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ARTICLE
A healthy lifestyle mitigates the risk of heart disease related to type 2
diabetes: a prospective nested case–control study in a nationwide
Swedish twin cohort
Rongrong Yang
1,2
&Hui Xu
2,3
&Nancy L. Pedersen
4,5
&Xuerui Li
2
&Jing Yu
6
&Cuiping Bao
7
&Xiuying Qi
2
&Weili Xu
2,8
Received: 8 June 2020 /Accepted: 28 September 2020
#The Author(s) 2020
Abstract
Aims/hypothesis We aimed to examine the association between type 2 diabetes and major subtypes of heart disease, to assess the
role of genetic and early-life familial environmental factors in this association and to explore whether and to what extent a healthy
lifestyle mitigates the risk of heart disease related to type 2 diabetes.
Methods In this prospective nested case–control study based on the Swedish Twin Registry, 41,463 twin individuals who were
aged ≥40 and heart disease-free were followed up for 16 years (from 1998 to 2014) to detect incident heart disease. Type 2
diabetes was ascertained from self-report, the National Patient Registry and glucose-lowering medication use. Heart disease
diagnosis (including coronary heart disease, cardiac arrhythmias and heart failure) and onset age were identified from the
National Patient Registry. Healthy lifestyle-related factors consisted of being a non-smoker, no/mild alcohol consumption,
regular physical activity and being non-overweight. Participants were divided into three groups according to the number of
lifestyle-related factors: (1) unfavourable (participants who had no or only one healthy lifestyle factor); (2) intermediate (any two
or three); and (3) favourable (four). Generalised estimating equation models for unmatched case–control design and conditional
logistic regression for co-twin control design were used in data analyses.
Results Of all participants, 2304 (5.5%) had type 2 diabetes at baseline. During the observation period, 9262 (22.3%) had any
incident heart disease. In unmatched case–control analyses and co-twin control analyses, the multi-adjusted OR and 95% CI of
heart disease related to type 2 diabetes was 4.36 (3.95, 4.81) and 4.89 (3.88, 6.16), respectively. The difference in ORs from
unmatched case–control analyses vs co-twin control analyses was statistically significant (OR 1.57; 95% CI 1.42, 1.73;
p< 0.001). In stratified analyses by type 2 diabetes, compared with an unfavourable lifestyle, an intermediate lifestyle or a
favourable lifestyle was associated with a significant 32% (OR 0.68; 95% CI 0.49, 0.93) or 56% (OR 0.44; 95% CI 0.30,
0.63) decrease in heart disease risk among patients with type 2 diabetes, respectively. There were significant additive and
multiplicative interactions between lifestyle and type 2 diabetes on heart disease.
Rongrong Yang and Hui Xu contributed equally to this manuscript.
Supplementary Information The online version contains
supplementary material available at https://doi.org/10.1007/s00125-020-
05324-z.
*Xiuying Qi
qixiuying@tmu.edu.cn
*Weili Xu
weili.xu@ki.se
1
Public Health Science and Engineering College, Tianjin University
of Traditional Chinese Medicine, Tianjin, China
2
Department of Epidemiology and Biostatistics, School of Public
Health, Tianjin Medical University, Tianjin, China
3
Big Data and Engineering Research Center, Beijing Children’s
Hospital, Capital Medical University, National Center for Children’s
Health, Beijing, China
4
Department of Medical Epidemiology and Biostatistics, Karolinska
Institutet, Stockholm, Sweden
5
Department of Psychology, University of Southern California, Los
Angeles, CA, USA
6
Department of Physiology and Pathophysiology, School of Basic
Medicine, Tianjin Medical University, Tianjin, China
7
Department of Radiology, Tianjin Union Medical Centre,
Tianjin, China
8
Aging Research Center, Department of Neurobiology, Health Care
Sciences and Society, Karolinska Institutet and Stockholm
University, Stockholm, Sweden
https://doi.org/10.1007/s00125-020-05324-z
/ Published online: 10 November 2020
Diabetologia (2021) 64:530–539
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Conclusions/interpretation Type 2 diabetes is associated with more than fourfold increased risk of heart disease. The association
still remains statistically significant, even after fully controlling for genetic and early-life familial environmental factors.
However, greater adherence to a healthy lifestyle may significantly mitigate the risk of heart disease related to type 2 diabetes.
