Diabetologia

https://doi.org/10.1007/s00125-024-06171-y

ARTICLE

The association of chronic complications with time in tight range

and time in range in people with type 1 diabetes: a retrospective
cross‑sectional real‑world study
Jolien De Meulemeester1 · Sara Charleer1 · Margaretha M. Visser1 · Christophe De Block2 ·
Chantal Mathieu1 · Pieter Gillard1,3

Received: 26 January 2024 / Accepted: 9 April 2024

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024

Abstract
Aims/hypothesis The aim of this study was to evaluate the association of chronic complications with time in tight range
(TITR: 3.9–7.8 mmol/l) and time in range (TIR: 3.9–10.0 mmol/l) in people with type 1 diabetes.
Methods The prevalence of microvascular complications (diabetic retinopathy, diabetic nephropathy and diabetic peripheral neu-
ropathy [DPN]) and macrovascular complications according to sensor-measured TITR/TIR was analysed cross-sectionally in 808
adults with type 1 diabetes. Binary logistic regression was used to evaluate the association between TITR/TIR and the presence of
complications without adjustment, with adjustment for ­HbA1c, and with adjustment for ­HbA1c and other confounding factors (sex,
age, diabetes duration, BMI, BP, lipid profile, smoking, and use of statins and renin–angiotensin–aldosterone system inhibitors).
Results The mean TITR and TIR were 33.9 ± 12.8% and 52.5 ± 15.0%, respectively. Overall, 46.0% had any microvascular complica-
tion (34.5% diabetic retinopathy, 23.8% diabetic nephropathy, 16.0% DPN) and 16.3% suffered from any macrovascular complication.
The prevalence of any microvascular complication, diabetic retinopathy, diabetic nephropathy and a cerebrovascular accident (CVA)
decreased with increasing TITR/TIR quartiles (all ptrend<0.05). Each 10% increase in TITR was associated with a lower incidence of
any microvascular complication (OR 0.762; 95% CI 0.679, 0.855; p<0.001), diabetic retinopathy (OR 0.757; 95% CI 0.670, 0.856;
p<0.001), background diabetic retinopathy (OR 0.760; 95% CI 0.655, 0.882; p<0.001), severe diabetic retinopathy (OR 0.854; 95%
CI 0.731, 0.998; p=0.048), diabetic nephropathy (OR 0.799; 95% CI 0.699, 0.915; p<0.001), DPN (OR 0.837; 95% CI 0.717, 0.977;
p=0.026) and CVA (OR 0.651; 95% CI 0.470, 0.902; p=0.010). The independent association of TITR with any microvascular com-
plication (OR 0.867; 95% CI 0.762, 0.988; p=0.032), diabetic retinopathy (OR 0.837; 95% CI 0.731, 0.959; p=0.010), background
diabetic retinopathy (OR 0.831; 95% CI 0.705, 0.979; p=0.027) and CVA (OR 0.619; 95% CI 0.426, 0.899; p=0.012) persisted after
adjustment for ­HbA1c. Similar results were obtained when controlling for ­HbA1c and other confounding factors.
Conclusions/interpretation TITR and TIR are inversely associated with the presence of microvascular complications and CVA in
people with type 1 diabetes. Although this study was not designed to establish a causal relationship, this analysis adds validity to the
use of TITR and TIR as key measures in glycaemic management.
Trial registration ClinicalTrials.gov NCT02601729 and NCT02898714

Keywords Continuous glucose monitoring · Macrovascular complications · Microvascular complications · Time in range ·
Time in tight range · Type 1 diabetes
Abbreviations
CGM Continuous glucose monitoring
CVA Cerebrovascular accident
* Pieter Gillard CVD Cardiovascular disease
pieter.gillard@uzleuven.be
DPN Diabetic peripheral neuropathy
1
Department of Endocrinology, University Hospitals Leuven FUTURE Flash Glucose Monitoring Study for Diabetes
– KU Leuven, Leuven, Belgium RAAS Renin–angiotensin–aldosterone system
2
Department of Endocrinology, Diabetology & Metabolism, RESCUE Reimbursement Study of Continuous Glucose
University Hospital Antwerp – University of Antwerp, Monitoring in Belgium
Edegem, Belgium TIR Time in range
3
Fonds Wetenschappelijk Onderzoek, Brussels, Belgium TITR Time in tight range

Vol.:(0123456789)

