25].” rics (TIR + time below range) are suggested to be com- plementary to HbA1c. A limitation of the study is that Relationship between CGM-derived glycemic variables most of the subjects were white and non-Hispanic. Since and the corresponding HbA1c levels were also found by the relationship between HbA1c and average glucose dif- analyzing individual-level data from four randomized fers by race/ethnicity, the findings of this study may be clinical trials [27]. Those lasted ≥ 24  weeks, had end-of- inaccurate for non-Caucasians. study HbA1c levels and at least 2  weeks of continuous Additionally, TIR could be a useful metric along HbA1c glucose monitoring data collected from 530 adults with to assess glycemic control in children. Petersson et  al. T1DM and insulin-requiring T2DM. Participants were [23] evaluated 133 children and adolescents from Swe- categorized based on end-of-study HbA1c levels ranging den that used rt-CGM or isCGM and demonstrated a from < 6.5 to ≥ 8.5% and were separated into categories G abbay et al. Diabetol Metab Syndr (2020) 12:22 Page 5 of 8 Future directions based on CGM-derived metrics. HbA1c was strongly Usage of CGM enabled diabetologists, endocrinologists correlated with mean glucose value (r = 0.80), TIR and diabetes educators to analyze more than one com- (r = − 0.75) and percentage of glucose values > 250 mg/dL ponent of glycemic control. One of the possibilities for (r = 0.729), but was weakly correlated with the percent- the future is the combination of various metrics trying to age of glucose values < 70  mg/dL (r = − 0.39) or < 54  mg/ better define glycemic control [31]. dL (r = − 0.21). More than 90% of participants with either Composite indices could have a numeric, visual or even mean glucose < 140  mg/dL or time in range > 80% had having both indices aligned together. Composite indices HbA1c levels ≤ 7.0%. For participants with HbA1c ≥ 8.0%, that have a numeric representation include the Index the median TIR was 44%, with 90% of participants having of Glycemic Control (IGC), Q-score, Composite Con- a TIR < 59%. tinuous Glucose Monitoring Index (COGI) and others. TIR has also evaluated in the intensive care unit (ICU) Moreover, those with a visual representation include the scenario. Omar et  al. [28] determined the whole time of graphical display of CGM [32, 33], and indices with both insulin infusion (A) and the time within the proposed a numeric and visual representation include the Hypo- target range (B) during insulin infusion and expressed Triad and the Comprehensive Glucose Pentagon (CGP) TIR as TIR = (B/A) × 100. They found that patients with [34]. more than 80% TIR, with or without diabetes, had better The Q-Score is a new metric suitable to screen for outcomes (wound infection, lengths of ventilation, and CGM profiles that require therapeutic action. It identi - ICU stay) than those with less than 80% TIR. Addition- fied five primary factors that determined CGM profiles ally, they had less hypoglycemia. Krinsley and Preiser [29] (central tendency, hyperglycemia, hypoglycemia, intra- had previously found that survival in critically ill patients and inter-daily variations) where one parameter from without diabetes is strongly associated with TIR (70 to each factor was selected for constructing the formula. 140 mg/dL) above 80%. Their findings are independent of The Q-Score should allow the categorization of glycemic the ICU length of stay and severity of the individual’s ill- control from very good to poor it also allows identifica - ness. The authors suggest that individualized algorithms tion of factor(s) underlying the profiles that are mainly for patients with and without diabetes could replace responsible for the quality of metabolic control in each published working guidelines that may be unnecessarily patient [35]. restrictive. Leelarathna et  al. created the COGI which consists of There are many methods described in the literature three key components of glucose control, as assessed to evaluate glycemic control. Rodbard evaluated vari- by CGM: TIR, TBR, and GV. It was evaluated in adults ous metrics of glycemic control, and compared TIR, with T1DM, using hybrid closed-loop (HCL) therapy and time in hypoglycemia (TBR) and Time in Hyperglycemia MDI therapy combined with rtCGM [36]. They weighted (TAR) with previously described risk indices, intend- each of the components differently, determined arbitrar - ing to validate metrics for quality of glycemic control, ily by their importance in 50% for TIR, 35% for TBR and hypoglycemia and hyperglycemia [30]. The analysis of 15% for GV. COGI ranges from 0 to 100; a one percent the mathematical properties of these methods were increase of time < 70  mg/dL is equivalent to almost 5% described in detail through linear regressions and corre- reduction of TIR while 9 mg/dL increase in SD is equiva- lations between conceptual groups. The report consisted lent to 3% reduction in TIR. They found that patients in of different “risk indices” of glycemic control (M100, CSII with HbA1c between 7.5 and 10%, COGI was sig- Blood Glucose Risk Index, Glycemic Risk Assessment nificantly higher in HCL compared to sensor-augmented Diabetes Equation, Index of Glycemic Control, J-Index, pump therapy, mean (SD) 60.3 (8.6) versus 69.5 (6.9), Low Blood Glucose Index (LBGI), percentage of GRADE (p < 0001), and those CSII users with HbA1c < 7.5% COGI attributable to hypoglycemia (GRADE % Hypoglycemia), improved from 59.9 (11.2) to 74.8 (6.6) (p < 0001). MDI Hypoglycemia Index, High Blood Glucose Index (HBGI), users had similar results. The authors concluded that percentage of GRADE attributable to hyperglycemia COGI is a concise metric that unifies three important (GRADE  %Hyperglycemia) and Hyperglycemia Index aspects of CGM data and it could be used to evaluate glu- and suggested that it is unlikely that those risk indices cose control and to demonstrate the differences between could provide additional information. Of interest, TIR different treatment modalities. was highly negatively correlated with   %TAR but poorly Finally, the CGP which includes five key metrics of correlated with   %TBR. Thus, for the SBD experts, TIR, glycemic control derived from CGM such as mean sen- TBR, and TAR are understandable and straightforward sor glucose, GV, severity of hypo- and hyperglycemia, criteria with high