Body Weight Time in Target Range and Cardiovascular Outcomes in Adults with Overweight/Obesity and Type 2 Diabetes

Abstract

Aims
Prescription of weight loss to individuals is often characterized by weight fluctuations. However, current body weight management metrics may have difficulty characterizing the changes in body weight over time. We aims to characterize the long-term changes using body weight time in target range (TTR) and test its independent association with cardiovascular outcomes.

Methods
We included 4,468 adults from the Look AHEAD (Action for Health in Diabetes) trial. Body weight TTR was defined as the percentage of time during which body weight was within the Look AHEAD weight loss goal range. The associations of body weight TTR with cardiovascular outcomes were analyzed using multivariable Cox modeling and restricted cubic spline function.

Results
Among the participants (mean age 58.9 years, 58.5% women, 66.5% White), there were 721 incident primary outcomes (cumulative incidence: 17.5%, 95% confidence interval [CI]: 16.3%-18.8%) during a median of 9.5 years of follow-up. Each 1-SD (standard deviation) increase in body weight TTR was significantly associated with a decreased risk of the primary outcome (hazard ratio [HR]: 0.84, 95% CI: 0.75-0.94) after adjusting for mean and variability of body weight and traditional cardiovascular risk factors. Further analyses using restricted cubic spline indicated the inverse association between body weight TTR and primary outcome in a dose-dependent manner. Similar associations remained significant among the participants with a lower baseline or mean body weight.

Conclusion
In adults with overweight/obesity and type 2 diabetes, higher body weight TTR was independently associated with lower risks of cardiovascular adverse events in a dose-response manner.

Full text

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Body weight time in target range and
cardiovascular outcomes in adults with
overweight/obesity and type 2 diabetes
Menghui Liu
1,2
, Xingfeng Xu
1,2
, Xiaohong Chen
3
, Yue Guo
1,2
, Shaozhao Zhang
1,2
,
Yifen Lin
1,2
, Huimin Zhou
1,2
, Miaohong Li
1,2
, Peihan Xie
1,2
, Wenhao Xia
4
,
Lichun Wang
1,2
, Xiaodong Zhuang
1,2
*, and Xinxue Liao
1,2
*
1
Department of Cardiology, The First Afliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Rd, Guangzhou 510080, China;
2
NHC Key Laboratory of Assisted Circulation (Sun Yat-
sen University), 74 Zhongshan 2nd Rd, Guangzhou 510080, China;
3
Department of Otorhinolaryngology, The Third Afliated Hospital of Sun Yat-sen University, Guangzhou, China; and
4
Department of Hypertension and Vascular Disease, The First Afliated Hospital, Sun Yat-sen University, Guangzhou, China
Received 12 November 2022; revised 3 May 2023; editorial decision 9 May 2023; accepted 9 May 2023
Aims Prescription of weight loss to individuals is often characterized by weight uctuations. However, current body weight man-
agement metrics may have difculty characterizing the changes in body weight over time. We aim to characterize the long-
term changes using body weight time in target range (TTR) and test its independent association with cardiovascular
outcomes.
Methods
and results
We included 4468 adults from the Look AHEAD (Action for Health in Diabetes) trial. Body weight TTR was dened as the
percentage of time during which body weight was within the Look AHEAD weight loss goal range. The associations of body
weight TTR with cardiovascular outcomes were analysed using multivariable Cox modelling and restricted cubic spline func-
tion. Among the participants (mean age 58.9 years, 58.5% women, 66.5% White), there were 721 incident primary out-
comes [cumulative incidence: 17.5%, 95% condence interval (CI): 16.3–18.8%] during a median of 9.5 years of follow-
up. Each 1 SD increase in body weight TTR was signicantly associated with a decreased risk of the primary outcome (hazard
ratio: 0.84, 95% CI: 0.75–0.94) after adjusting for mean and variability of body weight and traditional cardiovascular risk fac-
tors. Further analyses using restricted cubic spline indicated the inverse association between body weight TTR and the pri-
mary outcome in a dose-dependent manner. Similar associations remained signicant among the participants with lower
baseline or mean body weight.
Conclusion In adults with overweight/obesity and type 2 diabetes, higher body weight TTR was independently associated with lower
risks of cardiovascular adverse events in a dose–response manner.
--------------------------------------------------------------------------------------------------------------------------------------------------------------
Lay summary We used time in target range (TTR) to characterize the long-term changes in body weight among 4468 adults with over-
weight/obesity and type 2 diabetes and assessed the associations of body weight TTR with cardiovascular outcomes.
•Participants with TTR of >50–100% achieved and maintained the target of body weight loss during the 10 years of follow-
up.
•Higher body weight TTR was independently associated with lower risks of cardiovascular adverse events in a dose–re-
sponse manner.
* Corresponding authors. Tel/Fax: +0086-020-87338190, Email: liaoxinx@mail.sysu.edu.cn (X.L.), Email: zhuangxd3@mail.sysu.edu.cn (X.Z.)
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
European Journal of Preventive Cardiology (2023) 00, 1–9
https://doi.org/10.1093/eurjpc/zwad165
FULL RESEARCH PAPER
Nutrition/obesity (diet, alcohol)