Introduction
The DCCT demonstrated that high H ­ bA1c levels are asso-
ciated with an increased risk of developing chronic com-
plications, such as diabetic retinopathy, diabetic nephropa-
thy, diabetic autonomic neuropathy, diabetic peripheral
neuropathy (DPN) and cardiovascular disease (CVD) [1].
As a result, monitoring ­HbA1c became the gold standard
to evaluate glycaemic management and guide therapeutic
decisions in people with type 1 diabetes. However, use of
­HbA1c has some limitations in individual diabetes manage-
ment, namely that ­HbA1c measurements may be affected by
a number of conditions such as anaemia, haemoglobinopa-
thies and iron deficiency, as well as physiological factors
such as pregnancy and ethnic background [2]. In addition, a
given ­HbA1c is known to be associated with a wide range of
possible mean glucose levels [3], which may be explained
by inter-individual differences in erythrocyte life span [4]
and glycation rate [5]. Furthermore, as H ­ bA1c provides an
average of glucose levels over the previous 2–3 months, this
metric fails to reflect short-term glycaemic variability that
may result in acute glycaemic excursions such as hypo- and
hyperglycaemia. Thus, monitoring an individual’s glycaemic
profile based on ­HbA1c as the sole metric may be misleading
and result in insufficient therapeutic advice. The limitations
of ­HbA1c highlight the need to look beyond ­HbA1c towards
other glycaemic metrics when assessing the glucose levels
of people with type 1 diabetes.
Diabetologia
The wealth of information generated by continuous
glucose monitoring (CGM) has led to implementation of
a set of metrics of short-term glycaemic management that
may be used to interpret CGM-measured data as a com-
plement to H­ bA1c [6]. Based on the recommendations of
the international consensus on CGM use, time in range
(TIR: 3.9–10.0 mmol/l) has been adopted in clinical prac-
tice as a key metric in glycaemic management and as an
endpoint in clinical trials [7]. Evidence supporting the
consensus target of >70% for TIR is based on the strong
inverse correlation between TIR and H ­ bA1c (r=−0.73),
with a target of 70% TIR being in line with an H ­ bA1c of
53 mmol/mol (7.0%) [8]. Given the relationship between
­HbA1c and TIR, the impact of low TIR on the prevalence
of chronic diabetes complications has been investigated
[9–11]. However, despite the increasing acceptance of TIR
as a useful metric in diabetes care, the independent asso-
ciation between TIR and various chronic complications in
type 1 diabetes is still unclear [12]. Recently, guidelines
have recommended that time in tight range (TITR) should
also be reported [13]; this is defined as the percentage
of time spent in normoglycaemia (3.9–7.8 mmol/l) [14].
TITR lowers the upper threshold for glucose levels, and
thus may become the metric to focus on in the future to
reduce the risk of complications. So far, however, there
is no evidence directly showing the association of TITR
with these complications. Therefore, this study evaluated
the association of CGM-measured TITR and TIR with the
Diabetologia
presence of various micro- and macrovascular complica-
tions in a large real-world population of adults with type
1 diabetes.
Methods
Study design and population In this retrospective cross-
sectional study, data were gathered from 1067 individu-
als who participated in RESCUE (Reimbursement Study
of Continuous Glucose Monitoring in Belgium) [15] and
FUTURE (Flash Glucose Monitoring Study for Diabe-
tes) [16] at the University Hospitals of Leuven. RESCUE
analysed data from adults with type 1 diabetes on insulin
pump therapy who started real-time CGM between Sep-
tember 2014 and December 2016 [15]. FUTURE analysed
data from adults with type 1 diabetes on insulin pump
therapy or multiple daily injections who started intermit-
tently scanned CGM between July 2016 and July 2018
[16]. Unbiased recruitment was conducted in a tertiary
centre, resulting in a study population characterised by
higher levels of education and a better socioeconomic
status.
The protocols of RESCUE and FUTURE were approved
by the coordinating institutional review board (Ethics Com-
mittee of University Hospitals Leuven, Belgium). The stud-
ies were performed in line with the good clinical practice
guidelines of the Declaration of Helsinki in its latest form
at the time of study initiation.
Data collection Clinical data including sex, age, diabetes
duration and type of insulin therapy were collected at the
time that participants started using CGM. Sex and eth-
nicity data were self-reported. The most recent clinical
data recorded before participants started using CGM were
gathered from the medical electronic files, and included
BMI, systolic and diastolic BP, lipid profile (total choles-
terol, triglycerides, HDL-cholesterol, LDL-cholesterol),
use of statins, use of renin–angiotensin–aldosterone sys-
tem (RAAS) inhibitors, smoking, ­HbA1c, and information
on the presence of microvascular complications (diabetic
retinopathy, diabetic nephropathy and DPN) and mac-
rovascular complications (stenosis of the carotid artery,
CHD, cerebrovascular accident [CVA] and peripheral
arterial disease). TITR, TIR, SD, CV and CGM use were
obtained and averaged from the first 2 weeks after CGM
initiation from sensor downloads. Participants with less
than 70% CGM use (n=56) were not excluded from the
analysis.
Classification of disease states Diabetic retinopathy was
classified as (1) no diabetic retinopathy; (2) the presence
of non-proliferative/background diabetic retinopathy; or
(3) the presence of severe diabetic retinopathy if partici-
pants had proliferative diabetic retinopathy, maculopathy or
underwent laser treatment in the past. Diabetic nephropa-
thy was classified as (1) no diabetic nephropathy; or (2)
the presence of diabetic nephropathy if the urinary albu-
min excretion was ≥30 mg/24h, eGFR was <60 ml/min
or participants were taking RAAS inhibitors because of a
history of albuminuria. DPN was classified as (1) no DPN;
or (2) the presence of DPN if monofilament tests were
abnormal (<6/6) or abnormal nerve conduction velocities
were detected by electromyography. Macrovascular com-
plications were classified as (1) no CVD; (2) the presence
of stenosis of the carotid artery if duplex ultrasonography
indicated more than 20% or more than 50% stenosis; (3)
the presence of CHD if participants underwent coronary
artery bypass grafting or percutaneous coronary inter-
vention, or had a myocardial infarct; (4) the presence of
ischaemic CVA; or (5) the presence of peripheral arterial
disease. The presence of any microvascular complication
was scored as positive if a participant presented with one or
more microvascular complications. The presence of diabetic
retinopathy was scored as positive if a participant presented
with any stage of diabetic retinopathy. The presence of any
macrovascular complication was scored as positive if a par-
ticipant had any form of macrovascular disease.
Outcomes The primary outcome was to assess the preva-
lence of microvascular complications (diabetic retinopathy,
diabetic nephropathy and DPN) and macrovascular com-
plications (stenosis of the carotid artery, CHD, CVA and
peripheral arterial disease) in relation to TITR and TIR. Sec-
ondary outcomes were the association between TITR/TIR
and the presence of micro- and macrovascular complications
without adjustment, with adjustment for ­HbA1c, and with
adjustment for ­HbA1c as well as other confounding factors.
Other secondary endpoints were to identify risk factors that
may predict the presence or absence of micro- and macro-
vascular complications.
Statistical analysis Descriptive analyses of population char-
acteristics are presented as means ± SD for normally dis-
tributed continuous variables, as median and IQR for non-
normally distributed continuous variables, and as count and
percentages for categorical variables. Comparisons between
population characteristics according to the presence of
micro- and macrovascular complications were made using
Student’s unpaired t test for normally distributed continuous
variables, the Mann–Whitney U test for non-normally dis-
tributed continuous variables, and the χ2 test for categorical
variables. The study population was divided into four groups
according to the 25th, 50th and 75th percentiles for TITR
and TIR, separately. For TITR, the Q1 group were those with
TITR ≤26%, the Q2 group were those with TITR >26% to
 Diabetologia

