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Diabetes mellitus and the risk of abdominal aortic aneurysm:
a systematic review and meta-analysis of prospective studies.
Dagfinn Aune 1,2,3, Sabrina Schlesinger 4, Teresa Norat 1, Elio Riboli 1
Affiliations
1 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College
London, London, United Kingdom
2 Bjørknes University College, Oslo, Norway
3 Department of Endocrinology, Morbid Obesity and Preventive Medicine,
Oslo University Hospital, Oslo, Norway
4 Institute for Biometry and Epidemiology, German Diabetes Center, Leibniz Institute for
Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Short title: Diabetes and abdominal aortic aneurysm
Word count abstract: 216
Word count text: 1627
Correspondence to: Dagfinn Aune, Department of Epidemiology and Biostatistics,
School of Public Health, Imperial College London, St. Mary's Campus, Norfolk Place,
Paddington, London W2 1PG, UK.
3
Abstract
Background: Diabetes mellitus has been associated with reduced risk of abdominal aortic
aneurysm in a number of epidemiological studies, however, until recently little data from
prospective studies have been available. We therefore conducted a systematic review and
meta-analysis of prospective studies to quantify the association.
Material and methods: Two investigators searched the PubMed and Embase databases for
studies of diabetes and abdominal aortic aneurysm up to May 8th 2018. Prospective studies
were included if they reported adjusted relative risk (RR) estimates and 95% confidence
intervals (95% CIs) of abdominal aortic aneurysm associated with a diabetes diagnosis.
Summary relative risks were estimated by use of a random effects model.
Results: We identified 16 prospective studies with 16 572 cases among 4 563 415
participants that could be included in the meta-analysis. The summary RR for individuals
with diabetes compared to individuals without diabetes was 0.58 (95% CI: 0.51-0.66,
I2=40.4%, pheterogeneity=0.06). The results persisted when stratified by sex, duration of follow-
up, and in most of the subgroup analyses. There was no evidence of publication bias with
Egger's test, p=0.64 or by inspection of the funnel plots.
Conclusions: These results suggest that individuals with diabetes mellitus are at a reduced
risk of abdominal aortic aneurysm, however, whether pharmacological agents for diabetes
mellitus explain this observation needs to be clarified in future studies.
4
Keywords: Diabetes mellitus, abdominal aortic aneurysm, systematic review, meta-analysis.
5
Introduction
Aortic aneurysms are localized dilatations of the aorta which when ruptured have very high
mortality rates with 80% of those reaching hospital and 50% of those undergoing surgery for
ruptured aortic aneurysms dying as a consequence (1;2). Globally aortic aneurysms
accounted for 168200 deaths and 2.9 million disability-adjusted life years in 2015 (3;4). Most
aortic aneurysms are abdominal aortic aneurysms. The incidence of new abdominal aortic
aneurysms is 0.4-0.67% in Western populations (5-7), and ten-fold lower in Asian
populations (8). Some of the established risk factors for abdominal aortic aneurysm include
age, male sex, hypertension, coronary heart disease, peripheral artery disease, chronic
obstructive pulmonary disease and smoking (9;10).
Although individuals with diabetes mellitus are at increased risk of several
cardiovascular diseases (11;12), evidence from epidemiological studies have paradoxically
suggested that a history of diabetes mellitus is associated with a reduced risk of abdominal
aortic aneurysms (10;13-24), although not all of these studies found a statistically significant
association (14;15;19;20;23). Although the underlying mechanisms are not firmly established
it has been suggested that individuals with diabetes mellitus have excess vascular matrix
which might protect against the loss of the arterial wall matrix that is typically seen in
abdominal aortic aneurysms. A previous meta-analysis suggested an inverse association
between diabetes mellitus and abdominal aortic aneurysms, however, most of the studies
included had a cross-sectional design and there was a limited number of cohort studies
included (25). Four cohort studies (three publications) (16;17;19) may have been missed in
the previous meta-analysis and at least six additional cohort studies (five publications) (20-
24) have since been published on the topic. For this reason we conducted an up-to-date
6
systematic review and meta-analysis of diabetes mellitus and abdominal aortic aneurysm to
provide updated data on the association using data from a stronger study design (prospective
studies) and to investigate sources of heterogeneity by conducting subgroup and sensitivity
analyses.