Keywords Heart disease .Lifestyle .Prospectivenestedcase–control study in twins .The SwedishTwin Registry .Type 2 diabetes
Abbreviations
AP Attributable proportion
GEE Generalised estimating equation
NPR National Patient Registry
RERI Relative excess risk due to interaction
SALT Screening Across the Lifespan Twin study
SI Synergy index
STR Swedish Twin Registry
Introduction
Worldwide, diabetes affected 451 million people (8.4% of the
world’s population) in 2017, and this number might dramati-
cally rise to 693 million (9.9%) by 2045 [1]. Patients with type
2 diabetes are at increased risk of several chronic diseases and
associated clinical complications, such as heart disease [2],
which, in turn, is associated with cerebral vascular disease,
dementia, disability and premature mortality [3].
Coronary heart disease, heart failure and cardiac arrhyth-
mias are the common types of heart disease [3]. Thus far,
population-based longitudinal studies have consistently
shown that type 2 diabetes is associated with the risk of total
CVD, mainly including coronary heart disease and stroke
[2,4–7]. However, the associations between type 2 diabetes
and certain subtypes of heart disease independently remain
unclear. Several cohort studies examined the relationship
between type 2 diabetes and atrial fibrillation and flutter, and
showed inconsistent results [8–12]. Discrepancies in previous
findings can be attributed to the different study populations,
follow-up times and sample size, and lack of consideration of
possible confounders.
Although type 2 diabetes may be linked to heart disease
through several biologically plausible pathways, our under-
standing of the mechanisms for such an association is still
limited. Both type 2 diabetes and heart disease are complex
genetic and lifestyle-related disorders [3]. Genetic and early-
life familial environmental factors may contribute to the
development of type 2 diabetes [13] and heart disease [14].
However, their role in the association between type 2 diabetes
and heart disease is uncertain. Twins are generally reared
together and share genetic background. Thus, twin studies
provide the possibility to assess whether genetic and/or early
familial environmental factors play a role in a given associa-
tion [15]. In addition, previous studies have suggested that an
individual healthy lifestyle factor (such as maintaining a
531Diabetologia (2021) 64:530–539
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normal weight, being a non-smoker, non-heavy drinking or
regular exercise) was associated with lower risk of both type 2
diabetes and CVD in the general population [3,16]. Currently,
accumulating evidence has shown that adopting an overall
and combined healthy lifestyle can be a more effective
prevention strategy for patients with type 2 diabetes to reduce
the risk of cardiovascular complications (such as cause-
specific mortality rate) [17,18]. However, the question
remains whether and to what extent a combined healthy life-
style may counteract the risk of heart disease associated with
type 2 diabetes.
In the current study, we sought to: (1) examine the associ-
ation between type 2 diabetes and the risk of heart disease
including its major subtypes; (2) explore whether genetic
and early-life familial environmental factors play a role in this
association; and (3) investigate whether and to what extent a
healthy lifestyle could mitigate the risk of heart disease related
to type 2 diabetes.
Methods
Study population This prospective, nested case–control study
included twins from the nationwide Swedish Twin Registry
(STR), which was started in the 1960s [19]. In 1998–2002, all
living twins in the registry who were born in 1958 or earlier
were invited to participate in the Screening Across the
Lifespan Twin study (SALT), a full-scale screening that gath-
ered data on an extended set of variables via computer-
assisted telephone interviews. Out of 44,919 twin individuals
eligible for the telephone interview, we excluded 3184 with
heart disease before screening and 272 with type 1 diabetes,
resulting in 41,463 individuals with data for the current
analyses (Fig. 1).
Data collection Information on age, sex, educational attain-
ment, marital status and zygosity was obtained from the
SALT survey [19]. All twins were categorised as monozygot-
ic, dizygotic or of undetermined zygosity. Education was
defined as the maximum years of formal schooling attained,
and dichotomised into <8 vs ≥8 years. Marital status was
defined as married/cohabiting vs single (including divorced
and widows/widowers).
Information on history of type 2 diabetes and heart disease
was derived from the National Patient Registry (NPR), which
covers all inpatient diagnoses in Sweden from the 1960s to the
end of 2014, and outpatient (specialist clinic) diagnoses since
2001. Each medical record in the NPR included up to eight
discharge diagnoses according to the ICD. The seventh revi-
sion (ICD-7) was used up to 1968, the eighth revision (ICD-8)
from 1969 to 1986, the ninth revision (ICD-9) from 1987 to
1996 and the tenth revision (ICD-10) since 1997.
