Original Contribution
Adiponectin and Risk of Stroke
Prospective Study and Meta-analysis
Maria Arregui, PhD; Brian Buijsse, PhD; Andreas Fritsche, MD; Romina di Giuseppe, PhD;
Matthias B. Schulze, DrPH; Sabine Westphal, MD; Berend Isermann, MD;
Heiner Boeing, MSPH, PhD; Cornelia Weikert, MD, MPH
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Background and Purpose—The favorable cardiovascular effects attributed to adiponectin may lower risk of stroke. We
investigated this in a prospective study and meta-analysis.
Methods—A case–cohort study nested within the Potsdam cohort of the European Prospective Investigation into Cancer was
performed, with 170 incident cases of ischemic stroke and a randomly selected subcohort of 2155 participants without
major cardiovascular disease at baseline. A random-effects dose–response meta-analysis was performed on prospective
studies reporting on adiponectin and incident stroke in healthy populations up to April 2013, identified through MEDLINE
and EMBASE.
Results—In European Prospective Investigation into Cancer-Potsdam, after adjustment for cardiovascular risk factors, the
hazard ratio of ischemic stroke per 5-µg/mL higher total-adiponectin was 1.10 (95% confidence interval, 0.89–1.37).
Participants with higher total-adiponectin had higher high-density lipoprotein-cholesterol and lower high-sensitivity
C-reactive protein and triglyceride levels, and had less often diabetes mellitus. Additional adjustment for these putative
mediators yielded a hazard ratio of 1.31 (95% confidence interval, 1.04–1.64). Nine studies (19 259 participants, 2960
cases), including European Prospective Investigation into Cancer-Potsdam, were meta-analyzed. Pooling relative risks
adjusted for cardiovascular risk factors not including putative mediators indicated moderate between-study heterogeneity
(I2=52.2%). This was explained by the smallest study, and the pooled relative risk (95% confidence interval) before and
after its exclusion was 1.03 (0.98–1.08) and 0.99 (0.96–1.01) per 5 µg/mL, respectively. The pooled relative risk (95%
confidence interval) additionally adjusted for potential mediators was 1.08 (1.01–1.15) and 1.05 (1.00–1.11) before and
after excluding the same study, respectively.
Conclusions—Adiponectin is not associated with risk of stroke. If anything, adiponectin relates directly to stroke risk after
controlling for risk factors that favorably correlate with adiponectin. (Stroke. 2014;45:00-00.)
Key Words: adiponectin ◼ meta-analysis ◼ myocardial infarction ◼ stroke
A
diponectin is a hormone derived from adipose tissue. Its
levels are usually higher in women than in men and are
downregulated with increasing central adiposity.1 Adiponectin
has been suggested to exert anti-inflammatory, antiatherogenic, and insulin-sensitizing effects,2 to promote high-density
lipoprotein-cholesterol formation,3 to reduce plasma triglyceride levels,4 and it has been inversely associated with carotid
intima-media thickness.5,6 Total-adiponectin circulates in the
blood stream as globular-adiponectin, and as full-length fractions of low-molecular weight, medium-molecular weight,
and high-molecular weight (HMW). HMW adiponectin has
been proposed as the most active fraction for glucose homeostasis,2 whereas the lower weight fractions have been associated with anti-inflammatory effects.7
The favorable cardiovascular effects attributed to adiponectin may lower risk of stroke. We evaluated this in the Potsdam
cohort of the European Prospective Investigation into Cancer
(EPIC). Because of the antiatherogenic properties of adiponectin, we focused on ischemic stroke (IS). To assess the consistency of the association between adiponectin and risk of
stroke in apparently healthy populations, we also performed a
meta-analysis on prospective studies.
Received April 24, 2013; accepted September 25, 2013.
From the Departments of Epidemiology (M.A., B.B., R.d.G., H.B., C.W.) and Molecular Epidemiology (M.B.S.), German Institute of Human Nutrition
(DIfE), Potsdam-Rehbrücke, Nuthetal, Germany; Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry,
Department of Internal Medicine, University of Tübingen, Tübingen, Germany (A.F.); Department for Clinical Chemistry and Pathobiochemistry, Ottovon-Guericke-University Magdeburg, Magdeburg, Germany (S.W., B.I.); and Institute of Social Medicine, Epidemiology, and Health Economics, Charité
University Medical Center, Berlin, Germany (C.W.).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
113.001851/-/DC1.
Correspondence to Maria Arregui, PhD, Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, ArthurScheunert-Allee 114–116, 14558 Nuthetal, Germany. E-mail [email protected]
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.113.001851
1
2 Stroke January 2014
Methods
EPIC-Potsdam Study
Study Population
EPIC-Potsdam study comprises 27 548 individuals from the general
population of the Potsdam area (Germany).8 The association of plasma total-adiponectin with risk of IS was analyzed using a case–cohort design. The study-set included all incident IS cases that occurred
during a mean follow-up of 8.2±2.2 years9 and a random subcohort
(n=2500). When both IS and myocardial infarction (MI) occurred in
the same participant (n=5), we only considered the first event. IS occurred before MI in 2 cases and MI before IS in 2 more. One participant had a stroke and MI on the same day; the MI was prioritized over
stroke. After exclusion of individuals because of prevalent IS or MI,
missing follow-up, or missing adiponectin or covariate information,
the final study population comprised a subcohort of 2155 participants
and 170 IS cases (11 being fatal and 27 belonging to the subcohort).
A total of 605 participants were fasting for ≥8 hours before the blood
draw. Informed consent was obtained from all study participants.
The study was approved by the Ethical Committee of the state of
Brandenburg, Germany.
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Biochemical Analyses
Baseline plasma levels of biomarkers were measured at Tübingen
University (Germany) in samples retrieved from frozen storage
(2007–2008). Adiponectin was determined with an ELISA (Linco
Research, St Charles, MO; intra-assay and interassay coefficients
of variation, 0.1%–6.2% and 5.0%, respectively). High-density
­lipoprotein-cholesterol, triglycerides, high-sensitivity C-reactive protein, and creatinine were determined with the Siemens ADVIA 1650.