≤33%, the Q3 group were those with TITR >33% to ≤41%, Table 1  Population characteristics
and the Q4 group were those with TITR >41%. For TIR, the Variable Value
Q1 group were those with TIR ≤43%, the Q2 group were
those with TIR >43% to ≤53%, the Q3 group were those n 808
with TIR >53% to ≤63%, and the Q4 group were those with Sex (male) 418 (51.7)
TIR >63%. The Cochran–Armitage trend test was used to Age, years 44.8 ± 15.2
assess trends in the prevalence of micro- and macrovascular BMI, kg/m2 25.6 ± 4.0
complications across the four TITR and TIR groups. The dif- Systolic BP, mmHg 136.8 ± 18.4
ference in prevalence of micro- and macrovascular compli- Diastolic BP, mmHg 77.1 ± 10.6
cations in participants who met the target of 50% for TITR or Lipid profile
70% for TIR compared with those who did not meet the tar- Total cholesterol, mmol/l 4.4 (3.8–5.0)
get was evaluated using the χ2 test. The 50% target for TITR Triglycerides, mmol/l 1.0 (0.7–1.5)
is based on recommendations from the 17th International HDL-cholesterol, mmol/l 1.7 ± 0.5
Conference On Advanced Technologies & Treatments for LDL-cholesterol, mmol/l 2.2 ± 0.7
Diabetes 2023 in Berlin and a recently published paper by Smoking (yes) 130 (16.1)
Akturk et al [17], as a TITR of 50% was found to be related Use of RAAS inhibitors 266 (32.9)
to an H
­ bA1c of 48 mmol/mol (6.5%) [18]. Multiple binary Use of statins 334 (41.3)
logistic regression analyses were performed to estimate the Diabetes duration, years 23.1 ± 13.6
ORs for the risk of micro- and macrovascular complications Insulin therapy
with a 10% increase in TITR and 10% increase in TIR with- Multiple daily injections 529 (65.5)
out adjustment, after adjustment for ­HbA1c, and after adjust- Insulin ­pumpa 279 (34.5)
ment for ­HbA1c as well as for other confounding factors (sex, CGM use, %b 85.7 ± 13.5
age, diabetes duration, BMI, BP, lipid profile, smoking, and Diabetes control
use of statins and RAAS inhibitors). Subsequently, receiver TITR, %b 33.9 ± 12.8
operating characteristic (ROC) curves and corresponding TIR, %b 52.5 ± 15.0
AUC were calculated to evaluate the performance of these SD, mmol/lb 4.1 ± 1.0
characteristics (TITR, TIR, ­HbA1c, sex, age, diabetes dura- CV, %b 43.9 ± 8.1
tion, BMI, BP, lipid profile, smoking, and use of statins and  ­HbA1c, mmol/mol 63 ± 13
RAAS inhibitors) in predicting the presence or absence of  ­HbA1c, % 7.9 ± 1.2
micro- and macrovascular complications. For all statistical Microvascular complication(s) p­ resentc 372 (46.0)
analyses, a p value <0.05 was considered significant. No Diabetic retinopathy 279 (34.5)
adjustment was made for multiple testing. Background diabetic retinopathy 154 (19.1)
All statistical analyses were performed using SPSS soft- Severe diabetic retinopathy 125 (15.5)
ware for Windows (IBM SPSS Statistics version 23; IBM, Diabetic nephropathy 192 (23.8)
USA). DPN 129 (16.0)
Macrovascular complication(s) ­presentc 132 (16.3)
Stenosis of the carotid artery 65 (8.0)
  20–50% 46 (5.7)
Results   >50% 19 (2.4)
CHD 40 (5.0)
Population characteristics Of the 1067 participants enrolled CVA (ischaemic) 28 (3.5)
in this study, 259 were excluded because data for TITR and Peripheral arterial disease 13 (1.6)
TIR were missing 2 weeks after initiation of CGM. This Data are as n (%), mean ± SD or median (IQR)
resulted in a total of 808 participants, of whom 82 (10.1%) a
None of the participants in the insulin pump group used a hybrid
were participants in RESCUE and 726 (89.9%) were par- closed-loop system
ticipants in FUTURE. An overview of population charac- b
Averages from 2 weeks after initiation of CGM
teristics is shown in Table 1. The participants had a mean c
There may be more than one microvascular/macrovascular complica-
age of 44.8 ± 15.2 years and a mean BMI of 25.6 ± 4.0 tion per participant
kg/m2. Both sexes were equally represented, avoiding sex
inequity. They had a long history of type 1 diabetes (23.1 ±
13.6 years), used mostly multiple daily injections (n=529, mol (7.9 ± 1.2%). Forty-six per cent of participants (n=372)
65.5%), and had a mean TITR of 33.9 ± 12.8%, a mean were affected by one or more microvascular complications
TIR of 52.5 ± 15.0% and a mean H ­ bA1c of 63 ± 13 mmol/ (34.5% [n=279] with diabetic retinopathy, 23.8% [n=192]
Diabetologia