All participants provided informed consent. The data
collection procedures were approved by the Regional Ethics
Committee at Karolinska Institutet, Stockholm, Sweden, and
by the Institutional Review Board of the University of
Southern California, USA.
Ascertainment of type 2 diabetes Type 2 diabetes was
ascertained based on self- and informant-reported history of
diabetes, glucose-lowering medication use or the NPR (ICD-7
code 260; ICD-8 and -9 code 250; and ICD-10 codes E10–
E14). The age at type 2 diabetes onset was estimated accord-
ing to the earliest recorded date of type 2 diabetes in the NPR
or the date of type 2 diabetes onset available in SALT.
Assessment of heart disease Information on heart disease
diagnoses (ICD-7 codes 420, 433 and 434; ICD-8 and -9
codes 410–414, 427 and 428; and ICD-10 codes I20–I25
and I48–I50) was obtained from the NPR. According to the
ICD codes, the major subtypes of heart disease included: (1)
coronary heart disease: angina pectoris, acute myocardial
infarction, chronic ischaemic heart disease and other coronary
heart disease (such as coronary thrombosis and Dressler’s
syndrome); (2) cardiac arrhythmias: atrial fibrillation and flut-
ter, and other cardiac arrhythmias (such as ventricular fibrilla-
tion and flutter, atrial premature depolarisation and junctional
premature depolarisation); and (3) heart failure: congestive
heart failure, left ventricular failure and unspecified heart fail-
ure. The age of heart disease onset was estimated as the earli-
est date that a heart disease diagnosis was recorded in the
NPR.
Assessment of lifestyle-related factors Information on
smoking status, alcohol consumption, physical activity and
BMI was obtained from the SALT survey. Smoking status
was dichotomised as never vs ever being a smoker. Data on
alcohol consumption were collected by a question on drinking
habits, ‘Think about your use of alcohol over your entire life.
Has there ever been a period in your life when you drank too
much?’, with two response options: (1) ‘no’; and (2) ‘yes’.We
defined ‘no’as ‘no/mild drinking’and ‘yes’as ‘heavy drink-
ing’. Data on physical activity were collected by a question on
average exercise, with seven response options: (1) ‘almost
never’;(2)‘much less than average’;(3)‘less than average’;
(4) ‘average’;(5)‘more than average’;(6)‘much more than
average’;and(7)‘maximum’[20]. For the analyses, we
combined these categories into two groups and defined
‘low’as exercise ‘almost never’to ‘much less than average’,
and ‘regular’physical activity as ‘less than average’to ‘maxi-
mum’. BMI was calculated as weight (kg) divided by height
squared (m
2
), and was categorised as non-overweight (BMI
<25) and overweight (BMI ≥25).
In the current study, we considered four healthy lifestyle-
related factors: being a non-smoker, no/mild alcohol
532 Diabetologia (2021) 64:530–539
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
consumption, regular physical activity and being non-over-
weight. Participants were divided into three groups according
to the number of lifestyle-related factors: (1) unfavourable:
participants who had no or only one healthy lifestyle factor;
(2) intermediate: those who had any two or three healthy life-
style factors; and (3) favourable: those who had four healthy
lifestyle factors.
Statistical analysis The characteristics of participants in differ-
ent groups were compared using χ
2
tests, ttest and Mann–
Whitney test. Generalised estimating equation (GEE) models
were used to analyse the unmatched case–control data while
controlling for the clustering of twins within a pair. To exam-
ine the associations between type 2 diabetes and risk of heart
disease independently, we looked at the first onset of one
specific subtype of heart disease with no others. Data for the
co-twin control study were analysed by using conditional
logistic regression, in which twin pairs were discordant for
outcome; thus, cases and control participants were comparable
with respect to early-life familial environmental factors (such
as shared childhood socioeconomic status and adolescent
environment) and genetic background (monozygotic twins
shared 100% of their genetic background and dizygotic twins
shared only 50%) [15]. In both GEE and conditional logistic
regression, the ORs and 95% CIs were estimated for the asso-
ciation between type 2 diabetes and heart disease.
