Andrew Advani
Abstract
Recent upswings in the use of continuous glucose monitoring (CGM) technologies have given people with diabetes and healthcare professionals unprecedented access to a range of new indicators of glucose control.
Some of these metrics are useful research tools and others have been welcomed by patient groups for providing insights into the quality of glucose control not captured by conventional laboratory testing. Among the latter, time in range (TIR) is an intuitive metric that denotes the proportion of time that a person’s glucose level is within a desired target range (usually 3.9–10.0 mmol/l [3.5–7.8 mmol/l in pregnancy]).
For individuals choosing to use CGM technology, TIR is now often part of the expected conversation between patient and healthcare professional, and consensus recommendations have recently been produced to facilitate the adoption of standardised TIR targets.
At a regulatory level, emerging evidence linking TIR to risk of complications may see TIR being more widely accepted as a valid endpoint in future clinical trials. However, given the skewed distribution of possible glucose values outside of the target range, TIR (on its own) is a poor indicator of the frequency or severity of hypoglycaemia.
Here, the state-of-the-art linking TIR with complications risk in diabetes and the inverse association between TIR and HbA1c are reviewed. Moreover, the importance of including the amount and severity of time below range (TBR) in any discussions around TIR and, by inference, time above range (TAR) is discussed.
This review also summarises recent guidance in setting ‘time in ranges’ goals for individuals with diabetes who wish to make use of these metrics.
For most people with type 1 or type 2 diabetes, a TIR >70%, a TBR <3.9 mmol/l of <4%, and a TBR <3.0 mmol/l of <1% are recommended targets, with less stringent targets for older or high-risk individuals and for those under 25 years of age.
As always though, glycaemic targets should be individualised and rarely is that more applicable than in the personal use of CGM and the data it provides.
Abbreviations
CGM
Continuous glucose monitoring (or continuous glucose monitor)
CSII
Continuous subcutaneous insulin infusion
DIAMOND
Multiple Daily Injections and Continuous Glucose Monitoring in Diabetes (study)
GMI
Glucose management indicator
isCGM
Intermittently scanned continuous glucose monitor
MARD
Mean absolute relative difference
PRO
Patient-reported outcome
rtCGM
Real-time continuous glucose monitor
SMBG
Self-monitoring of blood glucose
TAR
Time above range
TBR
Time below range
TIR
Time in range
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https://link.springer.com/article/10.1007/s00125-019-05027-0
Introduction
When the Diabetes Control and Complications Trial (DCCT)
first demonstrated that intensive glucose lowering reduces the
risk of long-term diabetes complications, intensive glucose
control involved self-monitoring of blood glucose (SMBG)
at least four times daily, a weekly blood glucose check at
03:00 hours and regular laboratory measurement of HbA1c [1].
Today, over a quarter of a century on, emphases on
individualised care and advances in glucose monitoring
technology have provided access to a wealth of alternative indices
of glucose control quality that are available to individuals
who have the means and desire to make use of continuous
glucose monitoring (CGM) technologies. Among these metrics,
time in range (TIR) has surfaced as a measure that is preferred
by patients because of its bearing on daily life [2]. Concurrently,
evidence is beginning to emerge indicating that TIR can predict
the risk of long-term diabetes complications [3, 4] and pregnancy
outcomes [5, 6]. However, for clinicians and researchers who
are most familiar with evidence supported by blood glucose
measurement and HbA1c, it may be difficult to know how to
interpret TIR, where to position TIR relative to other glucose
metrics and what TIR goals to discuss with patients.
In this short review, I summarise the state-of-the-art for TIR, emphasising
that TIR is largely determined by the extent of hyperglycaemia
and that any discussions around TIR goals should include
consideration of time below range (TBR) as well. I summarise
recent guidance for healthcare professionals in helping patients
interpret TIR goals and I consider the obstacles currently limiting
the broad application of TIR in diabetes management.
Evidence linking TIR to the risk of long-term
diabetes complications
Aside from being reflective of the day-to-day experience of
individuals with diabetes [2], evidence has recently come
to light indicating that TIR itself can predict the future risk
of diabetes complications [3, 4]. For instance, retrospective
analysis of CGM data collected over three consecutive
days from 3262 individuals with type 2 diabetes revealed
a significant inverse association of TIR with all stages of
retinopathy after adjusting for age, sex, BMI, diabetes
duration, blood pressure, lipids and HbA1c [4]. Data associating
TIR with a reduced risk of complications has also
recently been reported for participants in the DCCT.
During the course of that study, participants conducted
seven-point profile testing of blood glucose concentrations
for 1 day every 3 months. Although not computed with the
aid of a CGM device, investigators derived TIR from the
seven-point profiles and discerned that for every 10%
lowering of TIR the adjusted hazard rate for the retinopathy
outcome in the DCCT was increased by 64% (95% CI
51, 78) and the adjusted hazard rate for the microalbuminuria
outcome was increased by 40% (95% CI 25, 56) [3]. This
evidence is important because it begins to build the case that
CGM metrics could be considered acceptable endpoints for
clinical trials and accordingly used to inform regulatory decisions
in the future [3, 23].
Summary
In summary, among the host of possible metrics now available
to patients and healthcare professionals making use of
CGM technology, TIR has emerged as an intuitive metric
that may correlate better with PROs and that itself is associated
with the risk of long-term complications. However,
when engaged in discussions of TIR it is imperative that
healthcare professionals include an indicator of hypoglycaemia
and its severity in the conversation (i.e. TBR <3.9 mmol/l and
TBR <3.0 mmol/l). Based on current evidence, a TIR of >70%
would appear to be a reasonable target for most individuals,
roughly equating to an HbA1c of ≤53 mmol/mol (7.0%), if
it can be achieved with a TBR <3.9 mmol/l of <4% and a
TBR <3.0 mmol/l of <1%. As is always the case, though,
glycaemic goals should be individualised and rarely does
a better opportunity present itself to individualise treatment
goals than with the personal use of CGM in diabetes
self-management.
SUMMARY
TIR is a key metric of the quality of glucose control
Evidence is beginning to emerge linking lower TIR
to increased risk of long-term diabetes complications
and adverse pregnancy outcomes
TIR correlates inversely with HbA1c and is largely
indicative of the extent and magnitude of hyperglycaemia
Discussions on TIR should include discussions on
TBR
Recent consensus recommendations suggest
targets of TIR >70%, with TBR (<3.9 mmol/l) <4%
and TBR (<3.0 mmol/l) <1% for most individuals
with type 1 or type 2 diabetes, although targets
should be individualised
Different targets should be considered for older or
high-risk individuals, paediatric
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