N-terminal probrain-type natriuretic peptide was measured in all
­incident IS cases and in a random subsample of 1137 subcohort members (attributable to financial restrictions) at the Institute of Clinical
Chemistry, University of Magdeburg (2012) with an electrochemiluminescence immunoassay on the Immulite analyzer (Siemens AG,
Munich, Germany).
Statistical Analysis
Because women had higher total-adiponectin levels than men, baseline characteristics were cross-sectionally compared across sex-specific total-adiponectin tertiles based on the distribution among the
subcohort, by age-adjusted ANOVA.
Association of total-adiponectin with risk of IS was calculated
as hazard ratios using Cox proportional-hazard regression, modified according to Prentice,10 using a robust estimator to compute the
95% confidence interval. Age was the underlying time metric. HRs
were estimated per 5-µg/mL higher total-adiponectin and according to sex-specific tertiles of total-adiponectin in the subcohort. HRs
were adjusted for sex (M1); further for common cardiovascular risk
factors (waist circumference, smoking, sports activity, education,
alcohol consumption, prevalent hypertension, M2); and further for
fasting status and for metabolic factors that have been suggested to
be intermediate factors11 (diabetes mellitus, high-density lipoprotein-­
cholesterol, triglycerides, and high-sensitivity C-reactive protein, M3).
Effect modification by sex and by age were, respectively, evaluated by modeling the product-term sex times total-adiponectin, and
age times total-adiponectin along with the main effects in the Coxregression. Sensitivity analyses were performed after excluding fatal
IS cases; participants with total-adiponectin below/above the population-wide lower/upper deciles; with prevalent chronic diseases; central obesity; taking antihypertensive, antidiabetic or lipid-lowering
medication; those >60 years; smokers or alcohol consumers. Also the
first 4 years of follow-up were excluded to account for latency.
MI shares the atherosclerotic pathophysiological pathway with IS.
Because we focus on IS here, HRs of MI per 5-µg/mL higher adiponectin are presented in Table I in the online-only Data Supplement.
Identification and verification of incident MI cases have been
­described elsewhere.9 Study design, exclusion criteria, and adjustment models were the same as used for IS.
Meta-analysis of Prospective Studies
Meta-analysis of Observational Studies in Epidemiology guidelines12 were applied (Table II in the online-only Data Supplement).
Two investigators independently searched MEDLINE and
EMBASE for prospective studies performed in healthy populations, with adiponectin as exposure (total or either of its circulating fractions) and stroke (total stroke or IS) as outcome,
published until April 2013. Search terms used in MEDLINE
were (Adiponectin[Mesh] or adiponectin or acrp30 or apm) and
(Cerebrovascular Disorders[Mesh] or stroke or brain infarction)
and (Longitudinal Studies[Mesh] or prospective[Mesh] or prospective or nested or cohort). The equivalent search was constructed for EMBASE. Reference lists of retrieved articles were
hand-searched for additional studies. Data gathered included: first
author, publication year, location, study design, race/ethnicity,
number of participants, proportion of women, duration of followup, age, adiponectin assay, mean adiponectin levels and body mass
index among noncases, number of cases, case ascertainment, variables controlled for and comparison used.
Effect estimates were extracted for the least and most adjusted
models, with and without inclusion of presumed mediators. We contacted authors when data needed for the dose–response meta-analysis
were incompletely reported.13–15 Study-specific dose–response associations were calculated per 5-µg/mL higher adiponectin concentration
by using the generalized least squares for trend estimation method,
to combine comparable estimates with random-effect meta-analysis.
Heterogeneity between-study results was evaluated by using the I2
statistic. Publication bias was investigated by Egger test and by visual
inspection of the funnel plot. An influential analysis was performed
by omitting 1 study at a time. Statistical analyses were performed
using SAS Enterprise Guide 4.3 (SAS Institute Inc, Cary, NC) and
STATA SE version 12.1 (StataCorp, College Station, TX).
Results
EPIC-Potsdam Study
Baseline Characteristics of Participants
Baseline median (interquartile range) total-adiponectin levels
in men and women were 5.6 (4.15–7.36) and 8.6 (6.32–11.40)
µg/mL, respectively. Baseline characteristics of the subcohort
across adiponectin tertiles are shown in Table 1 separately for
men and women. Compared with those in the lower tertiles,
men and women in the highest tertiles were slightly older and
showed better cardiovascular profiles.
Adiponectin and Incident Stroke
Table 2 shows HRs of incident IS per 5-µg/mL higher totaladiponectin, and across sex-specific tertiles of adiponectin.
No significant associations were found after adjustment for
sex and common cardiovascular risk factors. After additional
adjustment for potential mediators, including high-density
lipoprotein-cholesterol, high-sensitivity C-reactive protein,
and diabetes mellitus, adiponectin was directly associated
with IS risk. Adjustment for creatinine, a crude estimate of
renal function, yielded essentially similar HRs. Adjustment
for N-terminal probrain-type natriuretic peptide, a discerning marker for heart damage, only slightly attenuated the
HRs (data not shown). The association between adiponectin and stroke did not differ by sex (P interaction=0.4) or
age (P interaction=0.1) after adjustment for variables in
M2 (Table III in the online-only Data Supplement). HRs
remained similar after exclusion of 11 fatal cases of IS.
Also, none of the other prespecified sensitivity analyses led
to different results.