............................................................................................................................................................................................
Graphical Abstract
Keywords Body weight •Cardiovascular outcomes •Obesity •Type 2 diabetes •Time in target range
Introduction
The dual prevalence of overweight/obesity and type 2 diabetes has risen
dramatically for decades leading to soaring levels of cardiovascular dis-
ease (CVD).
1–3
Guidelines recommend that weight management with
lifestyle, pharmacologic, or surgical interventions is one of the critical
therapeutic strategies in reducing the long-term cardiovascular risks
for individuals with overweight/obesity and type 2 diabetes.
4
Of note,
in the guidelines and large clinical trials, weight management is often
evaluated by the percentage of weight change at a single time point after
interventions.
4–6
This is problematic as body weight uctuates during
interventions. Approximately 80% of individuals regain their weight
within 1 year after achieving intentional weight loss.
7
Weight regains
might be more rapid in individuals with type 2 diabetes.
8
Moreover,
weight regains are associated with a deterioration of the cardiovascular
benets associated with weight loss.
9,10
Therefore, the measurement at
a single time point may not adequately reect weight change over time
and its effects on CVD risks.
Several studies evaluated long-term weight changes using body
weight variability and found that greater body weight variability is asso-
ciated with higher mortality and cardiovascular events in patients with
type 2 diabetes.
11–13
However, although considering the weight uctua-
tions over time, body weight variability is crude in the evaluation of
weight management. Body weight variability may be similar and narrow
when all body weight measures exceed or achieve the weight loss tar-
get. This suggests that a more accurate evaluation of long-term weight
management is needed for further assessing and managing cardiovascu-
lar risk.
We developed a patient-level measure that estimates the time with
body weight within the target range, termed body weight time in target
range (TTR). Our previous study has shown that the population in the
weight loss interventions can be classied by body weight TTR to iden-
tify the characteristics of body weight changes over time.
14
However,
the effects of body weight TTR on cardiovascular risk remain unknown,
which impedes the application of body weight TTR in long-term weight
management. Therefore, to demonstrate the usefulness of body weight
TTR as a predictor of cardiovascular events, we conducted a secondary
analysis of data from the Look AHEAD (Action for Health in Diabetes)
trial
5
to determine the association of body weight TTR with cardiovas-
cular outcomes in adults with overweight/obesity and type 2 diabetes.
Methods
Study design and study population
The present study is an observational analysis using data from the Look
AHEAD trial (trial registration NCT00017953). The primary results and
study design of the Look AHEAD trial have been published previously.
5,15
2Body weight TTR and cardiovascular outcomes