Logistic regression was used to test the difference in ORs
from GEE models and conditional logistic regression by
examining the difference between the proportions of type 2
diabetes in unmatched control participants and in co-twin
control participants [21–24]. Absence of a statistically
significant difference in ORs from the GEE and condition-
al logistic regression analyses suggests that genetic and
early-life familial environmental factors might not account
for the observed associations. In contrast, a statistically
significant difference in ORs from the GEE and condition-
al logistic regression analyses indicates that genetic and/or
shared environmental factors likely play a role in the
observed associations [15,21–25].
The combined effect of the type 2 diabetes and lifestyle on
heart disease risk was assessed by creating dummy variables
based on the joint exposures to both factors. The presence of
an additive interaction was examined by estimating the rela-
tive excess risk due to interaction (RERI), the attributable
proportion (AP) and the synergy index (SI). Additionally,
we examined multiplicative interaction by incorporating the
two variables and their cross-product term in the same model.
Age, sex, education, BMI, smoking, alcohol consumption,
marital status and physical activity were considered as poten-
tial confounders in the type 2 diabetes–heart disease associa-
tion. Missing values on education (n= 1217), smoking (n=
1167), alcohol consumption (n= 1261), BMI (n= 1918),
marital status (n= 755) and physical activity (n= 5938) were
imputed by chained equation to obtain valid statistical infer-
ences with five completed datasets generated. All statistical
analyses were performed using SAS statistical software
version 9.4 (SAS Institute, Cary, NC, USA) and IBM SPSS
Statistics 24.0 (IBM Corp, New York, NY, USA).
44,919 individual twins participated in the screening (1998–2002)
41,463 individual twins in the analysis (followed up to December 2014)
•2304 (5.5%) with type 2 diabetes
•9262 (22.3%) with incident heart disease
•9262 heart disease cases
•32,201 control participants
Unmatched case–control analyses
GEE model
Co-twin control analyses
conditional lo
g
istic re
g
ression
•3184 had heart disease before screening
•272 had type 1 diabetes
•3808 heart disease-
discordant twin pairs
Fig. 1 Flowchart of the study
population
533Diabetologia (2021) 64:530–539
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Results
Characteristics of the study population Among all partici-
pants, 18,838 (45.4%) were men and 22,625 (54.6%) were
women (χ
2
= 30.95, p< 0.001). In total, 2304 (5.5%) had type
2 diabetes. Compared with type 2 diabetes-free participants,
those with type 2 diabetes were more likely to be older, male,
single and non-smokers; to engage in low levels of physical
activity; and to have lower educational attainment and higher
BMI (Table 1).
Association between type 2 diabetes and heart disease in
unmatched case–control analyses During 1998–2014, 9262
(22.3%) participants had incident heart disease. Compared
with type 2 diabetes-free participants, the multi-adjusted OR
for any heart disease associated with type 2 diabetes was 4.36
(95% CI 3.95, 4.81); for angina pectoris, OR 4.23 (95% CI
3.62, 4.94); for acute myocardial infarction, OR 4.93 (95% CI
4.25, 5.72); for chronic ischaemic heart disease, OR 5.14
(95% CI 3.82, 6.91); for atrial fibrillation and flutter, OR
3.14 (95% CI 2.71, 3.64); for congestive heart failure, OR
5.76 (95% CI 3.96, 8.38); and for left ventricular failure, OR
4.45 (95% CI 2.65, 7.49) (Table 2).
Association between type 2 diabetes and heart disease in co-
twin control analyses Compared with the OR in GEE
models, the association between type 2 diabetes and
heart disease became stronger (OR 4.89; 95% CI 3.88,
6.16) in the co-twin control analyses (including all twin
pairs). The difference in ORs from the GEE models
based on unmatched case–control analyses vs co-twin
control analyses in all twin pairs was statistically signif-
icant (OR 1.57; 95% CI 1.42, 1.73; p< 0.001). In addi-
tion, the multi-adjusted OR (95% CI) of heart disease
associated with type 2 diabetes was 4.07 (3.15, 5.27) in
dizygotic twins and 10.83 (4.67, 25.10) in monozygotic
twins. These results suggest that type 2 diabetes is still
associated with heart disease, even after fully control-
ling for genetic and early-life familial environmental
factors (Table 3).
Association between lifestyle-related factors and heart
disease In multi-adjusted GEE models, being a non-smoker,
regular physical activity, no/mild drinking and being non-
overweight were associated with a decreased risk of heart
disease. In further analysis, an intermediate lifestyle and a
favourable lifestyle were significantly associated with a lower
risk of heart disease (Table 4).