with diabetic nephropathy and 16.0% [n=129] with DPN).
Sixteen per cent (n=132) suffered from any macrovascular
complication.
Characteristics of participants with complications Compar-
isons between population characteristics according to the
presence of micro- and macrovascular complications are
presented in Table 2. Participants with any microvascular
complication were older, had a higher BMI, were more likely
to use RAAS inhibitors and statins, and had a longer dura-
tion of diabetes than those without microvascular complica-
tions (p<0.001). They had sub-optimal glycaemic manage-
ment as indicated by lower TITR and TIR and higher ­HbA1c
compared with those without microvascular complications
(p<0.001). Similarly, participants with any macrovascular
complication were older, had higher systolic blood pressure,
were more likely to use RAAS inhibitors and statins, and
had a longer duration of diabetes than those without macro-
vascular complications (p<0.001). Unlike participants with
a microvascular complication, those with macrovascular
complications had comparable glycaemic management to
those without macrovascular complications.
Association of TITR and TIR with the presence of chronic
complications TITR showed an inverse relationship with
the presence of microvascular complications (Fig. 1a). The
percentage of participants with any microvascular compli-
cation was 54.4% in the lowest TITR quartile group (TITR
≤26%) compared with 35.4% in the highest TITR quartile
group (TITR >41%) (ptrend<0.001). A similar decreasing
trend was found in people suffering from diabetic retin-
opathy (ptrend<0.001), diabetic nephropathy (ptrend=0.009)
and DPN (ptrend=0.061) across increasing TITR quartiles.
When all participants with a macrovascular complication
were combined, no clear association was observed, nor when
each macrovascular complication was considered separately,
except for CVA (ptrend=0.012) (Fig. 1b). Results for the
entire group with stenosis of the carotid artery >20% are pro-
vided, as the outcomes did not substantially differ compared
with the group with >50% stenosis. The prevalence of any

Table 2  Population characteristics according to the absence or presence of chronic complications

Microvascular complications Macrovascular complications
None present (n=436) Any present (n=372) p value None present (n=676) Any present (n=132) p value