7
Material and methods
Search strategy
Two investigators (DA, SS) searched the Pubmed, and Embase databases up to July 20th 2017
for eligible studies and the search was later updated to May 8th 2018. The search terms used
are found in Supplementary Text. We followed standard MOOSE criteria for reporting meta-
analyses (26). In addition, we searched the reference lists of the identified publications for
further studies.
Study selection and inclusion criteria
We included published retrospective and prospective cohort studies and nested case-control
studies within cohorts that investigated the association between diabetes mellitus and the risk
of abdominal aortic aneurysm. Adjusted estimates of the relative risk (RR) had to be
available with the 95% confidence intervals (CIs) in the publication. A list of the excluded
studies can be found in Supplementary Table 1.
Data extraction
The following data were extracted from each study: The first author’s last name, publication
year, country where the study was conducted, study period, sample size, number of cases and
participants, exposure and subgroup, RRs and 95% CIs and variables adjusted for in the
analysis. Data was extracted by one author (DA) and checked for accuracy by a second
author (SS).
8
Statistical methods
We calculated summary RRs and 95% CIs of abdominal aortic aneurysm for individuals with
diabetes mellitus compared with individuals without diabetes mellitus using the random-
effects model by DerSimonian and Laird (27) which takes into account both within and
between study variation (heterogeneity). The average of the natural logarithm of the RRs was
estimated and the RR from each study was weighted using random effects weights.
Heterogeneity between studies was evaluated using Q and I2 statistics (28). I2 is a
measure of how much of the heterogeneity is due to between study variation rather than
chance. We conducted main analyses (all studies combined) and stratified by study
characteristics including sex, outcome type (incidence, mortality), duration of follow-up,
geographic location, number of cases, study quality and by adjustment for confounding
factors to investigate potential sources of heterogeneity. Study quality was assessed using the
Newcastle Ottawa scale which rates studies according to selection, comparability and
outcome assessment with a score range from 0 to 9 (29). Influence analyses were conducted
excluding one study at a time from the analysis and assessing the influence of each study on
the summary estimate. Results from these influence analyses are reported excluding the two
studies with the most positive and negative impact on the summary estimates.
Publication bias was assessed using Egger’s test (30) and Begg-Mazumdar’s test (31)
and by inspection of funnel plots. The statistical analyses were conducted using the software
package Stata, version 13.1 software (StataCorp, Texas, US).
9
Results
We identified 16 cohort studies (13 publications, 14 risk estimates) (10;13-24) that could be
included in the analysis of diabetes mellitus and risk of abdominal aortic aneurysm including
16 572 cases among 4 563 415 participants (Figure 1, Table 1). Eight of the studies were
from the USA, seven were from Europe and one was from Asia. Three publications
(19;23;24) contained data from two studies each and two of these publications only provided
a combined risk estimate for two studies each (23;24). The summary relative risk for patients
with diabetes mellitus versus patients without diabetes was 0.58 (95% CI: 0.51-0.66, I2=40%,
pheterogeneity=0.06) (Figure 2). There was no evidence of publication bias with Egger’s test,
p=0.64, or with Begg’s test, p=0.19 (Supplementary Figure 1). In sensitivity analyses
excluding one study at a time from the analysis, the summary RR ranged from 0.57 (95% CI:
0.50-0.64) when excluding the study by Wang et al (16) to 0.60 (95% CI: 0.53-0.69) when
excluding the study by Shah et al (21) (Supplementary Table 2).
Subgroup and sensitivity analyses
Inverse associations were observed in all subgroup analyses defined by sex, outcome type,
duration of follow-up, geographic location, number of cases, study quality and adjustment for
confounding factors (including age, education, alcohol, smoking, BMI, and physical activity,
hypertension, hypercholesterolemia, cholesterol, coronary heart disease, stroke, and chronic
obstructive pulmonary disease) (Table 2). With meta-regression analyses there was no
evidence that the results differed between these subgroups. The heterogeneity was in general
low to moderate, and there was little or no heterogeneity among the studies when stratified by
sex, among studies with longer duration of follow-up and among the studies with adjustment
10
for education, physical activity, and cholesterol (Table 2). The mean (median) study quality
score was 6.9 (7.0).