In stratified analyses by type 2 diabetes, compared with an
unfavourable lifestyle, an intermediate lifestyle or a
favourable lifestyle was associated with a significant 32%
(OR 0.68; 95% CI 0.49, 0.93) or 56% (OR 0.44; 95% CI
0.30, 0.63) decrease in heart disease risk among patients with
type 2 diabetes, respectively (Fig. 2and electronic supplemen-
tary material [ESM] Table 1).
Joint effect of type 2 diabetes and lifestyle-related factors on
heart disease risk In joint effect analyses, there was a significant
additive interaction between type 2 diabetes and lifestyle on heart
disease risk (RERI 3.507; 95% CI 0.929, 6.084; AP 0.414; 95%
CI 0.231, 0.597; SI 1.885; 95% CI 1.318, 2.696) (ESM Table 2).
The multi-adjusted OR for type 2 diabetes multiplied by
unfavourable lifestyle was 1.30 (95% CI 1.07, 1.57; p= 0.008)
for heart disease.
Supplementary analysis Considering possible sex differ-
ences in heart disease development, we performed strat-
ified analysis, and the associations between type 2
diabetes and heart disease risk did not vary by sex
(ESM Table 3). The results were not much altered
compared with those from initial analyses when we
repeated analyses: (1) with additional adjustment for
survival status (ESM Table 4); and (2) excluding miss-
ing values for covariates (ESM Table 5).
Table 1 Baseline characteristics of the study participants by type 2
diabetes status (N= 41,463)
Characteristic T2D-free
n= 39,159
T2D
n=2304
pvalue
Age (years), mean ± SD 58.1 ± 10.6 64.7 ± 10.5 <0.001
Male sex, n(%) 17,662 (45.1) 1176 (51.0) <0.001
Education, n(%) <0.001
<8 years 12,510 (32.0) 1091 (47.4)
≥8 years 26,649 (68.0) 1213 (52.6)
Marital status, n(%) <0.001
Married/cohabiting 28,626 (73.1) 1487 (64.5)
Single 10,533 (26.9) 817 (35.5)
Zygosity, n(%) 0.879
Monozygotic 7759 (19.8) 458 (19.9)
Dizygotic 26,233 (67.0) 1534 (66.6)
Undetermined 5167 (13.2) 312 (13.5)
BMI, mean ± SD 24.8 ± 3.4 26.9 ± 4.1 <0.001
<25 (Non-overweight) 21,880 (55.9) 768 (33.3) <0.001
≥25 (Overweight) 17,279 (44.1) 1536 (66.7)
Smoking status, n(%) 0.024
Never 19,058 (48.7) 1177 (51.1)
Ever a smoker 20,101 (51.3) 1127 (48.9)
Alcohol consumption, n(%) 0.247
No/mild drinking 36,204 (92.5) 2115 (91.8)
Heavy drinking 2955 (7.5) 189 (8.2)
Physical activity, n(%) 0.007
Low 3905 (10.0) 270 (11.7)
Regular 35,254 (90.0) 2034 (88.3)
Data are presented as mean ± SD or number (proportion, %)
T2D, type 2 diabetes
534 Diabetologia (2021) 64:530–539
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Discussion
In this large-scale, nationwide, genetically informative sample
of Swedish twins, we found that type 2 diabetes was indepen-
dently associated with increased risk of heart disease and its
major types, specifically angina pectoris, acute myocardial
infarction, chronic ischaemic heart disease, atrial fibrillation
and flutter, and heart failure. The association remained signif-
icant, even after controlling for genetic and early-life familial
environmental factors. However, a healthy lifestyle might
significantly mitigate the risk of heart disease related to type
2 diabetes compared with an unfavourable lifestyle.
