Glycosylated hemoglobin (HbA1c) has been the sole surrogate marker for assessing diabetic complications. However, consistently reported limitations of HbA1c are that it lacks detailed information on short-term glycemic control and can be easily interfered with by various clinical conditions such as anemia, pregnancy, or liver disease. Thus, HbA1c alone may not represent the real glycemic status of a patient. The advancement of continuous glucose monitoring (CGM) has enabled both patients and healthcare providers to monitor glucose trends for a whole single day, which is not possible with HbA1c. This has allowed for the development of core metrics such as time spent in time in range (TIR), hyperglycemia, or hypoglycemia, and glycemic variability. Among the 10 core metrics, TIR is reported to represent overall glycemic control better than HbA1c alone. Moreover, various evidence supports TIR as a predictive marker of diabetes complications as well as HbA1c, as the inverse relationship between HbA1c and TIR reveals. However, there are more complex relationships between HbA1c, TIR, and other CGM metrics. This article provides information about 10 core metrics with particular focus on TIR and the relationships between the CGM metrics for comprehensive understanding of glycemic status using CGM.
Glycosylated hemoglobin (HbA1c) has been the sole surrogate marker for optimal glycemic control and predicting diabetic complications [
As is well known, in the Diabetes Control and Complications Trial (DCCT), intensive therapy effectively delayed the progression of long-term microvascular complications [
Continuous glucose monitoring (CGM) overcomes the problems inherent in HbA1c and SMBG by informing consequent glucose level with various CGM metrics to better understand an individual’s unique glycemic profiles, eventually leading to improved glycemic control. Moreover, since the sensor accuracy [
In February 2019, consensus statements on 10 CGM core metrics, including time spent in the time in range (TIR, 70 to 180 mg/dL), which has emerged as an important metric to complement HbA1c, were published [
CGM allows users to obtain a complete glucose profile by measuring interstitial glucose level every 5 to 15 minutes (96 to 288 measurements/day). It also allowed for development of core metrics for comprehensive understanding of glycemic status, such as time spent in TIR, hyperglycemia, or hypoglycemia, and glycemic variability (See
When sufficient data have been collected to interpret it, an Ambulatory Glucose Profile (AGP) report (
CGM-derived mean glucose and glucose management indicator (GMI) are included in the core metrics. GMI is the estimated HbA1c from CGM-measured mean glucose. By GMI, we can even estimate HbA1c during short periods, as the laboratory HbA1c reflects long-term glycemic status over 2 to 3 months. This makes GMI a much more personalized metric in diabetes management than laboratory HbA1c when used along with the other core metrics. Recently, Bergenstal et al. [
However, the published GMI is limited with the populations being restricted to the pooled data of clinical trials. Populations with HbA1c higher than 9.9% and those with hypoglycemia unawareness were excluded. In addition, data sets were restricted to specific races (non-Hispanic whites) and sensor types (real time CGM [rt-CGM], e.g., Dexcom G4 and G5). Thus, the published GMI may be inaccurate for those with high or low mean glucose concentrations. When using the published GMI for treatment decisions, race and sensor type must be considered. Several studies have reported that the laboratory HbA1c is much higher than GMI derived from flash glucose monitoring (FGM, e.g., Freestyle Libre; Abbott, Abbott Park, IL, USA), especially in those with a mean glucose level below 200 mg/dL and in Asians [
A recent international consensus on the use of CGM emphasized the importance of how much time the patients spent in target range, or in hyper- and hypoglycemia, as well as HbA1c [
A TIR of >70% (16 hours, 48 minutes), level 1 TAR of <25% (6 hours), level 2 TAR of <5% (1 hour, 12 minutes), level 1 TBR of <4% (1 hour), and level 2 TBR of <1% (15 minutes) is recommended in both type 1 and 2 diabetes mellitus (T1DM and T2DM), respectively. Every 1% change in time equals 14 min/day (1 day=1,440 minutes). The 70% and 80% of each TIR approximately corresponds to HbA1c 7.0% and 6.5% [
TIR has been shown to have inversely linear relationship with HbA1c and hyperglycemic metrics (
However, while TIR has high correlation (more than 0.9 by Spearman correlation) with other CGM metrics for hyperglycemia, only moderate correlation (about 0.6 to 0.7 by Spearman correlation) was found with HbA1c [
Recently, Rodbard [
Another notable finding is that TIR has a weak correlation to hypoglycemic and glycemic variability metrics. Reducing the mean glucose level while minimizing hypoglycemia has always been challenging in diabetes treatment. Thus, TIR always needs to be complemented with HbA1c and hypoglycemic metrics such as TBR or CV to guide therapeutic decisions.