Discussion
This meta-analysis of 16 cohort studies including >16 000 cases of abdominal aortic
aneurysms among 4.5 million participants suggest that individuals with a diagnosis of
diabetes mellitus have a reduction in risk of abdominal aortic aneurysms by 42%. Inverse
associations were observed in both men and women and among studies in Europe, America
and Asian, however, no data were available from other geographic locations. The inverse
association was consistent in several other subgroup and sensitivity analyses. The findings are
consistent with a previous meta-analysis of 5 cohort studies (5099 cases, 595839
participants), but had more than 3 times the number of cases and more than 7 times the
number of participants (25).
The underlying mechanism(s) that may explain the inverse association between
diabetes mellitus and abdominal aortic aneurysms are not firmly established. It has been
observed that there is loss of vascular matrix and destruction of the aortic media in aortic
aneurysms (32) which is driven by matrix metalloproteinases (33). In contrast, individuals
with diabetes mellitus have been found to have excess vascular matrix (increased synthesis
and reduced degradation of matrix) via advanced glycation end products (34-36) and thicker
aortic walls which may reduce wall stress and thereby protect against the development of
abdominal aortic aneurysms (37). Experimental studies suggested that hyperglycemia may
lead to less aortic mural macrophage infiltration, elastolysis, and neovascularization and
limited the enlargement of abdominal aortic aneurysms compared to euglycemic mice, while
insulin treatment reduced serum glucose and reversed these effects (38;39). Although
11
epidemiological data are limited on the use of diabetes medications and risk of abdominal
aortic aneurysms, some animal studies have suggested that thiazolidinediones may protect
against abdominal aortic aneurysms (40). Rosiglitazone may decrease the expression of
matrix metalloproteinase in the aortic wall and may also reduce the development of aortic
aneurysms (41). It has been shown that metformin may improve aortic wall elasticity and
decrease matrix metalloproteinase and smooth muscle cell proliferation in the aortic wall
(42;43). An analysis of three cohort studies with 1697 abdominal aortic aneurysm patients
found a reduced risk of median or greater growth of abdominal aortic aneurysms among
patients who were prescribed metformin for the treatment of diabetes with odds ratios of 0.59
(95% CI: 0.39-0.87), 0.38 (95% CI: 0.18-0.80) and 0.13 (95% CI: 0.03-0.61) across the three
cohort studies, respectively (43), and another study found similar results (36). Consistent with
this are the results of a nested case-control study from Taiwan which found that use of
metformin, sulfonylurea and thiazolidinedione were associated with 18-28% reductions in
risk of aortic aneurysms (44), however, a Danish study reported only a non-significant
reduction in risk of ruptured abdominal aortic aneurysms with used of metformin (odds
ratio=0.84, 95% CI: 0.61-1.17) (45).
The current systematic review and meta-analysis may have been affected by
limitations of the individual studies that were included in the analysis. We cannot exclude the
possibility that confounding by other risk factors could have affected the findings. We found
that the results persisted in numerous subgroup analyses when stratified by adjustment for
age, education, alcohol intake, smoking status, BMI or obesity, physical activity,
hypertension, hypercholesterolemia, serum cholesterol, coronary heart disease, stroke or
chronic obstructive pulmonary disease and there was no evidence of heterogeneity between
these subgroup analyses with meta-regression analyses. Although residual confounding by
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for example smoking is possible, smoking is associated with increased risk of both type 2
diabetes and abdominal aortic aneurysms so any confounding by smoking would likely
attenuate rather than exaggerate the observed associations. Similarly, residual confounding by
the other risk factors evaluated in subgroup analyses would also most likely attenuate rather
than exaggerate the inverse association because of the paradoxical association between
diabetes mellitus and abdominal aortic aneurysms. Therefore it seems less likely that
confounding by the above-mentioned risk factors could explain the observed association,
however, the possibility that other risk factors could confound the association cannot be
entirely excluded.
Although these data suggest a reduction in risk of abdominal aortic dissection among
individuals with diabetes mellitus compared to individuals without diabetes mellitus, this
benefit is greatly outweighed by adverse effects of diabetes mellitus upon the risk of many
other chronic diseases including coronary heart disease, stroke, heart failure, atrial
fibrillation, several cancers, digestive diseases, kidney stones, infections, respiratory diseases,
neurological disorders and all-cause mortality (11;12;46-48). Because of these wide-ranging
complications of diabetes mellitus efforts to reduce the incidence of diabetes mellitus should
continue worldwide. Therefore, the public health implications of the current results are
limited other than trying to clarify the underlying mechanisms behind the reduced risk of
abdominal aortic aneurysms, which potentially could result in preventive therapeutic
interventions in the future.