Sex (male) 232 (53.2) 186 (50.0) 0.397 343 (50.7) 75 (56.8) 0.201
Age, years 39.1 ± 14.4 51.5 ± 13.3 <0.001 41.6 ± 14.1 61.1 ± 8.7 <0.001
BMI, kg/m2 25.2 ± 3.7 26.2 ± 4.2 <0.001 25.6 ± 3.9 25.9 ± 4.5 0.455
Systolic BP, mmHg 135.3 ± 17.2 138.6 ± 19.6 0.012 135.4 ± 17.3 143.6 ± 22.1 <0.001
Diastolic BP, mmHg 78.4 ± 10.3 75.5 ± 10.8 <0.001 77.8 ± 10.4 73.6 ± 10.7 <0.001
Lipid profile
Total cholesterol, mmol/l 4.5 (3.9–5.1) 4.3 (3.8–4.9) 0.027 4.5 (3.9–5.1) 3.9 (3.4–4.6) <0.001
Triglycerides, mmol/l 1.0 (0.7–1.5) 1.1 (0.8–1.5) 0.101 1.0 (0.7–1.5) 1.1 (0.8–1.5) 0.398
HDL-cholesterol, mmol/l 1.7 ± 0.5 1.7 ± 0.5 0.380 1.7 ± 0.5 1.7 ± 0.6 0.094
LDL-cholesterol, mmol/l 2.2 ± 0.7 2.1 ± 0.8 0.060 2.3 ± 0.7 1.8 ± 0.7 <0.001
Smoking (yes) 64 (14.7) 66 (17.7) 0.250 103 (15.2) 27 (20.5) 0.136
Use of RAAS inhibitors 65 (14.9) 201 (54.0) <0.001 183 (27.1) 83 (62.9) <0.001
Use of statins 126 (28.9) 208 (55.9) <0.001 222 (32.8) 112 (84.8) <0.001
Diabetes duration, years 16.6 ± 10.6 30.6 ± 12.7 <0.001 21.1 ± 12.4 33.2 ± 14.7 <0.001
Insulin therapy
Multiple daily injections 290 (66.5) 239 (64.2) 0.505 433 (64.1) 96 (72.7) 0.055
Insulin pump 146 (33.5) 133 (35.8) 0.505 243 (35.9) 36 (27.3) 0.055
Diabetes control
TITR, %a 35.8 ± 13.6 31.6 ± 11.3 <0.001 34.1 ± 13.0 32.5 ± 11.5 0.141
TIR, %a 54.4 ± 15.3 50.3 ± 14.3 <0.001 52.7 ± 15.1 51.3 ± 14.3 0.305
SD, mmol/la 4.1 ± 1.0 4.2 ± 1.0 0.045 4.1 ± 1.0 4.1 ± 1.0 0.843
CV, %a 44.0 ± 8.3 43.7 ± 7.8 0.503 44.0 ± 8.2 43.4 ± 7.6 0.432
 ­HbA1c, mmol/mol 61 ± 12 66 ± 13 <0.001 63 ± 13 65 ± 12 0.037
 ­HbA1c, % 7.7 ± 1.1 8.2 ± 1.2 <0.001 7.9 ± 1.2 8.1 ± 1.1 0.037

Data are n (%), mean ± SD or median (IQR)

a
Averages from 2 weeks after initiation of CGM
 Diabetologia

a c

Prevalence microvascular complications (%)

Prevalence microvascular complications (%)

ptrend <0.001
60 60 ptrend <0.001

ptrend <0.001
ptrend <0.001

40 40
ptrend = 0.009 ptrend = 0.026

ptrend = 0.061 ptrend = 0.063

20 20

0 0

Any microvascular Diabetic Diabetic DPN Any microvascular Diabetic Diabetic DPN
complication retinopathy nephropathy complication retinopathy nephropathy

b d
Prevalence macrovascular complications (%)

Prevalence macrovascular complications (%)

ptrend = 0.235
ptrend = 0.221
20 20

15 15
ptrend = 0.941
ptrend = 0.889
10 10 ptrend = 0.018
ptrend = 0.726 ptrend = 0.012 ptrend = 0.691

ptrend = 0.185 ptrend = 0.110

5 5

0 0

Any macrovascular Stenosis of CHD CVA Peripheral Any macrovascular Stenosis of CHD CVA Peripheral
complication the carotid artery arterial disease complication the carotid artery arterial disease

Time in tight range Q1 (≤26%) Q2 (>26 to ≤33%) Q3 (>33 to ≤41%) Q4 (>41%) Time in range Q1 (≤43%) Q2 (>43 to ≤53%) Q3 (>53 to ≤63%) Q4 (>63%)

Fig. 1  Prevalence of microvascular (a, c) and macrovascular (b, d) Q1–Q4 (a, b) and TIR quartile group Q1–Q4 (c, d). TITR: 3.9–7.8
complications according to TITR and TIR. Data represent the per- mmol/l; TIR: 3.9–10.0 mmol/l
centage of participants with a complication per TITR quartile group