Briey, the Look AHEAD trial was a multicentre, randomized controlled
trial comparing the cardiovascular effects of an intensive lifestyle interven-
tion (ILI), focused on weight loss and increased physical activity, with those
of a control arm, diabetes support and education (DSE), in 5145 patients
with overweight/obesity and type 2 diabetes. From 2001 to 2004, all parti-
cipants were enrolled and randomly assigned to the ILI (n=2570) or con-
trol (n=2575) groups. The intervention was stopped in September 2012
due to the similar cardiovascular risks between the two arms. The
Institutional Review Boards at each site approved the Look AHEAD trial,
and all participants provided written informed consent.
In the present study, we used data from 4906 Look AHEAD participants
that were available in the public access datasets. Participants with missing
data on covariates (n=169) or the primary outcome (n=5) and partici-
pants who had less than three tests of body weight within the rst 4 years
(n=264) were both excluded from this observational analysis. Finally, the
study cohort included 4468 participants in the primary analysis (see
Supplementary material online, Figure S1). The clinical characteristics at
baseline were similar between the included and excluded participants
(see Supplementary material online, Table S1).
Longitudinal body weight measurement
We calculate TTR, mean, and variability of body weight using at least three
longitudinal measurements during Years 0–4 to evaluate long-term body
weight management for the participants with overweight/obesity and
type 2 diabetes. The rst 4 years were chosen owing to the more frequent
group sessions and individual supervision for participants at this time period.
According to the design of the Look AHEAD trial,
15
the weight loss target
for participants in the ILI arm was dened as a weight loss of at least 7% of
baseline. Based on this target, body weight TTR was dened as the percent-
age of time during which the body weight was within the target range (weight
loss of ≥7% of baseline) and was calculated for each participant by linear in-
terpolation.
14,16
Mean and variability of body weight were calculated as the
weighted mean and standard deviation (SD) of at least three longitudinal
body weight measurements during the rst 4 years, respectively.
Cardiovascular outcomes
To reduce the selection bias of the study endpoint, we restricted our ana-
lyses to the pre-specied endpoints of the Look AHEAD trial,
5
adjudicated
by a masked outcome committee. The primary outcome was dened as the
rst occurrence of death from cardiovascular causes, non-fatal myocardial
infarction (MI), non-fatal stroke, or admission to hospital for angina. The
three secondary composite outcomes and four individual components of
the primary outcome were also examined in the present analyses: second-
ary composite Outcome 1: cardiovascular mortality, non-fatal MI, or non-
fatal stroke; secondary composite Outcome 2: all-cause mortality, non-fatal
MI, non-fatal stroke, or admission to hospital for angina; and secondary
composite Outcome 3: all-cause mortality, non-fatal MI, non-fatal stroke,
admission to hospital for angina, percutaneous coronary intervention, cor-
onary artery bypass grafting, carotid endarterectomy, admission to hospital
for heart failure, or peripheral vascular disease. The four individual compo-
nents of the primary outcome included cardiovascular mortality, MI, admis-
sion to hospital for angina, and stroke.
Statistical analysis
The characteristics of participants were presented as counts (percentages)
for categorical data and mean (SD) for continuous data and were compared
using the χ
2
test or variance test, as appropriate.
For the included participants, the associations between study interven-
tion (ILI vs. DSE) and the risk of cardiovascular outcomes were evaluated
by Cox proportional hazard regression models. The log-likelihood ratio
test was used to assess the signicance of interaction effects by adding
the interaction term between body weight TTR and study intervention in
the Cox models.
After pooling the participants from both study intervention arms, the
correlations of body weight TTR with mean and variability were examined
using scatter plots and Pearson’s correlation analysis. The Kaplan–Meier
method was used to estimate the cumulative incidence of cardiovascular
outcomes. The independent association between body weight TTR and
the primary outcome was assessed using hazard ratios (HRs) and 95% con-
dence intervals (CIs) derived from the ve multivariable-adjusted Cox
models, including the crudely adjusted model (age, sex, and race); partly ad-
justed model (variables in the crudely adjusted model plus education level,
smoking status, drinking status, systolic blood pressure [SBP], diastolic
blood pressure [DBP], body mass index [BMI], total cholesterol, high-
density lipoprotein cholesterol [HDL-c], low-density lipoprotein choles-
terol [LDL-c], triglyceride, fasting glucose, serum creatinine, and history
of CVD and hypertension); partly adjusted model plus mean body weight;
partly adjusted model plus body weight variability; and fully adjusted model
(variables in the partly adjusted model plus mean body weight and body
weight variability). We used the Schoenfeld residual test to check the fully
adjusted Cox model for its fullment of the proportional hazard assump-
tions and conrmed that the assumption was met in exploring the associ-
ation between body weight TTR and the primary outcome (see
Supplementary material online, Figure S2). The associations of body weight
TTR with other cardiovascular outcomes were assessed by the crudely and
fully adjusted models. The HRs per 1 SD increase were estimated in the ana-
lysis of body weight TTR as a continuous variable. In the analysis of categor-
ical body weight TTR, the participants were classied into three TTR groups
(0%, >0–50%, and >50–100%). Moreover, we graphically displayed the
changes in the percentage of body weight loss against baseline during
follow-up among the three TTR groups. To evaluate and visualize the po-
tential non-linear association, we modelled TTR against the risk-adjusted
primary outcome with a restricted cubic spline method using three knots
located in the 33rd, 66th, and 99th percentiles.
The analyses of key variables (age, sex, race, BMI, SBP, LDL-c, fasting glu-
cose, and smoking status) were also conducted to evaluate the risk of pri-
mary outcomes associated with body weight TTR in the different
subgroups. An interaction term between body weight TTR and the key vari-
able was individually added to the fully adjusted model, and the Pfor inter-
action was estimated.
The analyses were repeated among the participants with lower baseline
(<101.1 kg) or mean (<98.0 kg) body weight. The values of 101.1 and
98.0 kg were the overall mean of baseline and mean body weight, respect-
ively. Due to the recommendation from the guidelines
4
that lifestyle inter-
vention to achieve and maintain ≥5% weight loss is recommended for most
people with overweight/obesity and type 2 diabetes, we dened ≥5%
weight loss as the target to calculate body weight TTR and further tested
assumptions of the overall analyses. Among participants with no previous
history of CVD (n=3853), the sensitivity analyses were conducted using
similar adjusted Cox models. Furthermore, considering that body weight
TTR was calculated during the rst 4 years, we conducted a sensitivity ana-
lysis after excluding those without a follow-up time of >4 years (n=339).
A two-sided Pvalue <0.05 was considered statistically signicant. All ana-
lyses were performed using Stata version 14 (StataCorp, College Station,
TX, USA).
Results
Effects of intensive lifestyle intervention
on cardiovascular outcomes
The present study included 4468 participants from the Look AHEAD
trial who were randomized to ILI (n=2267) vs. DSE (n=2201), with
similar baseline characteristics (see Supplementary material online,
Table S2). During a median follow-up of 9.5 years (interquartile range:
8.6–10.3 years), 721 (16.1%) cases of the primary outcome were iden-
tied, of which 363 (16.0%) and 358 (16.3%) were, respectively, iden-
tied in the ILI and DSE arms. Consistent with the primary ndings of
the Look AHEAD trial,
5
ILI did not affect the risk of primary cardiovas-
cular outcomes compared with DSE (HR: 1.06, 95% CI: 0.90–1.25, P=
0.490) in the multivariable-adjusted Cox model. A similar lack of effect
was observed for the three secondary composite outcomes and four
individual components of the primary outcome (all P>0.05) (see
Supplementary material online, Table S3). Furthermore, the association
between ILI and the primary outcome was not modied by body weight
TTR levels (Pfor interaction =0.267). Based on these results, the ILI
and DSE arms were pooled together to explore the association be-
tween body weight TTR and the risk of cardiovascular outcomes.
M. Liu et al. 3