Arregui et al Adiponectin and Risk of Stroke 3
Table 1. Baseline Characteristics of the EPIC-Potsdam Subcohort by Sex-Specific Adiponectin Tertiles
Men
n
Adiponectin mean (range),
µg/mL
Age, y
Women
Lowest
Middle
Highest
268
268
268
3.5 (1.2–4.5)
5.6 (4.6–6.6)
51.1±0.49
52.3±0.49
P Value*
…
Lowest
Middle
Highest
450
451
450
P Value*
…
9.4 (6.7–26.3)
…
5.3 (0.6–7.1)
8.6 (7.2–10.2)
13.5 (10.3–33.0)
…
53.0±0.49
0.005
47.7±0.44
49.0±0.44
50.0±0.44
<0.001
Education (%)
Vocational school or less
28.9
30.63
31.54
0.32
44.39
38.74
39.67
0.01
Technical school
13.2
16.03
18.19
0.03
29.39
31.68
28.19
0.96
University degree
58.0
53.34
50.27
0.01
26.22
29.58
32.14
0.005
Physical activity <2 h/wk
75.1
75.62
79.54
0.92
78.76
77.12
72.84
0.03
Current ≥20 cigarettes/d
27.9
28.4
31.4
0.90
57.15
58.87
57.41
0.007
Current <20 cigarettes/d
Smoking status, %
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34.2
38.6
34.6
0.86
14.55
17.32
20.53
0.13
Former ≤5 y
9.3
7.2
8.5
0.93
6.47
8.02
6.83
0.95
Former >5 y
16.6
16.8
14.7
0.66
17.11
12.67
13.08
0.005
Never
12.0
9.0
10.7
0.86
4.7
3.1
2.2
0.95
Alcohol intake, %
0 g/d
>0–12 g/d
0
0
0
…
0.0
0.0
0.0
…
39.2
38.0
34.7
0.16
56.1
55.2
48.8
0.003
>12–24 g/d
25.9
27.3
26.7
0.96
23.2
24.4
24.8
0.04
>24 g/d
34.8
34.7
38.6
0.17
20.7
20.4
26.4
0.15
6.4
7.0
3.4
0.13
5.7
2
1.4
0.003
63.3
57.2
52.2
0.001
51.2
38.8
33.6
<0.001
<0.001
Prevalent diabetes
mellitus, %
Prevalent hypertension, %
Use of medication, %
18.8
22.1
17.3
0.57
26.3
14.5
10.9
Lipid-lowering medication
Antihypertensive
6.6
3.3
5.0
0.82
4.9
3.9
2.2
0.10
Antidiabetic
3.6
3.3
2.4
0.33
3.6
0.9
0.4
0.002
Body mass index, kg/m 2
27.33±0.21
26.99±0.21
25.73±0.21
<0.001
27.4±0.20
25.4±0.20
24.4±0.20
<0.001
Waist circum­ference, cm
95.6±0.58
94.8±0.58
91.2±0.58
<0.001
85.3±0.50
80.3±0.49
76.7±0.50
<0.001
HDL-cholesterol, mg/dL
43.4±0.74
45.8±0.74
52.0±0.74
<0.001
50.7±0.62
56.1±0.62
62.1±0.62
<0.001
130.7
(114.1–149.7)
106.5
(93.2–121.8)
88.4
(77.9–100.4)
<0.001
100.2
(91.9–109.2)
83.8
(77.2–90.9)
65.8
(60.8–71.2)
<0.001
Triglycerides, mg/dL†
hs-CRP, mg/L
0.76 (0.65–0.89) 0.63 (0.54–0.74) 0.51 (0.44–0.60)
0.004
1.22 (1.08–1.39) 0.76 (0.67–0.86) 0.60 (0.53–0.68)
<0.001
Creatinine, mg/dL‡
0.89 (0.87–0.91) 0.91 (0.89–0.93) 0.86 (0.85–0.88)
0.10
0.72 (0.71–0.73) 0.72 (0.71–0.73) 0.73 (0.72–0.74)
0.10
NTproBNP, pg/mL§
55.9 (47.9–65.4) 55.0 (47.0–64.4) 66.7 (57.7–77.1)
0.01
68.7 (63.2–74.6) 64.7 (59.7–70.2) 72.1 (66.8–77.9)
0.13
Shown are mean±SE or geometric mean (95% confidence interval), unless otherwise indicated. EPIC indicates European Prospective Investigation into Cancer; HDL,
high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; and NTproBNP, N-terminal probrain-type natriuretic peptide.
*P value based on modeling adiponectin as a continuous variable. All variables other than age are adjusted for age.
†Based on 235 men or 370 women in fasting status.
‡Based on 2112 observations.
§Based on 1137 observations.
Meta-analysis of Prospective Studies
Sixty-four hits from EMBASE and 82 from MEDLINE were
retrieved. After exclusion of duplicates and of articles that
did not meet the inclusion criteria (Figure I in the onlineonly Data Supplement), 9 articles11,13–20 reporting results for
8 independent study populations were eligible for inclusion.
Nine studies,11,13–16,18–20 including EPIC-Potsdam, reported
on total-adiponectin. The Cardiovascular Health Study11
and the Women’s Health Initiative Study17,18 reported also
on HMW-adiponectin, with findings being similar to totaladiponectin. Therefore, our analysis includes risk estimates
of total-adiponectin only. Thus, together with the EPICPotsdam study, ≤9 independent studies were meta-analyzed
(Table 3) in total 19 259 participants and 2960 incident
stroke cases.
Five studies were nested case–control14–18 and 4 were
cohort11,13,19,20 studies. Study populations were from Europe
(predominantly white),13–15,20 Japan,4 and the United States
4 Stroke January 2014
Table 2. Association of Total-Adiponectin With Incident Ischemic Stroke: EPIC-Potsdam Study
Lowest
Middle
170
48
53
69
1.05 (0.85–1.30)
Referent
0.95 (0.63–1.44)
1.18 (0.79–1.76)
Cases (n)
M1*
HR (95% CI) for Sex-Specific Tertiles of Total-Adiponectin
HR (95% CI) per 5-µg/mL
Higher Total-Adiponectin
Highest
M2†
1.10 (0.89–1.37)
Referent
1.01 (0.66–1.55)
1.36 (0.90–2.07)
M3‡
1.31 (1.04–1.64)
Referent
1.20 (0.78–1.86)
1.94 (1.22–3.06)
CI indicates confidence interval; EPIC indicates European Prospective Investigation into Cancer; HR, hazard ratio; and M, model.