In recent decades, many epidemiologic studies have shown
that type 2 diabetes is associated with a two- to sixfold
increased risk of total CVD and coronary heart disease
[2,4–6]. However, the association between type 2 diabetes
and atrial fibrillation has been addressed in a number of epide-
miologic studies with inconclusive results. Some studies
showed an increased risk of atrial fibrillation among people
with type 2 diabetes [8,9,12], but others indicated no clear
association [10,11]. In a recent meta-analysis of 32 cohort
studies, type 2 diabetes was associated with a modest 30%
increased atrial fibrillation risk [26]. In the present study, we
found that type 2 diabetes conferred a more than fourfold
greater risk of coronary heart disease and a doubled atrial
fibrillation risk. Several studies have shown that type 2 diabe-
tes is positively associated with heart failure, but in most of
these the influences of other subtypes of heart disease were not
Table 2 ORs and 95% CIs of
different forms of heart disease
related to type 2 diabetes from
GEE models (type 2 diabetes-free
as the reference)
Heart disease No. of cases OR (95% CI)
a
OR (95% CI)
b
All types 9262 4.71 (4.27, 5.19) 4.36 (3.95, 4.81)
Coronary heart disease 4403 5.14 (4.58, 5.78) 4.83 (4.30, 5.43)
Angina pectoris 1936 4.53 (3.88, 5.29) 4.23 (3.62, 4.94)
Acute myocardial infarction 2089 5.20 (4.49, 6.03) 4.93 (4.25, 5.72)
Chronic ischaemic heart disease 362 5.49 (4.09, 7.37) 5.14 (3.82, 6.91)
Other coronary heart disease 16 15.08 (4.85, 46.86) 15.39 (4.69, 50.49)
Cardiac arrhythmias 3471 3.35 (2.92, 3.84) 3.14 (2.74, 3.60)
Atrial fibrillation and flutter 2835 3.40 (2.94, 3.94) 3.14 (2.71, 3.64)
Other cardiac arrhythmias 636 3.03 (2.28, 4.03) 3.04 (2.28, 4.04)
Heart failure 1388 5.31 (4.45, 6.34) 4.89 (4.09, 5.84)
Congestive heart failure 181 6.29 (4.30, 9.21) 5.76 (3.96, 8.38)
Left ventricular failure 110 4.92 (2.91, 8.29) 4.45 (2.65, 7.49)
Unspecified heart failure 1097 4.86 (4.01, 5.90) 4.52 (3.72, 5.49)
a
Adjusted for age, sex and education
b
Additionally adjusted for marital status, BMI, smoking, alcohol consumption and physical activity
Table 3 ORs and 95% CIs for the
association between type 2
diabetes and heart disease in co-
twin control analyses using
conditional logistic regression
Co-twin without heart disease Co-twin with heart disease
All types
a
Dizygotic only Monozygotic only
T2D-free T2D T2D-free T2D T2D-free T2D
T2D-free 3193 464 2278 337 588 65
T2D 90 6176 366 17
Basic-adjusted OR (95% CI)
b
5.07 (4.04, 6.38) 4.32 (3.35, 5.56) 10.88 (4.71, 25.11)
Multi-adjusted OR (95% CI)
c
4.89 (3.88, 6.16) 4.07 (3.15, 5.27) 10.83 (4.67, 25.10)
a
Including dizygotic twins, monozygotic twins and twins of undetermined zygosity. The 3808 heart disease-
discordant pairs were divided into four groups with respect to exposure (T2D) status. In 3193 twin pairs, both
were T2D-free. In 61 twin pairs, both had T2D. In 464 twin pairs, the healthy (heart disease-free) co-twin was
T2D-free and the diseased twin had T2D.In 90 twin pairs, the diseased co-twin was T2D-free and the healthy twin
had T2D
b
Adjusted for sex and education
c
Adjusted for sex, education, marital status, BMI, smoking, alcohol consumption and physical activity
T2D, type 2 diabetes
535Diabetologia (2021) 64:530–539
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taken into account [2,27,28]. As the onset and progression of
angina pectoris, acute myocardial infarction and atrial fibrilla-
tion may also contribute to heart failure, we looked at the first
onset of heart failure with no previous coronary heart disease
and cardiac arrhythmias and found that the higher risk of heart
failure with type 2 diabetes was independent of other specific
subtypes of heart disease.
Accumulating evidence has shown that molecular defects,
intrauterine environment and socioeconomic factors are asso-
ciated with the development of type 2 diabetes, and also
contribute to an increased risk of heart disease [13,29].
Twins are generally raised together and share the same genetic
background as well as intrauterine, childhood and adolescent
environments. Twin studies provide us with an opportunity to
investigate whether the association between type 2 diabetes
and heart disease is potentially confounded by genetic and/or
early-life familial environmental backgrounds. In the present
study, results of co-twin control analyses implicate that type 2
diabetes is still associated with an increased risk of heart
disease, even after fully controlling for genetic and early-life
familial environmental backgrounds.