Characteristics of study population
Among the included 4468 participants, the mean age was 58.9 ±6.7
years, 1852 (41.5%) were men, 2970 (66.5%) were White, the overall
mean of baseline body weight was 101.1 ±19.3 kg, and 615 (13.8%) had
a history of CVD, as seen in Table 1. Compared with lower body weight
TTR (≤50%), the participants with higher body weight TTR (>50%)
were more likely to be White, to have hypertension and lower educa-
tion level, and to be in the ILI arm. No signicant clinical differences
were observed among the three body weight TTR groups for other
baseline characteristics. Furthermore, Figure 1 describes the changes
in the percentage of body weight loss against baseline during the 10
years of follow-up among the three TTR groups and shows that the
participants with TTR of >50–100% achieved and maintained the target
of body weight loss.
Time in target range, mean, and variability
of body weight
The mean of body weight TTR was 23.3 ±32.4% for the entire study
population, and the frequency distribution was shown in
Supplementary material online, Figure S3. Body weight TTR was 0%
in 2361 (52.8%) participants, >0–50% in 1103 (24.7%) participants,
and >50–100% in 1004 (22.5%) participants. The mean body weight
during Years 0–4 for the entire study population was 98.0 ±19.0 kg,
and the overall mean of body weight variability was 4.4 ±3.3 kg
(Table 1). Of note, participants with greater body weight TTR tended
to have lower mean body weight and higher body weight variability.
Pearson’s correlation analyses showed that body weight TTR had a
negative correlation with mean body weight (r= −0.193, P<0.001)
and positive correlation with body weight variability (r=0.559, P<
0.001) (see Supplementary material online, Figure S4).
Associations between body weight time in
target range and cardiovascular outcomes
For the included participants with overweight/obesity and type 2 dia-
betes, the cumulative incidence (95% CIs) of the primary cardiovascular
outcome was 17.5% (16.3–18.8%) (Table 2). Each 1 SD increase in body
weight TTR was signicantly associated with a decreased risk of primary
outcomes in the crudely (HR: 0.88, 95% CI: 0.82–0.95, P=0.001) and
partly (HR: 0.90, 95% CI: 0.83–0.98, P=0.013) adjusted models. This
association remained signicant after adjusting for variables in the partly
adjusted model plus mean body weight (HR: 0.87, 95% CI: 0.80–0.96, P
=0.004) or body weight variability (HR: 0.87, 95% CI: 0.78–0.96, P=
0.008). In the fully adjusted model, each 1 SD increase in body weight
TTR was associated with a 16% decreased risk of primary outcomes,
independent of mean body weight, body weight variability, and trad-
itional cardiovascular risk factors (HR: 0.84, 95% CI: 0.75–0.94, P=
0.002) (Figure 2). In Figure 3, we used restricted cubic splines to exibly
model and visualize the association of body weight TTR with the pri-
mary outcome. At a TTR of >41.4%, a higher TTR was signicantly as-
sociated with a lower risk of primary outcomes. Moreover, interaction
testing revealed no heterogeneity in the key subgroups (age, sex, race,
BMI, SBP, LDL-c, fasting glucose, or smoking status) for the association
of body weight TTR with the primary outcome (see Supplementary
material online, Figure S5).
In the fully adjusted model, a greater increase in body weight TTR
was also signicantly associated with the lower risk of secondary com-
posite Outcome 1 (HR: 0.84, 95% CI: 0.73–0.96, P=0.010), secondary
composite Outcome 2 (HR: 0.85, 95% CI: 0.77–0.94, P=0.001), and
secondary composite Outcome 3 (HR: 0.85, 95% CI: 0.77–0.93, P<
0.001) (Table 2). For the individual components of the primary out-
come, body weight TTR was associated with hospitalization for angina
but not for cardiovascular death, MI, or stroke (Table 2).
When the participants were classied into three TTR groups (0%,
>0–50%, and >50–100%), the cumulative incidences (95% CIs) of
the primary outcome decreased progressively, from 18.5% (16.8–
20.2%) to 17.7% (15.5–20.3%) and to 15.0% (12.7–17.7%) (see
Supplementary material online, Table S4). In the fully adjusted model,
compared with the participants with body weight TTR of 0%, the
TTR of >50–100% was associated with a lower risk of the primary out-
come (HR: 0.69, 95% CI: 0.53–0.91, P=0.008), but no differences were
observed in participants with TTR of >0–50% (HR: 1.01, 95% CI: 0.82–
1.23, P=0.953). Results were similar for the three secondary compos-
ite outcomes (Figure 4).
Associations of body weight time in target
range with cardiovascular outcomes in
participants with lower baseline or mean
body weight
In the fully adjusted model, each 1 SD increase in body weight TTR was
associated with a decreased risk of primary outcomes among the par-
ticipants with lower baseline body weight (HR: 0.80, 95% CI: 0.69–0.93,
P=0.003) or lower mean body weight during the rst 4 years (HR:
0.78, 95% CI: 0.66–0.92, P=0.003). Similar associations were also
found in the analyses for the three secondary composite outcomes
(see Supplementary material online, Table S5).
Sensitivity analyses
In a sensitivity analysis that calculated body weight TTR according to the
guideline-recommended body weight loss target (≥5% weight loss),
higher body weight TTR was also signicantly associated with a lower
risk of the primary outcome (HR: 0.86, 95% CI: 0.77–0.95, P=0.005)
and secondary composite outcomes (see Supplementary material
online, Table S6). Results of the sensitivity analyses after excluding par-
ticipants with CVD history at baseline (see Supplementary material
online, Table S7) or without a follow-up time of >4 years (see
Supplementary material online, Table S8) were consistent with the
main ndings.
Discussion
In the secondary analysis of the overall cohort of the Look AHEAD trial
(i.e. with the ILI and DSE arms combined), greater body weight TTR
was signicantly associated with a decreased risk of cardiovascular out-
comes among the participants with overweight/obesity and type 2 dia-
betes, independent of mean body weight, body weight variability, and
traditional cardiovascular risk factors. Furthermore, this association re-
mained signicant even among the participants with lower baseline or
mean body weight. These ndings suggest that using body weight
TTR to measure the levels of long-term weight management might pro-
vide more accurate estimates for the CVD risks to population-based
weight management monitoring and clinical trial–based weight loss in-
terventions. Appropriate approaches to elevate body weight TTR may
help lower the risk of adverse cardiovascular outcomes in patients with
overweight/obesity and type 2 diabetes.
Current guidelines emphasize the importance of long-term body
weight management and recommend maintaining lower body weight
over the long term after weight loss for patients with overweight/
obesity and type 2 diabetes.
4
Prior studies explored several ap-
proaches to monitoring an individual patient’s long-term body weight
management, but the measuring approaches were crude in observa-
tional studies and clinical trials. A secondary analysis of the Look
AHEAD trial measured the long-term change of body weight in the
ILI participants merely through the proportion of body weight change
in Years 1 and 4.
17
Similar measurements based on the proportion at a
4Body weight TTR and cardiovascular outcomes