*Derived from Prentice-weighted Cox proportional-hazards regression with age as underlying time variable, stratified by age at
baseline, and adjusted for sex.
†As in * and further adjusted for waist circumference, smoking status (never smoker, former smoker, current smoker <20 cigarettes/d,
current smoker ≥20 cigarettes/d), sports activity (<2 and ≥2 h/wk), education (vocational school or less, technical school, university),
alcohol consumption (men: 0, >0–12, >12–24, >24; women: 0, >0–6, >6–12, >12 g/d), prevalent hypertension.
‡As in † and further adjusted for fasting status (yes/no), prevalent diabetes mellitus, high-density lipoprotein-cholesterol, triglycerides,
high-sensitivity C-reactive protein.
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(multiple ethnic groups),11,17–19 and included men,13,15,20
women,17,18 or both.11,14,16,19 Mean age ranged from 4713 to
74.411 and follow-up time from 4.914 to 2713 years. Adiponectin
was measured in serum17 or plasma.11,13–16,18–20 Incident stroke
was ascertained by review of medical records or death certificates in all studies. Relative risks (RR) were provided as odds
ratio14,16–18 or hazard ratios.11,13,15,19,20 Odds ratios were assumed
to reasonably approximate the RR.
Table 3. Characteristics of Prospective Studies Reporting on the Association Between Adiponectin and Incident Stroke in
Healthy Populations
First Author,
Year of
Publication
Study, Country
Study
Design
Mean
Age, Y
No. Participants
(% Women)
Adiponectin
Fraction,
Mean Among
Noncases,
µg/mL
Mean BMI
Among
Noncases,
kg/m2
Mean
Follow-up, Y
Outcome,
No. Cases
828 (43.1)
4.9
TS, 276
Double-antibody
radioimmunoassay
(Linco Res.)
Men: 11.5;
women: 18.2
25.9
Adiponectin Assay
Soderberg,
200414
MONICAVästerbotten
Intervention
Program, Sweden
Nested
case–control
54.9
Matsumoto,
200816
Jichi Medical
School Cohort
Study, Japan
Nested
case–control
66
746–809 (≈49)
9.7
TS, 179;
IS, 116
Solid phase
ELISA (Otsuka
Pharmaceutical
Co Ltd)
Men: 6.73;
women:
10.09
22.6
Khalili, 201013
Malmo Preventive
Project, Sweden
Cohort
47
3512 (0)
27
IS, 373
In-house
time-resolved
immunofluorometric
assay* (Aarhus
Denmark)
5.72
24.8
Rajpathak,
201118
Women’s Health
Initiative, USA
Nested
case–control
68.7
1944 (100)
15–20
IS, 972
Milliplex Human
Adipokine Panel A
27.0
27.0
Prugger,
201215
Prospective
Epidemiological
Study on
Myocardial
Infarction, France
and Ireland
Nested
case–control
55.5
240 (0)
<10
IS, 80
Human CVD
panel-1 multiplex
immunoassay
(Linco Res.)
13.5
26.6
Gardener,
201319
Northern
Manhattan Study,
USA
Cohort
69
2900 (63)
10
TS, 269
Sandwich ELISA
(Mercodia)
11.4
28.0
Kizer, 201311
Cardiovascular
Health Study, USA
Cohort
74.4
3290 (63.0)
10.5
IS, 492
Immunoassay
(Millipore)
12.3
26.8
Wannamethee,
201320
British Regional
Heart Study, UK
Cohort
68.4
3411 (0)
9
TS, 192
ELISA (R&D
Systems)
6.77
26.8
Arregui, 2013,
current study
EPIC-Potsdam,
Germany
Nested
case–cohort
50.1
2325 (62.7)
8.2
IS, 190
ELISA (Linco Res.)
8.03
26.1
BMI indicates body mass index; IS, ischemic stroke; NR, not reported; and TS, total stroke.
*Based on a method using monoclonal antibodies and recombinant human adiponectin.
Arregui et al Adiponectin and Risk of Stroke 5
Studies evaluated adiponectin in quartiles,15–21 quintiles,13
and as a continuous variable, either untransformed11,15,19 or
log-transformed (Table 4).16 Outcomes were total stroke,14,19,20
IS,11,13,15,17,18 or both.16 For 1 study13 that reported RR only for a
subgroup of smokers, we calculated the crude odds ratio from
the reported contingency table including participants. One
study14 provided separate RR for men and women (personal
correspondence), and these were included in the analysis as
separate RR. For another study,11 we used a fixed-effects metaanalysis to combine the RRs corresponding to before and after
the knot of the spline-regression. Before and after adjustment
for potential mediators, adiponectin was significantly related
to stroke risk only in 115 and 3 studies,15,19 including EPICPotsdam, respectively.
The Figure (A) shows the pooled multivariable-adjusted RR
without adjustment for mediators. Initially, we observed moderate heterogeneity across study results (I2=52.2%; P=0.027).