Conclusion
In conclusion, this meta-analysis suggest that individuals with diabetes mellitus have a 42%
reduction in the relative risk of developing abdominal aortic aneurysm. Whether or not
13
pharmacological agents for diabetes mellitus explain this observation needs to be clarified in
future studies. As most of the current studies were from the US and Europe, additional studies
are needed from other geographic locations and any further studies should adjust for more
confounding factors.
Acknowledgement: DA conducted the literature search and analyses and wrote the first draft
of the paper. SS and DA contributed to the literature screening. All authors interpreted the
data, revised the subsequent drafts for important intellectual content, read and approved the
final manuscript. This work has been supported by funding from the South East
Regional Health Authority of Norway, the School of Public Health of
Imperial College London, and the Imperial College National Institute of
Health Research (NIHR) Biomedical Research Centre (BRC).
14
15
16
Figure 1. Flow-chart of study selection
17
Figure 2. Diabetes mellitus and abdominal aortic aneurysm
Relative Risk .1 .25 .5 .75 1 1.5 2
Study Relative Risk (95% CI)
Larsson, 2018 0.57 ( 0.40, 0.82) Wang, 2017 0.79 ( 0.57, 1.11) Tang, 2016 0.52 ( 0.36, 0.75) Jahangir, 2015 0.75 ( 0.53, 1.05) Shah, 2015 0.46 ( 0.35, 0.59) Tsai, 2015 0.60 ( 0.51, 0.71) Sode, 2013, CCHS 0.50 ( 0.20, 1.10) Sode, 2013, CGPS 1.10 ( 0.70, 2.00) Campbell, 2012 0.60 ( 0.50, 0.72) Ohrlander, 2012 0.39 ( 0.26, 0.58) Lederle, 2008 0.29 ( 0.13, 0.68) Iribarren, 2007 0.62 ( 0.36, 1.05) Wong, 2007 0.55 ( 0.26, 1.17) Tornwall, 2001 0.43 ( 0.16, 1.15)
Overall 0.58 ( 0.51, 0.66)
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Table 1. Prospective studies of diabetes mellitus and abdominal aortic aneurysm
First author, publication year, country
Study name or description
Study period Number of participants, number of cases
Type of diabetes mellitus, subgroup
Comparison Relative risk (95% confidence interval)
Adjustment for confounders
Tornwall ME et al, 2001, Finland
Alpha-Tocopherol, Beta-Carotene Study
1985-1988 - NA, 5.8 years follow-up
29133 male smokers, age 50-69 years: 181 AAA cases
Diabetes mellitus Yes vs. no 0.43 (0.16-1.15) Age, cigarettes per day, years of smoking, BMI, SBP, DBP, total cholesterol, HDL cholesterol, education, exercise
Iribarren C et al, 2007, USA
Kaiser Multiphasic Health Checkup Cohort Study
1965-1970 - 2003, 13 years follow-up
104813 men and women, age ≥18 years: 605 AAA cases
Diabetes, allDiabetes, menDiabetes, women
Yes vs. noYes vs. noYes vs. no
0.62 (0.36-1.05)0.65 (0.36-1.15)0.43 (0.10-1.75)
Age, sex, race, education, alcohol, smoking status and packs per day, height, weight, sagittal abdominal diameter, hypertension, serum total cholesterol, white blood cell count, history of coronary heart disease, COPD, stroke, intermittent claudication, estimated GFR, HT
Wong DR et al, 2007, USA
Health Professionals Follow-up Study
1986-2002, 14.6 years follow-up
39352 men, age 40-75 years: 376 AAA cases
Diabetes Yes vs. no 0.55 (0.26-1.17) Age, smoking, hypertension, physical activity, hypercholesterolemia, BMI
Lederle FA et al, 2008, USA
Women's Health Initiative
1993-1998 -2004-2005, 7.8 years follow-up
161808 women, age 50-79 years: 184 AAA cases