single time point were widely used to assess the long-term change in
body weight in epidemiologic studies and clinical trials.
18–20
This
measurement may not reect the full information of long-term
body weight management due to the neglect of body weight uctua-
tions over time. Furthermore, several studies used body weight vari-
ability to measure the long-term changes in body weight and found
that the risk of adverse cardiovascular events signicantly increased
with increasing body weight variability among the participants with
type 2 diabetes from a Korean cohort of 624 237 people and a
Swedish cohort of 100 576 people.
11,13
However, body weight vari-
ability has not by itself become a therapeutic target yet in body weight
management. Actually, it was challenging to identify the characteristic
of long-term body weight changes for each participant by body weight
variability in that it could be narrow even if all body weight measures
exceed the target range.
Previously, we had proposed the concept of ‘TTR’ in the eld of body
weight management and found that body weight TTR contributed to
describing and determining the characteristic of long-term body weight
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 1 Baseline characteristics of participants categorized by body weight TTR
Baseline characteristics Total TTR =0% 0% <TTR ≤50% 50% <TTR ≤100% Pvalue
n=4468 n=2361 n=1103 n=1004
Age, years 58.9 (6.8) 58.7 (6.7) 58.8 (6.9) 59.6 (6.8) 0.001
Sex, no. (%) 0.053
Men 1852 (41.5) 999 (42.3) 423 (38.8) 430 (42.8)
Women 2616 (58.5) 1362 (57.7) 680 (61.7) 574 (57.2)
Race, no. (%) <0.001
White 2970 (66.5) 1499 (63.5) 758 (68.7) 713 (71.0)
Black (not Hispanic) 737 (16.5) 427 (18.1) 189 (17.1) 121 (12.1)
Hispanic 602 (13.5) 347 (14.7) 112 (10.2) 143 (14.2)
Other/mixed 159 (3.6) 88 (3.7) 44 (4.0) 27 (2.7)
Body weight, kg 101.1 (19.3) 100.2 (18.8) 101.9 (19.7) 102.4 (19.9) 0.003
BMI, kg/m
2
36.0 (5.9) 35.6 (5.7) 36.4 (6.1) 36.3 (6.1) <0.001
SBP, mmHg 129.1 (17.2) 129.2 (17.1) 128.8 (17.4) 128.9 (17.2) 0.795
DBP, mmHg 70.2 (9.6) 70.6 (9.7) 70.0 (9.4) 69.4 (9.7) 0.003
Total cholesterol, mg/mL 191.3 (37.6) 192.6 (37.9) 191.1 (37.2) 188.4 (37.2) 0.011
HDL-c, mg/mL 43.5 (11.9) 43.3 (11.6) 44.1 (12.4) 43.5 (11.9) 0.194
LDL-c, mg/mL 112.7 (32.2) 114.4 (32.4) 111.8 (32.3) 109.8 (31.5) 0.001
Triglyceride, mg/mL 179.9 (115.3) 180.1 (117.9) 181.3 (116.1) 178.1 (108.0) 0.816
Fasting glucose, mg/mL 152.2 (44.6) 153.4 (46.0) 153.5 (44.7) 148.2 (40.6) 0.005
HbA1c, % 7.2 (1.1) 7.3 (1.2) 7.3 (1.1) 7.1 (1.1) <0.001
Serum creatinine, mg/mL 0.8 (0.2) 0.8 (0.2) 0.8 (0.2) 0.8 (0.2) 0.167
History of CVD, no. (%) 615 (13.8) 346 (14.7) 131 (11.9) 138 (13.7) 0.087
History of hypertension, no. (%) 3747 (83.9) 1951 (82.6) 931 (84.4) 865 (86.2) 0.034
Education level, no. (%) 0.002
<13 years 858 (19.2) 467 (19.8) 180 (16.3) 211 (21.0)
13–16 years 1667 (37.3) 917 (38.8) 396 (35.9) 354 (35.3)
>16 years 1943 (43.5) 977 (41.4) 527 (47.8) 439 (43.7)
Smoking, no. (%) 0.369
Never smoker 2228 (49.9) 1187 (50.3) 565 (51.2) 476 (47.4)
Past smoker 2056 (46.0) 1073 (45.4) 499 (45.2) 484 (48.2)
Current smoker 184 (4.1) 101 (4.3) 39 (3.5) 44 (4.4)
Drinking, no. (%) 0.401
None/week 2974 (66.6) 1561 (66.1) 727 (65.9) 686 (68.3)
≥1/week 1494 (33.4) 800 (33.9) 376 (34.1) 318 (31.7)
Treatment arm, no. (%) <0.001
ILI 2267 (50.7) 758 (32.1) 676 (61.3) 833 (83.0)
DSE 2201 (49.3) 1603 (67.9) 427 (38.7) 171 (17.0)
Mean of body weight, kg 98.0 (19.0) 100.8 (19.1) 97.9 (18.9) 91.8 (17.4) <0.001
Body weight variability (SD), kg 4.4 (3.3) 2.9 (1.8) 5.2 (3.3) 7.2 (3.8) <0.001
Body weight TTR, % 23.3 (32.4) 0 23.4 (13.9) 78.1 (12.8) <0.001
Continuous and categorical variables are presented as mean (SD) and number (%), respectively. Mean body weight and body weight variability were calculated as the mean and SD of body
weight during Years 0–4, respectively.
TTR, time in target range; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein
cholesterol; HbA1c, glycosylated haemoglobin; CVD, cardiovascular disease; DSE, diabetes support and education; ILI, intensive lifestyle intervention; SD, standard deviation.
M. Liu et al. 5