This was mainly driven by the smallest study,15 which after
exclusion reduced the I2 statistic to 3.2% (P=0.41) and yielded
a pooled RR of 0.99 (95% confidence interval, 0.96–1.01)
per 5-µg/mL higher adiponectin. Similar to EPIC-Potsdam,
combining RR additionally adjusted for potential mediators
Table 4. Relative Risks of Stroke According to Adiponectin Levels in Prospective Studies Performed in Healthy Populations
Study, Year
Soderberg, 200414
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Matsumoto, 200816
Outcome, Relative Risk
(95% CI)
Comparison, µg/mL
Model
Top vs bottom quartile;
men: ≥17.3 vs <8.3;
women: ≥27.6 vs
<14.5
M1
TS, men: 0.89 (0.50–1.60),
women: 0.77 (0.41–1.44)
Sex, age, date/type of health survey, region
M2
TS, men: 1.04 (0.56–1.94),
women: 0.82 (0.43–1.55)
M1+BMI, smoking, hypertension
M3
TS, men: 1.08 (0.56–2.08),
women: 0.85 (0.44–1.63)
M2+cholesterol, diabetes mellitus
M1
TS: 0.67 (0.40–1.11); IS: 0.49
(0.26–0.92)
Age, sex, community
M2
TS: 0.87 (0.49–1.54); IS: 0.63
(0.30–1.28)
M1+HDL-cholesterol, triglycerides, BMI, current smoking, SBP, hs-CRP
Top vs bottom quartile;
<5.6 vs ≥12.4
Controlled Variables
Khalili, 201013
Top (median, 16.57) vs
bottom (median, 2.37)
quintile
…
IS, 0.98 (0.65–1.47)
Unadjusted
Rajpathak, 201118
Top (median, 46.0) vs
bottom (median, 14.8)
quartile
M1
IS, 0.77 (0.59–1.01)
Age, race/ethnicity, date of study enrollment, follow-up time
M2
IS, 0.81 (0.61–1.08)
M1+BMI
M3
IS, 1.16 (0.82–1.63)
M2+current smoking, physical activity, nonsteroidal anti-inflammatory
drug use, hypertension medication use, SBP, history of coronary and
artery diseases, HDL-cholesterol, triglycerides, diabetes mellitus, WC
M1
IS, 2.05 (1.38–3.05)
Age, study center, date of examination
M2
IS, 1.99 (1.29–3.07)
M1+SBP, antihypertensive treatment, smoking, alcohol drinking
M3
IS, 2.18 (1.37–3.48)
M2+total-cholesterol, HDL-cholesterol, WC, diabetes mellitus, hs-CRP
M1
TS: 1.14 (0.79–1.61)
Age, sex, race/ethnicity
M2
TS: 1.47 (0.96–2.22)
M1+smoking, hypertension, diabetes mellitus, LDL-cholesterol, HDLcholesterol, triglycerides, WC, moderate alcohol use, moderate-heavy
physical activity, previous cardiac disease history
M3
TS: 1.64 (1.01–2.63)*
M2+hs-CRP
M1
IS, <20 µg/mL: 0.97
(0.82–1.15), ≥20 µg/mL: 1.14
(0.97–1.36)
Age, sex, race
M2
IS, <20 µg/mL: 0.91
(0.76–1.09), ≥20 µg/mL: 1.13
(0.95–1.34)
M1+BMI, income, education, center, smoking status, alcohol use, SBP,
antihypertensive medication, estrogen replacement therapy, eGFR,
aspirin use, health status, albumin
M3
IS, <20 µg/mL: 1.07
(0.88–1.30), ≥20 µg/mL: 1.15
(0.96–1.37)
M2+subclinical CVD, pre/diabetes mellitus, LDL-cholesterol, HDLcholesterol, triglycerides, hs-CRP
M1
TS: 0.74 (0.49–1.12)
Age, BMI
M2
TS: 0.73 (0.48–1.10)
M1+diabetes mellitus, angina, atrial fibrillation, smoking, social
class, alcohol intake, physical activity, lung function, SBP, use of
antihypertensive drugs
Prugger, 201215
Gardener, 201319
Kizer, 2013
11
Wannamethee,
201320
Per SD-increase (11.6
µg/mL)
Top (median, 33.6) vs
bottom (median, 4.6)
quartile
Per SD (7.9) increase
Top vs bottom quartile;
≥10.8 vs <4.3
BMI indicates body mass index; CI, confidence interval; CVD, cardiovascular diseases; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; HMW,
high-molecular weight; hs-CRP, high-sensitivity C-reactive protein; IS, ischemic stroke; LDL, low-density lipoprotein; M, model; SBP, systolic blood pressure; TS, total
stroke; and WC, waist circumference.
*Based on 2091 participants.
6 Stroke January 2014
A
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Study
RR (95% CI)
Söderberg, 2004 (men)
1.02 (0.88, 1.18)
Söderberg, 2004 (women)
0.96 (0.87, 1.06)
Matsumoto, 2008
1.02 (0.77, 1.36)
Khalili, 2010
1.04 (0.95, 1.13)
Rajpathak, 2011
0.97 (0.94, 0.99)
Prugger, 2012
1.35 (1.12, 1.62)
Gardener, 2013
1.05 (0.95, 1.16)
Kizer, 2013
1.01 (0.94, 1.09)
Wannamethee, 2013
1.09 (0.93, 1.27)
Arregui 2013, current study
1.10 (0.89, 1.36)
Overall (I−squared = 52.2%, p = 0.027)
1.03 (0.98, 1.08)
.75
1
Lower risk
B
1.25
1.5
2
Higher risk
Study
RR (95% CI)
Söderberg, 2004 (men)
1.03 (0.89, 1.21)
Söderberg, 2004 (women)
0.97 (0.88, 1.07)
Matsumoto, 2008
0.95 (0.69, 1.31)
Rajpathak, 2011
1.01 (0.97, 1.04)
Prugger, 2012
1.40 (1.14, 1.71)
Gardener, 2013
1.16 (1.03, 1.31)
Kizer, 2013
1.07 (0.98, 1.16)
Wannamethee, 2013
1.10 (0.94, 1.28)
Arregui 2013, current study
1.31 (1.04, 1.65)
Overall (I−squared = 63.1%, p = 0.006)
1.08 (1.01, 1.15)
.75
Lower risk
1
1.25
1.5
2
Higher risk
Figure. Most completely adjusted relative risks (RRs) of stroke per 5-μg/mL higher circulating adiponectin in individual studies and combined across studies in dose–response random-effects meta-analysis before (A) and after (B) adjustment for potential
intermediate factors.
