Original Article

Linked to: P. Stenvinkel and P. G. Shiels J Intern Med 2021; https://doi.org/10.1111/joim.13363 doi: 10.1111/joim.13355

Association of the metabolic syndrome with mortality

and major adverse cardiac events: A large chronic
kidney disease cohort
Lorenz M. Pammer1 , Claudia Lamina1 , Ulla T. Schultheiss2,3 , Fruzsina Kotsis2,3 , Barbara Kollerits1 ,
Helena Stockmann4 , Jan Lipovsek2 , Heike Meiselbach5 , Martin Busch6 , Kai-Uwe Eckardt4,5 ,
Florian Kronenberg1 & for the GCKD Investigators1
From the 1 Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck,
Austria; 2 Faculty of Medicine and Medical Center, Institute of Genetic Epidemiology, University of Freiburg, Freiburg, Germany;
3
Department of Medicine IV–Nephrology and Primary Care, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg,
Germany; 4 Department of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, Berlin, Germany; 5 Department of
Nephrology and Hypertension, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany; and 6 Department of Internal
Medicine III, Friedrich Schiller University Jena, Jena, Germany

Abstract. Pammer LM, Lamina C, Schultheiss UT, higher risk for all-cause mortality (hazard ratio
Kotsis F, Kollerits B et al. Association of the [HR] = 1.26, 95% confidence interval [CI]: 1.04–
metabolic syndrome with mortality and major 1.54) and cardiovascular events (HR = 1.48,
adverse cardiac events: A large chronic kidney dis- 95% CI: 1.22–1.79). The risk increased steadily
ease cohort. J Intern Med. 2021; 290: 1219–1232. with a growing number of metabolic syndrome
components (increased waist circumference, glu-
Background. Metabolic syndrome with its key com- cose, triglycerides, hypertension and decreased
ponents insulin resistance, central obesity, dyslipi- HDL cholesterol): HR per component = 1.09 (95%
daemia, and hypertension is associated with a high CI: 1.02–1.17) for all-cause mortality and 1.23
risk for cardiovascular events and all-cause mor- (95% CI: 1.15–1.32) for cardiovascular events. This
tality in the general population. However, evidence resulted in hazard ratios between 1.50 and 2.50 in
that these findings apply to patients with chronic the case when four or five components are present.
kidney disease (CKD) with moderately reduced esti- An analysis of individual components of metabolic
mated glomerular filtration rate and/or albumin- syndrome showed that the glucose component led
uria is limited. to the highest increase in risk for all-cause mortal-
ity (HR = 1.68, 95% CI: 1.38–2.03) and cardiovas-
Objectives. We aimed to investigate the association cular events (HR = 1.81, 95% CI: 1.51–2.18), fol-
between metabolic syndrome and its components lowed by the HDL cholesterol and triglyceride com-
with all-cause mortality and cardiovascular out- ponents.
comes in CKD patients.
Conclusions. We observed a high prevalence of
Methods. Prospective observation of a cohort of 5110 metabolic syndrome among patients with moder-
CKD patients from the German Chronic Kidney ate CKD. Metabolic syndrome increases the risk for
Disease study with 3284 (64.3%) of them having all-cause mortality and cardiovascular events. The
a metabolic syndrome at baseline. glucose and lipid components seem to be the main
drivers for the association with outcomes.
Results. During the follow-up of 6.5 years, 605
patients died and 650 patients experienced major Keywords: cardiovascular disease, chronic kidney
cardiovascular events. After extended data adjust- disease, metabolic syndrome, mortality, prospec-
ment, patients with a metabolic syndrome had a tive cohort study

© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. 1219
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
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Association of the metabolic syndrome / L. M. Pammer et al.