HbA1c has been the only prospectively evaluated tool for assessing the risk for diabetes complications. However, as TIR emerges as a new metric for assessing glycemic control in addition to HbA1c, numerous studies have reported TIR as a metric for correlation with diabetes complications (
The only preferred metric for glycemic variability presented in a recently published consensus report is CV. Percentage CV can be easily calculated from the following formula: [%CV= 100×(SD of glucose)/mean glucose]. It reflects amplitude of glycemic variability relative to mean blood glucose, thus, the linear relationship with mean glucose disappears and more precisely reflects the hypoglycemic excursion than SD [
There is tangible evidence from a number of studies that have shown correlation of CV with hypoglycemic metrics, including TBR [
The recent consensus recommended a threshold of 36% or less as stable glucose homeostasis. Monnier found that diabetes without insulinotropic agents had no CV higher than 36%, and hypoglycemia episodes were significantly higher in people who had a value of %CV >36 than those who were below the threshold [
Two types of CGM are now available: professional (blind) and personal (real time). The characteristics according to the type of CGM are outlined in
Professional CGM have huge advantages over personal CGM when using CGM blindly in clinical trials to obtain individual short-term glycemic status for determining the efficacy and safety of new drugs and devices, comparing drugs in improving glycemic status, or evaluating the correlation with chronic diabetic complications [
Professional CGM can accurately diagnose glycemic status and can be used as an education tool because it does not alter patients’ temporary behavior as can occur with personal CGM use. It also gives actional information by uncovering the presence of hypo- and hyperglycemia [
The use of CGM is gradually increasing but is still not widespread. Multiple challenges remain to be overcome in patients, providers, and even in technology aspects [
The main barriers include alarm fatigue, issues remaining in insurance, cost, device discomfort or unfamiliarity of device, pain, and possibility of infection. Sometimes the device leads to depressive mood [
Barriers exist in the patient’s point of view, but also to the healthcare providers in CGM use expansion. There is a time constraint to review and interpret CGM in outpatient clinics. Problems for accuracy still remain in the hypoglycemic and/or hyperglycemic range, though CGM systems typically have a higher accuracy in the euglycemic range [
CGM is reported to improve glycemic control of patients with T1DM or T2DM [
Among three of the studies using FGM without structured education, TIR increased by 53.9 minutes (3.7%), and TBR decreased by 56.3 minutes (3.7%), but without any significant change in HbA1c [
However, compared to previous studies, Hermanns et al. [
Structured diabetes education has been recognized as an essential part of diabetes therapy for a long time. There is also a study emphasizing the importance and effectiveness of CGM-specific education [
CGM technology has rapidly expanded. By measuring glucose level continuously, the 10 core CGM metrics emerged, making the understanding of an individual’s glycemic status more comprehensive. This has helped both health providers and patients make better treatment decisions than when using HbA1c alone. TIR in particular is similar to HbA1c but provides more information and can also reflect short-term periods of glycemic status. Evidence for TIR predicting diabetic complications is regularly being published, although prospective studies are currently lacking. Consistent efforts are needed to overcome barriers in using CGM. In the near future, we expect CGM metrics, including TIR, to be widely used in clinical practice and eventually replace HbA1c.
No potential conflict of interest relevant to this article was reported.
None
(A) Even in patients with the same glycosylated hemoglobin (HbA1c) or mean glucose, exact glycemic control may vary. For example, some patients can have excellent glycemic control, spending the whole day with glucose levels between 70 and 180 mg/dL; on the other hand, some patients’ glucose levels may range from 50 to 250 mg/dL. (B) Self-monitoring blood glucose (SMBG) cannot fully capture actual glycemic fluctuation like continuous glucose monitoring (CGM) measuring interstitial glucose level every 5 to 15 minutes (96 to 288 measurements/day). TAR, time above range; TBR, time below range; TIR, time in range.