Arregui et al Adiponectin and Risk of Stroke 7
available for 8 independent studies (Figure [B]) yielded a
direct association between adiponectin and stroke (RR, 1.08;
95% confidence interval, 1.01–1.15) per 5-µg/mL higher adiponectin. However, also here we observed moderate betweenstudy hetereogeneity (I2=63.1%; P=0.006). After omitting the
smallest study, the I2 became 45.1% (P=0.08) and the pooled
RR 1.05 (95% confidence interval, 1.00–1.11). The lack of
symmetry of the funnel plot as well as Egger test (P<0.05)
suggested lack of smaller studies reporting an inverse association between adiponectin and stroke.
Discussion
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
In EPIC-Potsdam, higher levels of total-adiponectin were
associated with better metabolic profiles. In contrast, totaladiponectin tended to be positively associated with IS risk.
Interestingly, this association became stronger and significant
after controlling for metabolic markers that have been suggested to be intermediates. Although (putative) overadjustment may have produced spurious results, unknown pathways
underlying the increased risk cannot be excluded. Results of
our meta-analysis based on 9 independent prospective studies
extend those from 2 recent meta-analyses on the relationship
between adiponectin and stroke, which included only 222 and
3 studies.23 Our meta-analysis indicated lack of association
between adiponectin and stroke risk. If anything, adiponectin
was directly related to stroke risk after controlling for metabolic factors that favorably correlate with adiponectin.
A trend toward increased risk of coronary heart disease11
and cardiovascular death21,24 associated with higher adiponectin despite better metabolic profiles has also previously been
observed in studies in older populations. One possible explanation is that the progression of cardiovascular diseases may
lead to adiponectin resistance.25 In the EPIC-Potsdam study,
we excluded participants with a clinical history of major cardiovascular disease events at baseline. We also lagged the
statistical analysis by 4 years to account for latency, which
did not alter our results. It has also been suggested that the
presence of diseases prompting to a hypercatabolic state may
induce compensatory increased adiponectin levels.26 Our findings, however, did not substantially change after excluding
prevalent cases of several chronic diseases or controlling for
creatinine, and adjusting for N-terminal probrain-type natriuretic peptide only slightly attenuated the risk estimates.
Also, the better metabolic profiles associated with higher
total-adiponectin would argue against these explanations. We
focused on total-adiponectin and not on HMW-adiponectin,
which is thought to be the most biologically active form.27
Nevertheless, total and HMW-adiponectin have shown to be
highly correlated,11 and recent findings do not support HMWadiponectin to be more strongly related to risk of stroke11 or
coronary heart disease.28 Adiponectin levels increase with age,
and this could be a critical factor in assessing the associations
between adiponectin and cardiovascular end points. However,
age did not modify the association between adiponectin and
incident stroke in our study population, which age was mostly
between 35 and 65 years. Finally, it has been suggested that
very high levels of adiponectin could have harmful effects by
means of the activation of complement mechanisms.29
Limitations of our prospective study include that a single
assessment of adiponectin may be susceptible to within-individual variation. Adiponectin concentrations, however, have
shown to be quite stable over time.30 Furthermore, only a third
of the study population was in fasting status. However, adiponectin values did not differ according to fasting status, and
adjusting for it did not affect our risk estimates.
The meta-analysis included studies that differed in population characteristics, methods, variables controlled for, and outcomes considered (total stroke/IS). However, we did not find
that these factors influenced results across studies. Although
we observed a potential risk for publication bias, it may be
unnecessary to evaluate the existence of preferential publication when very few studies reported significant results.31
Summary
This prospective study and meta-analysis shows that circulating
total-adiponectin does not relate to risk of stroke. If anything,
adiponectin relates directly to stroke risk after controlling for
metabolic factors that correlate favorably with adiponectin.
The number of studies on HMW-adiponectin is limited, and no
studies on other adiponectin fractions are available. Therefore,
it remains unclear whether specific molecular-weight fractions
of adiponectin may influence risk of stroke.
Acknowledgments
We are grateful to W. Fleischhauer for case ascertainment; E.
Kohlsdorf for data management; A. Bury, S. Herbert, and E. Eiden
for biochemical analyses; and to Drs Söderberg (Umeå University
Hospital, Sweden) and Prugger (Paris Cardiovascular Research
Centre, University of Paris Descartes, France) for kindly providing
additional data for the meta-analysis.
Sources of Funding
This study was supported by German Federal Ministry of Education;
German Federal Ministry of Science (01 EA 9401); European Union
(SOC 95201408 05F02 and SOC 98200769 05F02); and German
Cancer Aid (70-2488-Ha I).
Disclosures
None.
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Adiponectin and Risk of Stroke: Prospective Study and Meta-analysis
Maria Arregui, Brian Buijsse, Andreas Fritsche, Romina di Giuseppe, Matthias B. Schulze,
Sabine Westphal, Berend Isermann, Heiner Boeing and Cornelia Weikert
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Stroke. published online November 7, 2013;
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
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Data Supplement (unedited) at:
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ONLINE DATA SUPPLEMENT
Supplementary table I. Association of circulating total-adiponectin with incident myocardial
infarction: the EPIC-Potsdam Study
MI cases (n)
Model 1*
Model 2 †
Model 3 ‡
HR (95% CI) per 5-µg/ml
higher total-adiponectin
237
1.09 (0.85-1.39)
1.27 (1.02-1.60)
1.54 (1.24-1.90)
Abbreviations: CI, confidence interval; HR: hazard ratio, MI myocardial infarction. * Model 1: Derived from
Prentice-weighted Cox proportional-hazards regression models, with age as underlying time variable, stratified by
age at baseline. † Model 2: as model 1 with further adjustments for waist circumference, smoking status (never
smoker, former smoker, current smoker <20 cigarettes per day, current smoker ≥20 cigarettes per day), sports
activity (<2 h/week, ≥2 h/week), education (vocational school or less, technical school, university), alcohol
consumption (men: 0, >0-12, >12-24, >24; women: 0, >0-6, >6-12, >12 g/day), and prevalent hypertension. ‡ Model
3: As model 2 with further adjustments for fasting status (yes/no), prevalent diabetes, HDL-cholesterol, triglycerides,
and hs-CRP.