microvascular complication (ptrend<0.001), diabetic retin- 0.426, 0.899; p=0.012). The results obtained when controlling
opathy (ptrend<0.001), diabetic nephropathy (ptrend=0.026), for ­HbA1c and other confounding factors were similar to those
DPN (ptrend=0.063) and CVA (ptrend=0.018) decreased with obtained as when controlling for ­HbA1c alone (Fig. 2a).
ascending TIR quartiles (Fig. 1c,d). The odds of presenting with any microvascular complica-
The prevalence of complications among participants tion decreased by 17.2% (p<0.001), diabetic retinopathy by
divided into two groups according to the recommendations 17.4% (p<0.001), background diabetic retinopathy by 19.0%
for TITR and the targets designated by the international con- (p<0.001), diabetic nephropathy by 12.9% (p=0.013) and CVA
sensus for TIR is shown in electronic supplementary mate- by 25.1% (p=0.020) for each 10% increase in TIR when unad-
rial (ESM) Table 1. Participants with >50% TITR or >70% justed (Fig. 2b). After correction for H
­ bA1c, the negative associ-
TIR had a lower incidence of microvascular complications, ation between TIR and these complications was attenuated (OR
especially background diabetic retinopathy, compared with closer to 1), but the independent effect of TIR on the presence
participants who did not achieve those targets. of background diabetic retinopathy and CVA persisted. When
In the unadjusted model, the odds of having any microvas- ­ bA1c and other confounding factors, an independ-
adjusted for H
cular complication decreased by 23.8% (p<0.001), diabetic ent association of TIR with diabetic retinopathy (OR 0.796; 95%
retinopathy by 24.3% (p<0.001), background diabetic retinopa- CI 0.675, 0.938; p=0.007), background diabetic retinopathy (OR
thy by 24.0% (p<0.001), severe diabetic retinopathy by 14.6% 0.854; 95% CI 0.733, 0.994; p=0.042) and CVA (OR 0.617;
(p=0.048), diabetic nephropathy by 20.1% (p<0.001), DPN 95% CI 0.440, 0.866; p=0.005) was observed (Fig. 2b).
by 16.3% (p=0.026) and CVA by 34.9% (p=0.010) for each
additional 10% increase in TITR (Fig. 2a). After adjustment for Risk factors for the presence of chronic complications ESM
­HbA1c, TITR was found to be an independent risk factor for any Table 2 lists AUC for the predictive performance of risk fac-
microvascular complication (OR 0.867; 95% CI 0.762, 0.988; tors for each chronic complication. Using TITR or TIR as risk
p=0.032), diabetic retinopathy (OR 0.837; 95% CI 0.731, factors yielded limited predictive abilities for each complica-
0.959; p=0.010), background diabetic retinopathy (OR 0.831; tion, with AUC ranging from 0.484 to 0.663 for TITR and
95% CI 0.705, 0.979; p=0.027) and CVA (OR 0.619; 95% CI from 0.473 to 0.636 for TIR. The AUC of 0.663 for TITR and
Diabetologia

a b
0.762 (0.679, 0.855)*** 0.828 (0.753, 0.911)***
Any microvascular complication 0.867 (0.762, 0.988)* 0.939 (0.841, 1.049)
0.813 (0.682, 0.970)* 0.871 (0.751, 1.010)
0.757 (0.670, 0.856)*** 0.826 (0.747, 0.912)***
Diabetic retinopathy 0.837 (0.731, 0.959)* 0.909 (0.812, 1.017)
0.719 (0.588, 0.881)*** 0.796 (0.675, 0.938)**
0.760 (0.655, 0.882)*** 0.810 (0.719, 0.912)***
Background diabetic retinopathy 0.831 (0.705, 0.979)* 0.875 (0.766, 0.998)*
0.815 (0.676, 0.982)* 0.854 (0.733, 0.994)*
0.854 (0.731, 0.998)* 0.925 (0.815, 1.050)
Severe diabetic retinopathy 0.909 (0.764, 1.081) 0.989 (0.857, 1.142)
0.839 (0.652, 1.081) 0.898 (0.729, 1.105)
0.799 (0.699, 0.915)*** 0.871 (0.781, 0.971)*
Diabetic nephropathy 0.899 (0.775, 1.043) 0.975 (0.862, 1.103)
0.900 (0.746, 1.085) 0.955 (0.818, 1.114)
0.837 (0.717, 0.977)* 0.888 (0.783, 1.007)
DPN 0.915 (0.772, 1.086) 0.965 (0.838, 1.112)
0.877 (0.703, 1.095) 0.881 (0.734, 1.057)

0.901 (0.775, 1.047) 0.939 (0.829, 1.063)

Any macrovascular complication 0.955 (0.808, 1.129) 0.995 (0.864, 1.145)
0.933 (0.745, 1.169) 0.896 (0.738, 1.087)
0.986 (0.808, 1.204) 0.999 (0.843, 1.183)
Stenosis of the carotid artery 1.002 (0.800, 1.255) 1.016 (0.838, 1.232)
1.022 (0.789, 1.324) 0.973 (0.777, 1.218)
1.039 (0.812, 1.330) 1.072 (0.866, 1.328)
CHD 1.154 (0.885, 1.505) 1.190 (0.942, 1.504)
1.255 (0.874, 1.803) 1.164 (0.844, 1.607)
0.651 (0.470, 0.902)* 0.749 (0.588, 0.955)*
CVA 0.619 (0.426, 0.899)* 0.729 (0.550, 0.965)*
0.546 (0.347, 0.858)** 0.617 (0.440, 0.866)**
0.680 (0.426, 1.085) 0.736 (0.520, 1.042)
Peripheral arterial disease 0.779 (0.467, 1.298) 0.818 (0.552, 1.212)
0.807 (0.382, 1.703) 0.811 (0.470, 1.398)