changes for the participants with overweight/obesity and type 2 dia-
betes.
14
In the present study, body weight TTR was used to measure
the long-term body weight changes of each participant. This measure-
ment had a negative correlation with mean body weight and a positive
correlation with body weight variability, implying that it might incorpor-
ate both the mean body weight during long-term follow-up and the de-
gree of body weight variability. In addition, it could account for variation
within and outside the target range and measure the consistency of
long-term body weight management. Therefore, body weight TTR
might provide a more comprehensive assessment of the quality of long-
term body weight management.
To the best of our knowledge, it is the rst study to evaluate the asso-
ciation of body weight TTR with the risk of cardiovascular outcomes in pa-
tients with overweight/obesity and type 2 diabetes. Our results explored
the value of TTR for long-term body weight management and conrmed
its importance for health-related outcomes. Thus, achieving the weight loss
target and maintaining the consistency of weight loss over time for patients
with overweight/obesity and type 2 diabetes are needed in real-life clinical
practice. Over the past several decades, weight regains have always been a
huge barrier to long-term body weight management.
7,8
Recently, large clin-
ical trials indicated that several modern methods contributed to body
weight maintenance after weight loss.
19,21–24
The global Phase 3 STEP
(Semaglutide Treatment Effect in People with Obesity) programme has
demonstrated that once-weekly subcutaneous semaglutide, 2.4 mg, a
glucagon-like peptide-1 (GLP-1) receptor agonist, can sustainedly reduce
the body weight in people with overweight/obesity, with and without
type 2 diabetes.
19,23,24
In the SURMOUNT-1 (Study of Tirzepatide in
Participants with Obesity or Overweight) trial, once-weekly subcutaneous
Figure 1 Changes in the percentage of body weight loss against baseline during 10 years of follow-up among the participants with overweight/obesity
and type 2 diabetes categorized by body weight time in target range groups. Data are presented as mean (95% condence interval). TTR, time in target
range; CI, condence interval.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 2 Associations of body weight TTR (per 1 SD increase) with cardiovascular outcomes in adults with overweight/
obesity and type 2 diabetes
Outcome No. of events (%) Cumulative incidence, % (95% CI) Crudely adjusted Fully adjusted
HR (95% CI) Pvalue HR (95% CI) Pvalue
Primary outcome 721 (16.1) 17.5 (16.3–18.8) 0.88 (0.82–0.95) 0.001 0.84 (0.75–0.94) 0.002
Secondary outcome
Secondary Outcome 1 469 (10.5) 11.6 (10.6–12.7) 0.90 (0.82–0.99) 0.027 0.84 (0.73–0.96) 0.010
Secondary Outcome 2 877 (19.6) 21.8 (20.4–23.2) 0.91 (0.85–0.98) 0.007 0.85 (0.77–0.94) 0.001
Secondary Outcome 3 1010 (22.6) 24.4 (23.1–25.9) 0.91 (0.85–0.97) 0.002 0.85 (0.77–0.93) <0.001
Four individual components of the primary outcome
Cardiovascular death 84 (1.9) 2.2 (1.8–2.8) 0.90 (0.72–1.12) 0.357 0.75 (0.55–1.02) 0.066
MI 309 (6.9) 7.6 (6.8–8.5) 0.89 (0.79–1.00) 0.044 0.87 (0.73–1.03) 0.112
Hospitalization for angina 362 (8.1) 8.8 (7.9–9.7) 0.81 (0.73–0.91) <0.001 0.79 (0.67–0.94) 0.006
Stroke 141 (3.2) 3.5 (3.0–4.2) 0.92 (0.77–1.09) 0.317 0.81 (0.63–1.03) 0.082
Per 1 SD of body weight TTR =32.4%. Primary outcome: death from cardiovascular causes, non-fatal MI, non-fatal stroke, or hospitalization for angina. Secondary Outcome 1: death from
cardiovascular causes, non-fatal MI, or non-fatal stroke. Secondary Outcome 2: death from any cause, non-fatal MI, non-fatal stroke, or hospitalization for angina. Secondary Outcome 3:
death from any cause, non-fatal MI, non-fatal stroke, hospitalization for angina, coronary artery bypass grafting, percutaneous coronary intervention, hospital admission for heart failure,
carotid endarterectomy, or peripheral vascular disease. Crudely adjusted model: adjusted for age, sex, and race. Fully adjusted model: adjusted for variables in the crudely adjusted model +
education level, smoking status, drinking status, SBP, DBP, total cholesterol, HDL-c, LDL-c, triglyceride, fasting glucose, serum creatinine, history of hypertension and CVD, BMI, mean
body weight, and body weight variability.
TTR, time in target range; SD, standard deviation; HR, hazard ratio; CI, condence interval; BMI, body mass index; CVD, cardiovascular disease; DBP, diastolic blood pressure; HDL-c,
high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; MI, myocardial infarction; SBP, systolic blood pressure.
6Body weight TTR and cardiovascular outcomes