Introduction and 2012. Design and details of the study have

been published previously [10–12] and an extended
Both metabolic syndrome [1] and chronic kid-
description is given in the Supporting Informa-
ney disease (CKD) [2–4] are associated with an
tion (extended methods description). Briefly, the
increased risk for cardiovascular disease. Although
study aimed to enroll patients with an eGFR 30–
both conditions are common, only limited data are
60 ml/min/1.73 m2 (KDIGO stage G3, A1–3) or an
available on the association of metabolic syndrome
eGFR >60 ml/min/1.73 m2 in the presence of overt
with all-cause mortality and cardiovascular dis-
proteinuria (KDIGO stage G1–2, A3) under regular
ease in patients with CKD with moderately reduced
care by nephrologists. The study was approved by
estimated glomerular filtration rate (eGFR) and/or
the ethics committees of all participating institu-
albuminuria. In fact, whether metabolic syn-
tions and registered in the national registry for clin-
drome adds further to cardiovascular risk beyond
ical studies (DRKS 00003971). All methods were
the risks associated with CKD is controversial
carried out in accordance with approved guidelines
[5].
and the Declaration of Helsinki. Written informed
consent was obtained from each study participant.
In particular, studies on metabolic syndrome
and mortality in CKD patients with moderately Data are collected and managed using Askimed
reduced eGFR and/or albuminuria are scarce. (https://www.askimed.com) as a cloud-based web
platform.
Navaneethan et al. analysed data from a large elec-
tronic health record-based CKD registry and did
Patients are followed on a yearly basis by trained
not find metabolic syndrome to be associated with
and certified personnel who collected data on hos-
all-cause mortality during a relatively short obser-
pitalizations, outcome events and medical his-
vation period of 2.3 years [6]. Other studies were
tory using a structured interview. Any hos-
either small, examined individual metabolic syn-
pital discharge reports are collected from the
drome components and/or investigated a compos-
treating physicians and/or hospitals. Endpoints
ite endpoint which included progression of CKD,
are continually adjudicated from these reports
end-stage kidney disease and death [7, 8]. Surpris-
by an endpoint committee of trained medical
ingly, no large studies are available which prospec-
doctors.
tively investigated the association of metabolic syn-
drome with cardiovascular outcomes in patients
with moderately severe CKD.

Importantly, some risk factors behave differently in Definition of metabolic syndrome

patients with and without CKD and may even have
an opposite impact in CKD patients compared to The five metabolic syndrome components are
the general population. Due to this “reverse epi- defined as binary variables [13]: (1) waist circum-
demiology”, extrapolations from the general popu- ference ≥102 cm in men and ≥88 cm in women,
lation to patients with CKD need to be conducted (2) fasting triglycerides ≥150 mg/dl (1.69 mmol/L)
with great caution [9]. Given the increasing impor- or ≥175 mg/dl (1.98 mmol/L) for non-fasting
tance of the metabolic syndrome for public health, patients and/or drug treatment for elevated triglyc-
we, therefore, aimed to investigate the associations erides, (3) serum HDL cholesterol <40 mg/dl (1.03
of the metabolic syndrome and its components mmol/L) in males and <50 mg/dl (1.29 mmol/L)
with all-cause mortality and cardiovascular events in females and/or drug treatment for reduced HDL
in a large and well-defined cohort of patients with cholesterol, (4) systolic blood pressure ≥130 mm
moderately reduced eGFR and/or increased albu- Hg and/or diastolic blood pressure ≥85 mm Hg
minuria. and/or antihypertensive drug treatment, (5) fast-
ing glucose ≥100 mg/dl (5.55 mmol/L) or glyco-
sylated haemoglobin HbA1c > 42 mmol/mol (6%)
Methods and/or drug treatment for elevated glucose. The
presence of at least three out of these five com-
German Chronic Kidney Disease study
ponents constitutes a diagnosis of metabolic syn-
The German Chronic Kidney Disease (GCKD) drome. As study participants were not necessar-
study is a prospective cohort study with ongoing ily fasting at the time of blood collection, we set
follow-up investigations including 5217 Caucasian the threshold for the triglyceride component at 175
patients with CKD enrolled between the years 2010 mg/dl [14].

1220 © 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Journal of Internal Medicine, 2021, 290; 1219–1232
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Association of the metabolic syndrome / L. M. Pammer et al.

Definition of clinical endpoints ent causes of death. For cause-specific endpoints,