Diabetes mellitus Yes vs. no 0.29 (0.13-0.68) Age, ethnicity/race, height, weight, smoking status, pack-years, hypertension, drugs for high cholesterol, coronary artery disease, cerebrovascular disease, peripheral artery disease, venous thromboembolism, COPD, non-skin cancer, previous diagnosis of aortic aneurysm, HT, alcohol
Campbell PT et al, 2012, USA
Cancer Prevention Study 2
1982-2008, 26 years follow-up
1053831 men and women, age ≥30 years: 1404/2873 AA deaths
Diabetes mellitus, menDiabetes mellitus, women
Yes vs. noYes vs. no
0.59 (0.48-0.73)0.62 (0.44-0.87)
Age, education, BMI, smoking, alcohol, vegetables, red meat, physical activity, aspirin use
Ohrlander T et al, 2012, Sweden
Longitudinal Multilevel
1991 - 2003, 13 years
243223 men and women, age 60-
Diabetes mellitus, menDiabetes mellitus, women
Yes vs. noYes vs. no
0.38 (0.24-0.61)0.41 (0.19-0.88)
Age, income, hypertensive diseases, ischemic heart disease,
19
Analysis in Scania (LOMAS)
follow-up 90 years: 3335 AAA cases
cerebrovascular disease, atherosclerosis, chronic lower respiratory disease, and for women also adjustment for: inflammatory polyarthropathies, systemic connective tissue disorder, polymyalgia rheumatica, diseases of oral cavity and jaws, non-infective enteritis and colitisand for men also adjustment for: arthrosis, other diseases of intestines, diseases of peritoneum
Sode BF et al, 2013, Denmark
Copenhagen City Heart study
1976-1978 - 2010, 23 years follow-up
15072 men and women, age 20-≥80 years: 335 AAA cases
Diabetes mellitus Yes vs. no 0.5 (0.2-1.1) Age, sex, smoking, hypertension, BMI, hypercholesterolemia, alcohol
Sode BF et al, 2013, Denmark
Copenhagen General Population Study
2003 - 2010, 4 years follow-up
56211 men and women, age 20-≥80 years: 169 AAA cases
Diabetes mellitus Yes vs. no 1.1 (0.7-2.0) Age, sex, smoking, hypertension, BMI, hypercholesterolemia, alcohol
Tsai CL et al, 2015, Taiwan
The National Health Research Institute
1998-2008 - 2010, 6.2 years follow-up
807101 men and women, age ≥55 years: 1454 AAA cases
Type 2 diabetes mellitus, AAA without rupture
Type 2 diabetes, mellitus, AAA with rupture
NoUncomplicated DM2Advanced DM2NoUncomplicated DM2Advanced DM2
1.000.58 (0.45-0.74)0.53 (0.40-0.69)1.001.17 (0.70-1.95)0.57 (0.30-1.09)
Age, sex, hypertension, chronic kidney disease, ischemic heart disease, stroke, retinopathy, blindness
Jahangir E et al, 2015, USA
Southern Community Cohort Study
2002-2009, 4.94 years follow-up
18782 men and women, age ≥65 years: 281 cases
Diabetes, allDiabetes, menDiabetes, women
Yes vs. noYes vs. noYes vs. no
0.75 (0.53-1.05)0.68 (0.43-1.10)0.81 (0.49-1.34)
Age, sex, race, education, BMI, smoking status, history of MI/CABG, history of high blood pressure, history of high cholesterol
Shah AD et al, 2015, England
The CALIBER Programme
1998-2010, 5.5 years follow-up
1921260 men and women, age ≥30 years: 3113 AAA cases
Diabetes mellitus Yes vs. no 0.46 (0.35-0.59) Age, sex, BMI, deprivation, HDL cholesterol, total cholesterol, SBP, smoking status, statin, antihypertensive drug prescriptions
20
Tang W et al, 2016, USA
Atherosclerosis Risk in Communities Study
1987-1989 - 2013, 24 years follow-up
15703 men and women, age 45-64 years: 588 AAA cases
Diabetes mellitus Yes vs. no 0.52 (0.36-0.75) Age, sex, race, height, smoking status, pack-years of smoking, alcohol, HDL-cholesterol, LDL-cholesterol, triglycerides, hypertension, peripheral artery disease, total cholesterol
Wang L et al, 2017, USA
Physicians' Health Study I and Physicians' Health Study II