0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0

OR (95% CI) OR (95% CI)

Unadjusted Adjusted for HbA1c Adjusted for HbA1c and other confounding factors

Fig. 2  Association of TITR and TIR with the presence of micro- and factors are sex, age, diabetes duration, BMI, systolic and diastolic BP,
macrovascular complications. ORs and p values are estimated per 10% lipid profile (total cholesterol, triglycerides, HDL-cholesterol, LDL-
increase in TITR (a) and TIR (b). Asterisks indicate statistically sig- cholesterol), smoking, and use of statins and renin–angiotensin–aldos-
nificant differences: *p<0.05, **p<0.01, ***p<0.001. Confounding terone system inhibitors. TITR: 3.9–7.8 mmol/l; TIR: 3.9–10.0 mmol/l

0.635 for TIR were obtained for CVA, suggesting probabilities
of 66% and 64%, respectively, that TITR and TIR correctly
distinguish a person with CVA from a person without CVA.
­HbA1c showed only a slightly better predictive performance
compared with TITR and TIR, with AUC ranging from 0.528
to 0.701. After adding other risk factors (sex, age, diabetes
duration, BMI, BP, lipid profile, smoking and use of statins
and RAAS inhibitors) the AUC ranged from 0.750 to 0.982.
Discussion
The results from this retrospective cross-sectional study
show an inverse relationship of CGM-derived TITR and
TIR with the occurrence of microvascular complications
and CVA in a large heterogenous population of people liv-
ing with type 1 diabetes. A 10% increase in TITR or TIR was
associated with 23.8 and 17.2% lower incidences, respec-
tively, of any microvascular complication and 34.9 and
25.1% lower incidences, respectively, of CVA.
People with diabetes as well as healthcare providers are
increasingly recognising the importance of assessing CGM-
derived metrics as a complementary measure to H ­ bA1c when
evaluating glycaemic management, as such metrics allow a
more comprehensive understanding of an individual’s glu-
cose profile. Exploring the association between these metrics
and chronic complications further substantiates the validity
of their use in clinical practice.
To our knowledge, this study is the first to evaluate the asso-
ciation between TITR and the presence of chronic diabetes com-
plications. Our data showed an independent association between
TITR and the presence of any microvascular complication, dia-
betic retinopathy, background diabetic retinopathy and CVA.
This is important in light of the ongoing debate on the clinical
validity of TITR [19]. Our findings highlight the importance
of maintaining blood glucose levels within the normal range to
minimise the risk of chronic complications. TITR may become
the metric to focus on for setting therapeutic goals in people
with type 1 diabetes, as advances in automated insulin deliv-
ery systems enable the achievement of near-normal glycaemic
levels [17, 19]. A recent study in children revealed that TITR