1
Supplementary table II. MOOSE Checklist
Reported on
section (page)
Comments
Reporting of background
A meta-analysis was conducted to asses the consistency of the
association between adiponectin and risk of stroke in apparently
healthy populations
Problem
definition
Introduction (2)
Hypothesis
statement
Introduction (2)
The favourable cardiovascular effects attributed to adiponectin,
could have a beneficial impact on the risk to develop stroke
Description of
study outcomes
Introduction (2)
Risk to develop stroke
Type of
exposure
Introduction (2)
Total-adiponectin
Type of study
designs used
Introduction (2)
Prospective studies
Study
population
Introduction (2)
Apparently healthy populations
Qualifications
of searchers
MethodsSystematicreview and metaanalysis (5)
Two independent investigators
MethodsSystematicreview and metaanalysis (5)
Prospective studies conducted in healthy populations, with
adiponectin as exposure (total or either of its circulating fractions)
and stroke (total or ischemic) as outcome, published until April
2013.
Search terms used in MEDLINE were: (Adiponectin[Mesh] OR
adiponectin OR acrp30 OR apm) AND (“Cerebrovascular
Disorders”[Mesh] OR stroke OR 'brain infarction') AND
("Longitudinal Studies"[Mesh] OR prospective[Mesh] OR
prospective OR nested OR cohort), The equivalent search was
constructed for EMBASE:
'adiponectin'/syn OR 'acrp30'/syn OR 'apm'/syn AND ('stroke'/syn
OR 'brain infarction'/syn OR 'cerebrovascular') AND (prospective
OR longitudinal OR nested OR cohort) AND [humans]/lim AND
[embase]/lim
Reporting of search strategy
Search strategy,
including time
period used in
the synthesis
and key words
Effort to include
all available
studies
Databases and
registries
searched
Search software
used
Use of hand
searching
List of citations
located and
MethodsSystematicreview and metaanalysis (5)
MethodsSystematicreview and metaanalysis (5)
MethodsSystematicreview and metaanalysis (5)
MethodsSystematicreview and metaanalysis (5)
Supplementary
figure I
In case of missing important information, authors were contacted
MEDLINE and EMBASE databases
MEDLINE and EMBASE databases were searched by means of
their available on-line Web-based interfaces
Reference lists of retrieved papers were hand-searched for
additional studies
Records identified through database searching: 146 (MEDLINE:
n = 64; EMBASE: n = 82)
2
those excluded,
including
justification
˗
˗
˗
˗
˗
˗
˗
˗
Method of
addressing
articles
published in
languages other
than English
No language restrictions were applied, however no relevant
studies in languages other than English were retrieved
Method of
handling
abstracts and
unpublished
studies
Description of
any contact with
authors
Duplicates excluded: n = 42
Was not a prospective study: n = 1
Adiponectin was not the exposure: n = 43
Stroke was not the outcome: n = 24
Participants had already suffered a stroke: n = 6
Not healthy populations: n = 17
Review or meta-analysis: n = 4
Duplicity of study-population: n = 1
No limits on type of publication or publication status were applied
MethodsSystematicreview and metaanalysis (5)
Authors of three studies were approached twice in written form to
inquire additional information regarding risk estimates
Reporting of methods
Description of
relevance or
appropriateness
of studies
MethodsSystematicreview and metaanalysis (5)
Only prospective studies conducted in healthy populations, with
adiponectin as exposure (total or either of its circulating fractions)
and incident stroke (total or ischemic) as outcome, published until
April 2013 were included
Rationale for
the selection
and coding of
data
MethodsSystematicreview and metaanalysis (5)
Data extracted were relevant to the population characteristics,
study design, exposure and outcome.
Data gathered included: first author, publication year, location,
study-design, race/ethnicity, number of participants, proportion of
women, duration of follow-up, age, adiponectin assay, mean
adiponectin levels and BMI among non-cases, number of cases,
case ascertainment, variables controlled for and comparison used.
Effect estimates were extracted for the least, and most (where
possible two models: with and without inclusion of presumed
mediators) completely adjusting models
Documentation
of how data
were classified
and coded
MethodsSystematicreview and metaanalysis (4)
Assessment of
confounding
MethodsSystematicreview and metaanalysis (5)
Assessment of
study quality
MethodsSystematicreview and metaanalysis (5)
Two investigators independently searched MEDLINE and
EMBASE databases for relevant studies, and extracted the
necessary data from them to fill in a standardized table of
characteristics in a spreadsheet
From each study information regarding possible sources of
confounding, such as study-design, race/ethnicity, proportion of
women, duration of follow-up, age, assay used to asses
adiponectin, mean adiponectin levels and BMI among non-cases,
number of cases, case ascertainment, variables controlled for and
comparison used was extracted. Also, effect estimates were
extracted for the least, and most (where possible two models: with
and without inclusion of presumed mediators: HDL, hs-CRP,
triglycerides, diabetes) completely adjusting models
The influence of each study on the pooled estimate and I2 was
assessed by omitting 1 study at a time
3
Assessment of
heterogeneity
MethodsSystematicreview and metaanalysis (5)
Description of
statistical
methods in
sufficient detail
to be replicated
MethodsSystematicreview and metaanalysis (5)
Provision of
appropriate
tables and
graphics
Tables 3-4
Figure 1
Heterogeneity between studies was evaluated by using the I2
statistic
Study-specific dose-response associations were calculated per 5µg/ml higher adiponectin concentration by means of the
generalized least squares for trend estimation method, to allow for
the combination of comparable estimates with random-effect
meta-analysis. Heterogeneity between studies was evaluated by
using the I2 statistics. Publication bias was investigated by
Egger’s test besides funnel plot’s visual inspection. The influence
of each study on the pooled estimate and on I2 was assessed by
omitting 1 study at a time
Table 3. Characteristics of prospective studies investigating the
association of adiponectin and incident stroke in apparently
healthy populations
Table 4. Relative Risks of stroke according to adiponectin levels
in prospective studies conducted in healthy populations
Figure 1. Relative risks and 95% confidence intervals of stroke
per 5-µg/mL-increase of adiponectin across studies. RR for most
adjusted models before (A) and after (B) potential intermediates
Reporting of results
Graphic
summarizing
individual study
estimates and
overall estimate
Figure 1
Table giving
descriptive
information for
each study
included
Table 3
Results of
sensitivity
testing
Indication of
statistical
uncertainty of
findings
ResultsSystematicreview and metaanalysis (7-8)
Figure 1
ResultsSystematicreview and metaanalysis
Figure 1
Figure 1. Relative risks and 95% confidence intervals of stroke
per 5 µg/mL-increase of adiponectin across studies. RR for most
adjusted models without (A) and with (B) potential intermediates
Table 3. Characteristics of prospective studies investigating the
association of adiponectin and incident stroke in apparently
healthy populations
Sensitivity analysis revealed that the high heterogeneity observed
was mainly driven by the smallest study.