1982 - 20121996/1997 - 2012, 10.4 years follow-up
25554 men, age 40-84 years: 471 AAA cases
Diabetes mellitus Yes vs. no 0.79 (0.57-1.11) Age, race, randomized treatment assignment, BMI, smoking status, alcohol, vigorous exercise, hypertension, hypercholesterolemia, cardiovascular disease
Larsson SC et al, 2018, Sweden
Swedish Mammography Cohort Study and Cohort of Swedish Men
1997 - 2014, 28.1 years follow-up
71483 men and women, mean age 58.9/61.1 years: 1201 AAA cases
Type 2 diabetes mellitus Yes vs. no 0.57 (0.40-0.82) Age, sex, BMI, education, FH - MI, smoking status, pack-years of smoking, aspirin use, exercise, walking/bicycling, hypertension, hypercholesterolemia, alcohol, total energy, DASH diet score
AAA=abdominal aortic aneurysm, BMI=body mass index, CABG=coronary artery bypass grafting, CAD=coronary artery disease, COPD=chronic
obstructive pulmonary disease, DASH=Dietary Approaches to Stop Hypertension, FH=family history, GFR=glomerular filtration rate, HDL=high-
density lipoprotein, HT=hormone therapy, LDL=low-density lipoprotein, MI=myocardial infarction, NA=not available, PAD=peripheral artery disease,
SBP=systolic blood pressure
21
Table 2. Subgroup analyses of diabetes mellitus and abdominal aortic aneurysm
Diabetes mellitus and abdominal aortic aneurysm
n Relative risk (95% CI) I2 (%) Ph1 Ph
2
All studies 14 0.58 (0.51-0.66) 40.4 0.06
Gender
Men 7 0.60 (0.51-0.72) 16.1 0.31 0.74/
0.79 Women 5 0.56 (0.40-0.77) 27.1 0.24
Men, women 6 0.58 (0.48-0.70) 46.3 0.10
Outcome type
Incidence 13 0.58 (0.50-0.67) 44.8 0.04 0.87
Mortality 1 0.60 (0.50-0.72)
Follow-up
<10 years 6 0.60 (0.46-0.77) 64.4 0.02 0.78
≥10 years 8 0.58 (0.51-0.66) 9.5 0.36
Geographic location
Europe 6 0.54 (0.40-0.71) 54.7 0.05 0.45
America 7 0.66 (0.57-0.76) 54.9 0.03
Asia 1 0.60 (0.51-0.71)
Number of cases
<250 3 0.54 (0.22-1.33) 75.4 0.02 0.20
250-<1000 6 0.66 (0.55-0.79) 0 0.56
≥1000 5 0.54 (0.47-0.63) 38.7 0.16
Study quality
0-3 stars 0 0.83
4-6 stars 5 0.59 (0.42-0.82) 31.6 0.21
7-9 stars 9 0.58 (0.50-0.67) 48.1 0.05
Adjustment for confounding factors3
Age Yes 14 0.58 (0.51-0.66) 40.4 0.06 NC
22
No 0
Education Yes 4 0.62 (0.54-0.71) 0 0.68 0.45
No 10 0.56 (0.46-0.67) 53.4 0.02
Alcohol Yes 8 0.62 (0.52-0.75) 38.1 0.13 0.34
No 6 0.54 (0.44-0.66) 44.7 0.11
Smoking Yes 12 0.60 (0.52-0.70) 37.7 0.09 0.43
No 2 0.50 (0.33-0.76) 73.6 0.05
BMI or obesity Yes 11 0.61 (0.52-0.72) 41.4 0.07 0.33
No 3 0.52 (0.41-0.67) 49.3 0.14
Physical activity Yes 5 0.62 (0.54-0.71) 0 0.56 0.53
No 9 0.56 (0.46-0.68) 55.3 0.02
Hypertension Yes 12 0.58 (0.50-0.68) 48.5 0.03 0.95
No 2 0.59 (0.50-0.71) 0 0.52
Hypercholesterolemia Yes 8 0.62 (0.48-0.79) 57.8 0.02 0.40
No 6 0.57 (0.51-0.64) 0 0.45
Cholesterol No 2 0.57 (0.36-0.91) 0 0.52 0.91
Yes 12 0.58 (0.51-0.67) 48.6 0.03
Coronary heart disease Yes 6 0.59 (0.47-0.74) 57.0 0.04 0.78
No 8 0.57 (0.48-0.67) 26.8 0.22
Stroke Yes 4 0.50 (0.37-0.67) 52.8 0.10 0.26
No 10 0.61 (0.52-0.72) 38.7 0.10
Chronic obstructive
pulmonary disease
Yes 2 0.45 (0.22-0.94) 56.2 0.13 0.49
No 12 0.59 (0.52-0.67) 42.0 0.06
n denotes the number of risk estimates
1P for heterogeneity within each subgroup
2 P for heterogeneity between subgroups with meta-regression analysis
2 P for heterogeneity between men and women (excluding studies with both genders) with
23
meta-regression analysis
BMI, body mass index
NC, not calculable because no studies were present in one of the subgroups.