The ambulatory glucose profiles. Adapted from Ambulatory Glucose Profile [
(A) The inverse linear relationship between change in time in range (TIR) and change in glycosylated hemoglobin (HbA1c) differs by baseline HbA1c. A 10% increase in TIR only matches with a decrease of −0.4% of HbA1c in those with baseline HbA1c <7.0% but with a decrease of −1.0% in HbA1c in those with baseline HbA1c ≥8.0%. (B) The inverse linear relationship between TIR and mean glucose is preserved only in glucose values 120 to 200 mg/dL, and reversely falls when the glucose level decreases below 120 mg/dL. (C) The relationship between TIR and HbA1c differs by %CV. TIR was much lower in those with high %CV, even in those with the same HbA1c. Adapted from Beck et al. [
Estimation of HbA1c for given CGM-derived TIR
TIR (70–180 mg/dL) | Vigersky et al. |
Beck et al. |
Beck et al. |
Fabris et al. |
---|---|---|---|---|
20% | 10.6 | 9.4 | 8.8 | 9.3 |
30% | 9.8 | 8.9 | 8.4 | 8.9 |
40% | 9.0 | 8.4 | 8.0 | 8.5 |
50% | 8.3 | 7.9 | 7.6 | 8.1 |
60% | 7.5 | 7.4 | 7.2 | 7.7 |
70% | 6.7 | 7.0 | 6.8 | 7.3 |
80% | 5.9 | 6.5 | 6.4 | 6.9 |
90% | 5.1 | 6.0 | 6.0 | 6.5 |
Baseline HbA1c, % | NA | 7.5±1.0 | 7.2±0.8 | NA |
Equation | HbA1c=12.32–0.081×TIR | HbA1c=10.31–0.048×TIR | HbA1c=9.65–0.041×TIR | HbA1c=10.12–0.04×TIR |
Every 10% increase in TIR | ~0.8% HbA1c reduction | ~0.5% HbA1c reduction | ~0.4% HbA1c reduction | ~0.4% HbA1c reduction |
HbA1c, glycosylated hemoglobin; CGM, continuous glucose monitoring; TIR, time in range; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; NA, not applicable.
Data sets were from 18 clinical trials using CGM for a minimum of 3 days,
Data used in analyses were from four randomized trials using CGM for a minimum of 10 days for baseline and 14 days in month 6,
Linear regression analysis was used to analyze 3-month full CGM data for this equation.
Results of studies that evaluated the effect of TIR on diabetes complications
Study | Populations | Outcome | Results |
---|---|---|---|
Beck et al. (2019) [ |
1,440 Patients with T1DM in DCCT | Retinopathy, albuminuria | HRs for retinopathy and microalbuminuria by TIR; 7-point SMBG (each 10% decrease in TIR): 1.64 (1.51–1.78) and 1.40 (1.25–1.56) |
Lu et al. (2018) [ |
3,262 Patients with T2DM | Retinopathy | OR for any retinopathy by TIR; CGM (each 10% increase in TIR): 0.92 (0.88–0.96) |
Lu et al. (2020) [ |
2,215 Patients with T2DM | CIMT | OR for CIMT by TIR; CGM (each 10% increase in TIR): 0.936 (0.878–0.998) |
Yoo et al. (2020) [ |
866 Patients with T2DM | Albuminuria | OR for albuminuria by TIR; CGM (each 10% increase in TIR): 0.94 (0.88–0.99) |
Ranjan et al. (2020) [ |
26 Patients with T1DM with SAP | Albuminuria | HR for albuminuria by TIR; CGM (each 10% increase in TIR): 0.81 (0.72–0.90) |
Yang et al. (2020) [ |
364 Patients with diabetic polyneuropathy | Painful diabetic polyneuropathy | OR for painful diabetic polyneuropathy by TIR; CGM (quartile): 2.66 (1.16–6.10) |
TIR, time in range; T1DM, type 1 diabetes mellitus; DCCT, Diabetes Control and Complications Trial; HR, hazard ratio; SMBG, self-monitoring blood glucose; T2DM, type 2 diabetes mellitus; OR, odds ratio; CGM, continuous glucose monitoring; CIMT, carotid intima-media thickness; SAP, sensor-augmented insulin pump.
Comparison between professional and personal CGM
Professional CGM | Personal CGM | |
---|---|---|
Methods for obtaining glucose metrics | Blind, retrospective | Real-time (RT) observation or flash glucose monitoring (FGM) |
| ||
Duration | Intermittent use by healthcare providers | Continuous use by patients |
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Device available in Korea | Medtronic ipro2 | Medtronic Guardian Connect |
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Advantages | The results cannot bias patient and investigator use of trial products because they are unaware of the glucose values. | Patient can directly adjust their diet and exercise behavior or insulin dose with adequate patient education and training. |
Healthcare providers can make appropriate therapy changes with T1DM and even T2DM patients with unrecognized hypo- and hyperglycemia. | Useful for long-term monitoring in patients who are on regimens with basal and prandial insulin. | |
Both provide optimal therapy adjustment | ||
| ||
Limitations | No alarms for hypo- and hyperglycemia | Clinical trial results may be affected by response to real-time data (e.g., temporary behavior change, insulin dose adjustment, medication inherence, unethical behavior). |
Not allowed for long-term monitoring | Alarm or calibration fatigue | |
Time consuming for reviewing CGM data |
CGM, continuous glucose monitoring; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus,
Limited to Dexcom G5, Guardian connect.