correlation to other glycemic metrics and time out of range (the inverse of TIR), but eliminates that are more complex to calculate and more challenging HbA1C, demonstrates glycemic control both numerically to understand. Gabbay et al. Diabetol Metab Syndr (2020) 12:22 Page 6 of 8 and visually [31]. It showed potential to enable health sensors, independently of other possible confounding care providers, investigators and patients to better under- factors. Although the seven-point SMBG has been used stand the components of glycemic control and the effect for TIR evaluation, there is recent evidence that results of several interventions on the individual elements of that with this method might significantly differ from those control. This can be done on a daily, weekly, or monthly obtained through CGM [40], with overestimation of % basis [31, 34]. of hypo and hyperglycemia. Gathering more than one metric is an attractive idea when analyzing diabetes control and might be used more frequently over the next years. Currently, however, we Conclusion have no strong evidence about composite indexes, so in After reviewing the available data, the Brazilian Dia- our opinion, we should get used to the concept of TIR betes Society recommends the use of TIR as a new and before moving to other combined metrics. very useful tool to evaluate glycemic control. Data should The big challenge is to implement this practice more be extracted from sensors, for at least 10  days, but pref- widely in countries with a limited health public and pri- erentially for 14  days. In the absence of sensors, more vate budget as it occurs in Brazil. Could CGM be used studies should be done to validate SMBG obtained at dif- intermittently, for example, 14  days every 3  months, ferent times of the day and with the amount of data high looking for patterns of GV, TIR, and percentage of hyper enough to simulate the time in specific ranges. and hypoglycemia, before the medical appointments? “It Nevertheless, the most comprehensive data available is important to note that there are differences between until now are in T1D, they are considered for T2D as the professional short-term blinded continuous glu- well. cose monitoring (pCGM) and the personal CGM (real- Strategies to implement the use of this new metric time- rtCGM). Personal rtCGM allows an individual to into medical practice in Brazil and other developing self-monitor how his blood glucose responds to various countries middle-income countries is still a challenge. lifestyle factors on a daily basis, while pCGM is masked Cost-effective studies are needed to help understand to the user at the time of wear. Some studies evidenced the possibility of having sensors and include TIR evalu- improvement in HbA1c with the blinded device in T1D ation in clinical practice nationwide. and T2D patients, others did not show any difference regarding metabolic control [37–39]. In a 3-day blinded Abbreviations CGM study using the iPRO device in 106 consecutive ADA: American Diabetes Association; BG: Blood glucose; CIMT: Carotid intima: individuals, the authors concluded that the procedure media thickness; CGM: Continuous glucose monitoring; COGI: Composite con- tinuous glucose monitoring index; CSII: Continuous subcutaneous insulin infu- was ineffective for improving HbA1c levels in adults with sion; DCCT : Diabetes Control and Complications Trial; eA1c: estimated HbA1c; type 1 and 2 diabetes [38]. Nevertheless, the real effect of EASD: European Association for the Study of Diabetes; GV: Glucose variability; the pCGM is still controversial and need more evidence, HBGI: High Blood Glucose Index; HCL: hybrid closed: loop; IC-TIR: The Interna- tional Consensus in Time in Range; ICU: Intensive care unit; IHSG: International as the studies were conducted in a small number of sub- Hypoglycaemia Study Group; isCGM: Intermittent scan CGM; LBGI: Low Blood jects and heterogeneous populations, with limited data Glucose Index; MARD: Mean absolute relative difference; MDI: Multiple daily in T1DM children < 7  years and no cost-effectiveness injections; RBC: Red blood cell; rt- CGM: Real-time CGM; SBD: Brazilian Society of Diabetes; SMBG: Self- monitoring blood glucose; TIR: Time in Range; TAR: evaluation.” Time Above Range; TBR: Time Bellow Range; T1DM: Type 1; T2DM: Type 2. Alternatively, CGM could be indicated for those on multiple doses of insulin analogues who still have severe Acknowledgements None. hypo or nocturnal hypoglycemia, before witching to CSII? Should physicians prescribe a sensor-augmented Authors’ contributions pump for all young children and for those who already All authors were involved in the concept of the commentary and provided critical opinion of the data and gave approval of the final draft. All authors use CSII and persist with nocturnal or severe hypoglyce- participated in all steps of the manuscript. MG wrote all the suggestions down mia? Is the seven-point SMBG enough for TIR determi- in the end. All authors read and approved the final manuscript. nation or periodic use of CGM is essential in the clinical Funding practice? Clinical trials are urgently needed to elucidate Not applicable. these questions and establish adequate cost-effective clinical guidelines for middle-income countries. Availability of data and materials Not applicable. It is critical to emphasize that it has already been proven, even in developing countries, that increase in Ethics approval and consent to participate number of scans/days is related to increase in TIR and Not applicable. reduction in time in hypo and eA1c. These results sug - Consent for publication gested that better glucose control can be achieved with Not applicable. G abbay et al. Diabetol Metab Syndr (2020) 12:22 Page 7 of 8 Competing interests the Study of Diabetes and the American Diabetes Association Diabetes The authors declare that they have no competing interests. Technology Working Group. Diab Care. 2017;40:1614–21. 14. Riddle MC, Gerstein HC, Cefalu W. Maturation of CGM and glycemic Author details measurements beyond HbA1c. A turning point in research and clinical Diabetes Centre-UNIFESP, Federal University of São Paulo, São Paulo, Brazil. decisions. Diab Care. 2017;40:1611–3. 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Published: Mar 16, 2020

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