Thus far, previous studies have mainly focused on the
combined effect of an overall healthy lifestyle and type 2
diabetes on mortality or total CVD (including coronary heart
disease, stroke and peripheral vascular disease) risk, but data
specific for only heart disease risk are limited. One
population-based prospective cohortstudy of Chinese patients
with type 2 diabetes showed that active smoking, physical
inactivity, alcohol drinking and high carbohydrate intake
increased the risk of all-cause mortality and CVD mortality
after a mean follow-up of 4.02 years of follow-up [17].
Another prospective study including 11,527 participants with
type 2 diabetes suggested that an overall healthy lifestyle (diet,
smoking status, alcohol consumption and physical activity)
was associated with substantially lower risks of CVD inci-
dence (including stroke and coronary heart disease) and
CVD mortality during a mean follow-up of 13.3 years of
follow-up [18]. In contrast, at a median follow-up of almost
10 years, a multicentre randomised clinical trial found that an
intensive lifestyle intervention (diet modification and
increased physical activity) could produce improvements in
CVD risk factors (such as blood pressure and high-density
lipoprotein cholesterol levels) in individuals with type 2
diabetes, but not reduce CVD events (including stroke and
coronary heart disease) [30]. The discrepancy in findings
Table 4 ORs and 95% CIs of
heart disease in relation to BMI,
smoking status, alcohol
consumption and physical activi-
ty from GEE models
Lifestyle factor No. of cases Heart disease OR (95% CI)
a
Heart disease OR (95% CI)
b
BMI
≥25 (overweight) 4955 Reference Reference
<25 (non-overweight) 4307 0.71 (0.68, 0.75) 0.77 (0.74, 0.81)
Smoking
Yes 4697 Reference Reference
No 4565 0.86 (0.81, 0.90) 0.86 (0.82, 0.91)
Alcohol consumption
Heavy drinking 710 Reference Reference
No/mild drinking 8552 0.83 (0.76, 0.91) 0.89 (0.81, 0.98)
Physical activity
Low 1032 Reference Reference
Regular 8230 0.78 (0.72, 0.84) 0.82 (0.76, 0.89)
Lifestyle
Unfavourable 693 Reference Reference
Intermediate 6638 0.70 (0.64, 0.77) 0.73 (0.66, 0.81)
Favourable 1931 0.49 (0.44, 0.55) 0.54 (0.48, 0.60)
a
Adjusted for age, sex and education
b
Adjusted for age, sex, education, marital status and type 2 diabetes, as well as BMI, smoking, alcohol consump-
tion and physical activity, if applicable
1.00
0.68
0.44
Unfavourable Intermediate Favourable
0
0.2
0.4
0.6
0.8
1.0
1.2
ORs of heart disease
lifestyle
Fig. 2 Multi-adjusted ORs (95% CIs) of heart disease in relation to life-
style among patients with type 2 diabetes from GEE models (adjusted for
age, sex, education and marital status)
536 Diabetologia (2021) 64:530–539
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
might reflect differences in follow-up times, lifestyle factors
and definitions of outcome. To the best of our knowledge, the
current study is the first to provide evidence that a healthy
lifestyle consisting of being a non-smoker, no/mild alcohol
consumption, regular physical activity and being non-
overweight may greatly attenuate the risk of heart disease in
type 2 diabetes. In the current study, patients with type 2
diabetes who reported maintaining not only a favourable (four
healthy lifestyle factors) but also an intermediate lifestyle (any
two or three healthy lifestyle factors) had a significantly lower
heart disease risk than those with an unfavourable lifestyle (no
or only one healthy lifestyle factor).
The mechanisms responsible for the increased heart disease
morbidity attributable to type 2 diabetes are multifactorial and
incompletely understood. An important role of metabolic
disturbances, such as long-term hyperglycaemia, insulin resis-
tance and dyslipidaemia, has been hypothesised [31,32].