tirzepatide, an agonist of both the glucose-dependent insulinotropic poly-
peptide (GIP) and GLP-1 receptors, provided substantial and sustained re-
ductions in body weight in participants with obesity.
21
Furthermore, in a
10-year follow-up of a randomized controlled trial from Italy, adults with
severe obesity and type 2 diabetes had almost 30% weight reductions after
undergoing metabolic surgery and effectively maintained their lower body
weight during follow-up.
22
Therefore, body weight TTR might be a modi-
able metric to measure the quality of long-term body weight manage-
ment and might be of major clinical importance for optimal weight
management in everyday clinical practice. Introducing these interventions
to elevate body weight TTR in long-term body weight management might
contribute to further promoting cardiovascular health for patients with
overweight/obesity and type 2 diabetes.
Our study emphasized the importance of long-term body weight
management on cardiovascular health from the perspective of TTR.
These ndings advance the comprehensive management of body
weight in four important ways. First, body weight TTR may be a useful
surrogate endpoint in assessing long-term body weight changes. Adding
body weight TTR as a study outcome may be valuable to evaluate the
effectiveness of interventions in future studies regarding weight loss
Figure 3 Spline analysis of the association between continuous body weight time in target range and the primary outcome. The hazard ratio (indi-
cated by a solid line) and 95% condence interval (shadow inside dotted lines) were derived from fully adjusted Cox regression models (adjusted for age,
sex, race, education level, smoking status, drinking status, systolic blood pressure, diastolic blood pressure, body mass index, total cholesterol, high-
density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, fasting glucose, serum creatinine, history of cardiovascular disease
and hypertension, mean body weight, and body weight variability). Body weight time in target range was centred at the sample mean (time in target
range =23.5%) and modelled using a restricted cubic spline, with knots at the 33rd, 66th, and 99th percentiles. TTR, time in target range; HR, hazard
ratio; CI, condence interval.
Figure 2 Association of body weight time in target range with primary outcomes, independent of mean body weight, body weight variability, and
traditional cardiovascular risk factors. Crudely adjusted model: age, sex, and race. Partly adjusted model: variables in the crudely adjusted model + edu-
cation level, smoking status, drinking status, systolic blood pressure, diastolic blood pressure, body mass index, total cholesterol, high-density lipoprotein
cholesterol, low-density lipoprotein cholesterol, triglyceride, fasting glucose, serum creatinine, and history of cardiovascular disease and hypertension.
Fully adjusted model: variables in the partly adjusted model + mean body weight and body weight variability. TTR, time in target range; HR, hazard ratio;
CI, condence interval.
M. Liu et al. 7