24
Supplementary Text. Search terms for the PubMed search
diabetes OR diabetes[MeSH] OR glucose OR glucose[MeSH] OR "medical history" OR medical history[MeSH]
AND
"aortic aneurysm" OR aortic aneurysm[MeSH]
AND
"case-control" OR cohort OR prospective OR longitudinal OR retrospective OR "follow-up" OR "cross-sectional" OR "hazard ratio" OR "hazard ratios" OR "relative risk" OR "relative risks" OR "incidence rate ratio" OR "incidence rate ratios" OR "odds ratio" OR odds ratios OR incidence
Search terms for the Embase search
((diabetes or glucose or medical history).ab,ti. or diabetes/ or glucose/ or medical history/)
and
(aortic aneurysm.ab,ti. or aortic aneurysm/)
and
(case-control or cohort or prospective or longitudinal or retrospective or follow-up or cross-sectional or hazard ratio or hazard ratios or relative risk or relative risks or incidence rate ratio or incidence rate ratios or odds ratio or odds ratios or incidence).af.
25
Supplementary Table 1. List of excluded studies and exclusion reasons
Exclusion reason Reference numberAbstract (1)Aortic dissection (2)Case-control study (3-9)Case only study (10)Commentary, editorial (11-13)Cross-sectional study (14-22)Duplicates (23-25)HbA1c as exposure (26)Medications as exposure (27)Meta-analysis (28-34)No risk estimates (35-37)Not relevant exposure (38)Not relevant outcome (39)Reviews (40-45)Survival (46)Thoracic aortic aneurysm as outcome (47;48)
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Supplementary Figure 1. Funnel plot of diabetes mellitus and abdominal aortic aneurysm
0.1
.2.3
.4.5
s.e.
of l
ogrr
-1.5 -1 -.5 0 .5logrr
Funnel plot with pseudo 95% confidence limits
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Supplementary Figure 2. Influence analysis of diabetes mellitus and abdominal aortic aneurysm
0.50 0.58 0.51 0.66 0.69
Larsson, 2018
Wang, 2017
Tang, 2016
Jahangir, 2015
Shah, 2015
Tsai, 2015
Sode, 2013, CCHS
Sode, 2013, CGPS
Campbell, 2012
Ohrlander, 2012
Lederle, 2008
Iribarren, 2007
Wong, 2007
Tornwall, 2001
Study ommited Meta-analysis random-effects estimates (exponential form)
------------------------------------------------------------------------------ Study omitted | e^coef. [95% Conf. Interval]-------------------+---------------------------------------------------------- Larsson, 2018 | 0.58324391 0.50654268 0.67155927 Wang, 2017 | 0.5663572 0.49781173 0.64434099 Tang, 2016 | 0.58796215 0.5115422 0.67579854 Jahangir, 2015 | 0.5691492 0.49799052 0.6504758 Shah, 2015 | 0.60129404 0.5275467 0.68535066 Tsai, 2015 | 0.57854909 0.49564162 0.6753248 Sode, 2013, CCHS | 0.58429837 0.51099461 0.66811776 Sode, 2013, CGPS | 0.56865907 0.50740427 0.63730866 Campbell, 2012 | 0.57877702 0.49675906 0.67433667 Ohrlander, 2012 | 0.6001026 0.53054148 0.67878413 Lederle, 2008 | 0.59149033 0.52226812 0.66988736 Iribarren, 2007 | 0.58044702 0.50619096 0.66559613 Wong, 2007 | 0.58322543 0.50961477 0.66746867 Tornwall, 2001 | 0.58535528 0.51258343 0.66845858-------------------+---------------------------------------------------------- Combined | 0.58257625 0.51194192 0.66295625
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