Accelerated atherosclerosis and thrombosis in patients with
type 2 diabetes principally result from inflammation, reactive
oxygen species and endothelial dysfunction combined with
coagulation, platelet abnormalities and impaired fibrinolysis
[33]. Type 2 diabetes leads to autonomic dysfunction and
structural remodelling of the left atrium in the form of atrial
dilatation and interstitial fibrosis, which might contribute to
life-threatening arrhythmias [26]. In addition, how a
favourable lifestyle mitigates the risk of heart disease among
participants with or without type 2 diabetes may be explained
by multiple possible mechanisms—an overall healthy lifestyle
can improve glycaemic control, insulin sensitivity, blood pres-
sure, platelet function, lipid profile and body composition
[16,17,34].
There are several strengths and limitations in the current
study. First, the large, nationwide, population-based twin
cohort provided us with a unique opportunity to further exam-
ine the effect of type 2 diabetes on heart disease risk while
controlling for some unmeasured confounders such as genetic
and early-life familial environmental factors. Second, we used
GEE modelling, which is more appropriate than logistic
regression models in case–control design, since it accounts
for the clustering of twins within a pair. Nonetheless, the limi-
tations in our study need to be pointed out. First, blood glucose
level was not available in the STR or SALT. Consequently,
given the higher prevalence of undiagnosed type 2 diabetes in
elderly people [35], subjects with undiagnosed type 2 diabetes
might have been misclassified as type 2 diabetes-free,
which might have led to an underestimation of the
observed associations. Second, type 2 diabetes and heart
disease were associated with mortality risk, which may
contribute to under- or over-estimation of the observed
associations. In the current study, we repeated the analyses
with an additional adjustment for survival status, and the
results were not substantially altered. Third, because infor-
mation on lifestyle factors was obtained at baseline, it is
difficult to capture potential variations in lifestyle factors
during follow-up, which would result in underestimation
for the effect. Fourth, although some lifestyle-related factors
such as smoking, alcohol consumption and physical activity
were taken into account, information on diet, sleep duration
and other lifestyle-related factors was not available. Finally,
information bias might have occurred due to self-reported
information on lifestyle-related factors. This might have
caused non-differential misclassification leading to underes-
timation for the observed association.
Conclusions In conclusion, our study provides further
evidence that type 2 diabetes is associated with about fourfold
greater risk of heart disease, including coronary heart disease,
cardiac arrhythmias and heart failure. Moreover, the associa-
tion between type 2 diabetes and heart disease remains statis-
tically significant, even after fully controlling for genetic and
early-life familial environmental background. Patients with
type 2 diabetes who reported maintaining a healthy lifestyle
consisting of being a non-smoker, no/mild alcohol consump-
tion, regular physical activity and being non-overweight had a
significantly lower heart disease risk than those with an
unfavourable lifestyle. Our findings highlight the importance
of a healthy lifestyle in prevention of heart disease among
patients with type 2 diabetes.
Acknowledgements We are grateful to all the twins who took part in the
study and to the members of the survey teams. The Swedish Twin
Registry is managed by Karolinska Institutet and receives funding
through the Swedish Research Council under grant no. 2017-00641.
Data availability Raw data are available by request from qualified inves-
tigators applying to the Swedish Twin Registry.
Funding Open access funding provided by Karolinska Institute. This
work was supported by the Swedish Research Council (no. 2017-
00981), the National Natural Science Foundation of China (no.
81771519), the Konung Gustaf V:s och Drottning Victorias Frimurare
Foundation (no. 2016-2017), Demensfonden, Strokefonden, Cornells
Stiftelse and Alzheimerfonden (2017-2018). This project is part of
CoSTREAM (www.costream.eu) and received funding from the
European Union’s Horizon 2020 research and innovation programme
under grant agreement no. 667375.
Authors’relationships and activities The authors declare that there are
no relationships or activities that might bias, or be perceived to bias, their
work.
Contribution statement RY and WX had full access to all the data in the
study and take responsibility for the integrity of the data and the accuracy
of the data analysis. WX and XQ were involved in study concept and
design. RY and HX did the statistical analysis and drafted the manuscript.
NLP was involved in acquisition of data and had full access to all the data
in the study. XL, JY and CB contributed to analysis and interpretation of
data. All authors contributed to critical revision of the manuscript for
important intellectual content. WX obtained funding for the study. WX
and XQ were involved in study supervision. All authors gave their final
approval of the version to be published.
537Diabetologia (2021) 64:530–539
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Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing, adap-
tation, distribution and reproduction in any medium or format, as long as
you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
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otherwise in a credit line to the material. If material is not included in
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copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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