interventions. Second, in clinical practice, body weight TTR may be used
to inform decisions regarding weight loss interventions in that it pro-
vides a more holistic, long-term view of an individual patient’s body
weight changes. Third, patients with lower body weight TTR were
more likely to experience CVD outcomes. The TTR may therefore
be useful to the risk stratication for patients with overweight/obesity
and type 2 diabetes. Fourth, emphasizing the cardiovascular benets as-
sociated with higher body weight TTR may serve to motivate patients
with overweight/obesity and type 2 diabetes to become aware of the
importance of maintaining lower body weight after weight loss.
This study also has several limitations. First, the denite target for
weight loss remains unclear, which impedes the exact calculation of
body weight TTR. However, the TTR was calculated in the primary ana-
lysis according to the pre-specied weight loss target in the Look
AHEAD trial. Moreover, a sensitivity analysis was also conducted based
on the guideline-recommended weight loss target with similar results
to the main ndings. Second, the study population included adults
with overweight/obesity and type 2 diabetes enrolled in a clinical trial
focused on body weight management. Therefore, the ndings may
lack generalizability to the general population. Our results should be
veried in the study population derived from routinely collected clinical
data. Third, similar to other observational analyses, we could not ex-
clude the effects of residual measured or unmeasured confounders
on the results in the present study, although the common and import-
ant confounding factors had been adjusted in the risk estimation mod-
els. In addition, consistent results of several sensitivity analyses also
supported the robustness of the main ndings. Nonetheless, inferences
cannot be made regarding causality. The main ndings are merely
hypothesis-generating. Therefore, our ndings could be further tested
in both ongoing and future studies and also in real-world studies as new
and more successful medical and surgical therapies are now available for
managing body weight.
Conclusions
Among the adults with overweight/obesity and type 2 diabetes, higher
body weight TTR was associated with lower risks of cardiovascular ad-
verse events in a dose–response manner, independent of mean and
variability of body weight. Therefore, body weight TTR might be a use-
ful metric of body weight management for population-based quality as-
sessment and clinical trial interventions. Appropriate approaches to
elevate body weight TTR may help minimize the burden of CVD for
adults with overweight/obesity and type 2 diabetes.
Supplementary material
Supplementary material is available at European Journal of Preventive
Cardiology.
Acknowledgements
The authors thank the Look AHEAD trial investigators, study teams, and
participants for making these data available for secondary analyses.
Author contributions
Me.L., X.Z., and X.L. contributed to the conception or design of the work.
All authors contributed to the acquisition, analysis, or interpretation of data
for the work. Me.L., X.X., X.C., Y.G., S.Z., and Y.L. conducted the data ana-
lysis. H.Z., Mi.L., P.X., W.X., and L.W. revised the data analysis. Me.L. drafted
the manuscript. X.Z. and X.L. critically revised the manuscript. All authors
gave nal approval and agreed to be accountable for all aspects of the work.
Figure 4 Association of categorical body weight time in target range with the primary outcome and three secondary cardiovascular outcomes. Fully
adjusted for age, sex, race, education level, smoking status, drinking status, systolic blood pressure, diastolic blood pressure, body mass index, total
cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, fasting glucose, serum creatinine, history of cardio-
vascular disease and hypertension, mean body weight, and body weight variability. TTR, time in target range; HR, hazard ratio; CI, condence interval.
8Body weight TTR and cardiovascular outcomes

Funding
This study was supported by the National Natural Science Foundation of
China (81870195, 82070384 to X.L.; 81900329 to Y.G.), Guangdong
Basic and Applied Basic Research Foundation (2021A1515011668 to X.L.;
2019A1515011098, 2022A1515010416 to Y.G.; 2022A1515111181 to
Me.L.), and China Postdoctoral Science Foundation (2022M723635 to
Me.L.). The Look AHEAD trial was conducted by the Look AHEAD
Research Group and supported by the NIDDK, the National Institute of
Nursing Research, the National Heart, Lung, and Blood Institute, the
Ofce of Research on Women’s Health, the National Institute of
Minority Health and Health Disparities, and the Centers for Disease
Control and Prevention. The data from Look AHEAD were supplied by
the NIDDK Central Repository. The funders had no role in the study de-
sign, data collection and analysis, decision to publish, or preparation of
the manuscript.
Conict of interest: None declared.
Data availability
The datasets analysed in the current study are available on application at the
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Repository.
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