95% confidence intervals were presented with all summary
estimates
Reporting of discussion
Quantitative
assessment of
bias
ResultsSystematicreview and metaanalysis (8)
Justification for
exclusion
Supplementary
figure I
Assessment of
Results-
The asymmetry of the funnel plot and Egger's test results
(P<0.05) suggested lack of smaller studies reporting an an inverse
association between adiponectin and stroke.
Duplicates excluded: n = 42
Was not a prospective study: n = 1
Adiponectin was not the exposure: n = 43
Stroke was not the outcome: n = 24
Participants had already suffer a stroke: n = 6
Not healthy populations: n = 17
Review or meta-analysis: n = 4
Articles excluded due to duplicity of study population: n = 1
We discussed the potential reasons for the observed
4
quality of
included studies
Systematicreview and metaanalysis (7)
Consideration
of alternative
explanations for
observed results
Summary (9)
Generalization
of the
conclusions
Summary (10)
Guidelines for
future research
Summary (9)
Disclosure of
funding source
Sources of
funding (10)
heterogeneity. There was strong diversity among studies in terms
of populations, methodology, variables controlled for and
outcomes considered, however it did not seem to strongly
influence results across studies, as they were mostly quite
consistent. Sensitivity analysis revealed that the high
heterogeneity observed was mainly driven by the smallest study
Reporting of conclusions
There was large diversity among studies in terms of populations,
methodology, variables controlled for and outcomes considered
(TS/IS). Although we did not find that these factors influenced
results across studies, this may be better investigated in a future
larger meta-analysis.
Current evidence does not support a relationship between total
adiponectin and risk of stroke. The number of studies on HMWadiponectin and no studies reported on other adiponectin
fractions. Therefore, it remains unclear whether specific
molecular-weight fractions of adiponectin may influence risk of
stroke.
More studies on specific molecular weight fractions of
adiponectin may shed further light on the role of adiponectin and
risk of stroke.
German Federal Ministry of Education; German Federal Ministry
of Science (01 EA 9401); European Union (SOC 95201408
05F02 and SOC 98200769 05F02). German Cancer Aid (702488-Ha I).
5
Supplementary table III. Association of circulating total-adiponectin with incident ischemic
stroke: the EPIC-Potsdam study. Analysis stratified by sex and by age using 60y as cut-point.
Sex strata
Cases/non-cases (n)
Model 1*
Model 2†
Model 3‡
Age strata
Cases/non-cases (n)
Model 1*
Model 2†
Model 3‡
HR (95% CI) 5-µg/ml-increase in total-adiponectin
Men
Women
90/786
80/1342
0.97 (0.69-1.37)
1.09 (0.85-1.40)
0.93 (0.66-1.31)
1.17 (0.92-1.50)
1.15 (0.76-1.73)
1.30 (1.02-1.67)
Age≤60 y
97/1753
1.08 (0.81-1.44)
1.18 (0.89-1.56)
1.23 (0.92-1.66)
Age>60 y
73/375
1.02 (0.75-1.38)
1.00 (0.74-1.36)
1.36 (0.94-1.96)
Abbreviations: CI, confidence interval; HR, hazard ratio. * Model 1: Derived from Prentice-weighted Cox
proportional-hazards regression models, with age as underlying time variable and stratified by age at baseline. †
Model 2: As model 1 with further adjustments for waist circumference, smoking status (never smoker, former
smoker, current smoker <20 cigarettes per day, current smoker ≥20 cigarettes per day), sports activity (<2 h/week, ≥2
h/week), education (vocational school or less, technical school, university), alcohol consumption (men: 0, >0-12,
>12-24, >24; women: 0, >0-6, >6-12, >12 g/day), and prevalent hypertension. ‡ Model 3: As model 2 with further
adjustments for fasting status (yes/no), prevalent diabetes, HDL-cholesterol, triglycerides, and hs-CRP.
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Supplementary figure I. Flow diagram of the selection of studies in the meta-analysis
Records identified through
database searching: n = 146
• MEDLINE: n = 64
• EMBASE: n = 82
Duplicates excluded: n = 42
Records after exclusion of
duplicates: n = 104
Full-text articles assessed for
eligibility: n = 9
Records excluded: n = 95
• Was not a prospective study: n = 1
• Adiponectin was not the exposure: n = 43
• Stroke was not the outcome: n = 24
• Participants had already suffered a stroke: n = 6
• Not healthy populations: n = 17
• Review or meta-analysis: n = 4
Studies included in qualitative
synthesis: n = 9
Excluded due to duplicity of study
population: n = 1
EPIC-Potsdam study
Studies included in metaanalysis including
EPIC-Potsdam: n = 9
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