was notably higher in the group receiving hybrid closed-loop
therapy, emphasising the usefulness of hybrid closed-loop
insulin delivery systems in maintaining tight glucose control
to mitigate the risk of complications [20]. Our observation that
people already experiencing diabetes complications still had
sub-optimal glycaemic management underlines the urgent need
for more accessibility to these effective therapies in diabetes
management.
Because both ­HbA1c and other factors are known to affect
the risk of developing chronic complications, we adjusted for
this when evaluating the association with TITR and TIR. After
correction, the independent association between TITR/TIR and
the occurrence of diabetic retinopathy, background diabetic
retinopathy and CVA persisted, indicating an added effect of
TITR and TIR on the presence of these complications beyond
­HbA1c and other established risk factors. In line with findings
from a subsequent analysis of the DCCT dataset by Lachin et al
[12], the association between TITR/TIR and chronic compli-
cations weakened when controlling for H ­ bA1c and additional
risk factors. This is not surprising as TITR, TIR and H ­ bA1c are
strongly correlated, implying that the observed effects of TITR
and TIR are partially mediated by H ­ bA1c, and supporting the
need to consider both H ­ bA1c as a long-term metric as well as
TITR/TIR as short-term metrics to make well-informed thera-
peutic decisions to prevent the development of complications.
Our study reports a robust, independent association between
TITR/TIR and CVA. The noteworthy strength of this asso-
ciation, particularly with CVA as the singular macrovascu-
lar complication, may not be incidental. This observation is
probably influenced by our methodology, which did not distin-
guish between CVAs arising from large-artery atherosclerosis
or small-vessel occlusion. Except for CVA, no clear effect of
TITR or TIR on the occurrence of other macrovascular com-
plications was observed. The findings in studies of people with
type 1 diabetes have been contradictory, as one study found
no significant correlation between TIR and carotid artery wall
thickness [21], while another established that lower TIR levels
significantly contributed to CVD [11]. The lack of a clear asso-
ciation between TITR/TIR and macrovascular complications
other than CVA in our study may be due to the low number of
participants presenting with any of these complications and
the multifactorial nature of CVD. The increasing predictive
performance in differentiating the presence of macrovascular
complications after considering other risk factors in addition
to TITR, TIR and ­HbA1c reinforces the importance of a multi-
factorial approach that involves parameters beyond glycaemic
management. In view of the ever-expanding recognition of the
benefits of medication such as sodium–glucose cotransporter 2
inhibitors and glucagon-like peptide 1 receptor agonists on
the prevention of cardiovascular and renal complications in
people with type 2 diabetes, there is an urgent need for studies
investigating the beneficial effects of these therapies in people
with type 1 diabetes.
Diabetologia
This study has limitations. Due to the cross-sectional
design, no causal relationship could be explored between
TITR/TIR and the presence of complications, as exposure
and outcome were assessed at the same time. Therefore, we
cannot exclude the possibility that part of the observed asso-
ciation could be attributed to reverse causality, as glycaemic
targets may be increased out of caution in people with a his-
tory of stroke, for example. However, conducting a prospec-
tive longitudinal study similar to the DCCT would be ethically
unfeasible. Maintaining extensive records of people with type
1 diabetes over extended periods of time could allow us to
determine the long-term impact of maintaining tight glycae-
mic management as reflected by TITR/TIR on the develop-
ment of complications, and to answer the question of which
metric is more strongly associated with these outcomes [22].
In conclusion, CGM-measured TITR and TIR are
inversely associated with the presence of microvascular
complications and CVA in people with type 1 diabetes. Our
findings provide a new perspective on the association of
TITR with chronic complications, and support the growing
evidence on the association of TIR with chronic complica-
tions, adding validity to the use of TITR and TIR as key
measures in glycaemic management.
Supplementary Information The online version contains peer-reviewed
but unedited supplementary material available at https://​doi.​org/​10.​
1007/​s00125-​024-​06171-y.
Acknowledgements We would like to thank Steffen Fieuws for provid-
ing advice about the statistical analyses. Part of the results presented
in this manuscript was presented at the 15th International Conference
on Advanced Technologies & Treatments for Diabetes, 27–30 April
2022, in Barcelona, Spain.
Data availability This analysis is based on data from participants of
RESCUE [15] and FUTURE [16] at the University Hospitals of Leu-
ven. Selected anonymous data collected in the study and additional
documents can be made available to others not involved in the study,
on the basis of a reasonable request. Please contact Dr Pieter Gillard:
pieter.gillard@uzleuven.be.
Funding This research received no specific grant from any funding
agency in the public, commercial or not-for-profit sectors.
Authors’ relationships and activities JDM received research support
from Tandem and Dexcom via KU Leuven. SC received research sup-
port from Roche Diabetes Care, Novo Nordisk and Sanofi via KU Leu-
ven. MMV received non-financial support for travel from Novo Nordisk
and Boehringer Ingelheim via UZ Leuven. MMV serves or has served
on the speakers’ bureau for Dexcom; financial compensation for these
activities has been received by KU Leuven. CDB received consulting
fees and honoraria for speaking for Abbott, AstraZeneca, Boehringer
Ingelheim, Eli Lilly, Insulet, Medtronic, Novo Nordisk and Roche. CM
serves or has served on the advisory panel for Novo Nordisk, Sanofi,
Merck Sharp and Dohme Ltd, Eli Lilly and Company, Novartis, Astra-
Zeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeu-
tics, Pfizer, Imcyse, Insulet, Zealand Pharma, Avotres, Mannkind, San-
doz and Vertex. Financial compensation for these activities has been
received by KU Leuven; KU Leuven has also received research support
for CM from Medtronic, Imcyse, Novo Nordisk, Sanofi and ActoBio
Diabetologia
Therapeutics. CM serves or has served on the speakers’ bureau for
Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim,
Astra Zeneca and Novartis. Financial compensation for these activi-
ties has been received by KU Leuven. CM is president of EASD. All
external support of EASD is given on www.​easd.​org. PG serves or
has served on the advisory panel for Novo Nordisk, Sanofi-Aventis,
Boehringer Ingelheim, Janssen Pharmaceuticals, Roche, Medtronic,
Abbott and Bayer. Financial compensation for these activities has been
received by KU Leuven. PG serves or has served on the speakers’
bureau for Merck Sharp and Dohme, Boehringer Ingelheim, Bayer,
Medtronic, Insulet, Novo Nordisk, Abbott, Roche, VitalAire and Dex-
com. Financial compensation for these activities has been received
by KU Leuven. KU Leuven received non-financial support for travel
for PG from Sanofi-Aventis, A. Menarini Diagnostics, Novo Nordisk,
Medtronic and Roche.
Contribution statement JDM designed the study, collected and ana-
lysed the data, performed statistical analyses, wrote the manuscript, and
created figures and tables. SC, MMV, CM and PG designed the study,
collected and discussed the data, and edited the manuscript. CDB dis-
cussed the data and edited the manuscript. All authors approved the
final version to be published. JDM and PG are the guarantors of this
work, and, as such, had full access to all data in the study and take
responsibility for the integrity of the data and the accuracy of the data
analysis. All authors had final responsibility for the decision to submit
for publication.
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