patients were censored when the death occurred
The endpoints considered in the present analysis
by any other cause. In addition, associations
refer to the first 6.5 years of follow-up. Censor-
with these cause-specific endpoints were examined
ing was performed either at death or the study’s
using competing-risks survival regression, consid-
end. All-cause mortality was defined as the pri-
ering all deaths from other causes as compet-
mary endpoint. Specific causes of death and major
ing events. Therefore, both cause-specific hazard
cardiovascular events were considered secondary
ratios (HRs) and subdivision HRs are reported.
endpoints. Death from cardiovascular causes com-
For competing risk analyses, identical adjustments
prised myocardial infarction, coronary heart dis-
were used.
ease, sudden cardiac death, congestive heart fail-
ure, pulmonary embolism, cardiac valve disease
Data were analyzed using R 4.0.2 (https://www.
and ischaemic stroke. Major adverse cardiovascu-
r-project.org). Details on the various packages are
lar events (MACE) were either defined as 3-point
provided in the Supporting Information. Statistical
MACE including death from cardiovascular causes,
significance was set at α = 0.05.
such as myocardial infarction, coronary heart dis-
ease, sudden cardiac death and ischaemic stroke
as well as acute non-fatal myocardial infarction Results
(STEMI and NSTEMI), non-fatal stroke, or as 4- Baseline characteristics of the study population
point MACE additionally including fatal peripheral
ischaemia, amputation due to peripheral vascu- Table 1 shows the baseline characteristics of the
lar disease and surgical or percutaneous revascu- 5110 patients available for analysis. The most
larization due to peripheral vascular disease. The prevalent metabolic syndrome component was the
prospectively collected endpoints considered in the blood pressure component defined as systolic
present analysis refer to the first 6.5 years of follow- blood pressure ≥130 mm Hg and/or diastolic blood
up, data export 9 March 2020. pressure ≥85 mm Hg and/or antihypertensive
drug treatment in 97.8% of the patients. This was
Statistical methods followed by the waist circumference component
defined as waist circumference ≥102 cm in men
Mean ± SD for all variables was calculated. For and ≥88 cm in women in 67.6% of the patients.
variables with a skewed or non-normal distribu- The glucose component defined as fasting glucose
tion, median, 25th and 75th percentile were pro- ≥100 mg/dl or glycosylated haemoglobin HbA1c >
vided additionally. Group differences were tested 6% and/or drug treatment for elevated glucose was
using Kruskal–Wallis tests for continuous vari- present in 51.3% of the patients. Elevated fasting
ables and Pearson’s chi-square test for categorical triglycerides ≥150 mg/dl or ≥175 mg/dl for non-
variables. Kaplan–Meier curves were constructed fasting patients and/or drug treatment for elevated
to check for differences in survival, testing for sig- triglycerides were present in 49.6% of the patients
nificance with log-rank tests. We performed the fol- and decreased HDL cholesterol <40 mg/dl in males
lowing three main time to first event Cox models: and <50 mg/dl in females and/or drug treatment
model 1 adjusted for age and sex, model 2 addi- for reduced HDL cholesterol were present in 36.3%.
tionally for eGFR and urine albumin–creatinine At least three components had to be present to ful-
ratio (UACR) and model 3 additionally for prevalent fil the definition of a metabolic syndrome which
CVD, smoking status and LDL cholesterol. Model was the case in 3284 (64.3%) of all patients. When
4 was performed as sensitivity analysis including we compared patients with and without metabolic
high-sensitivity C-reactive protein (hs-CRP) as the syndrome, we observed notable differences in age,
further variable. sex, BMI, lipids, HbA1c, hs-CRP and the prevalence
of diabetes and prevalent CVD (Table 1).
Variables with a skewed or non-normal distri-
bution were transformed using natural logarithm
Observed endpoints during prospective follow-up
(LDL cholesterol, UACR, hs-CRP). Proportional
hazard assumptions were tested using Schoenfeld During a follow-up of up to 6.5 years, 605 deaths
residuals and fulfilled. To account for competing (11.8% of the 5110 patients) were recorded and 473
risks cumulative incidence curves and competing patients experienced a 3-point MACE defined as
risk models were calculated for the endpoints (3- a composite of death from cardiovascular causes
point MACE and 4-point MACE) and the differ- including myocardial infarction, coronary heart

© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. 1221
Journal of Internal Medicine, 2021, 290; 1219–1232
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Association of the metabolic syndrome / L. M. Pammer et al.

Table 1. Baseline characteristics of 5110 patients available for analysis by the presence or absence of metabolic syndrome
No metabolic Metabolic
Total syndrome syndrome
(N = 5110) (N = 1826) (N = 3284) p-Value
Age, years 60.1 ± 12.0 56.0 ± 13.6 62.3 ± 10.2 <0.001
Sex (female) 2050 (40.1%) 834 (45.6%) 1216 (37.0%) <0.001
Body mass index (BMI; 29.8 ± 6.0 26.1 ± 4.5 32.0 ± 5.7 <0.001
kg/m2 )
Waist circumference (cm) 103.6 ± 15.8 92.2 ± 12.7 110.1 ± 13.6 <0.001
104 [93, 114] 93 [83, 100] 109 [102, 118]
Current smokers 819 (16.1%) 311 (17.1%) 508 (15.5%) 0.15
Statin use 2442(47.8%) 659(36.1%) 1783(54.3%) <0.001
Metabolic syndrome components
Triglyceride component 2518 (49.6%) 250 (13.7%) 2268 (69.7%) <0.001
HDL cholesterol component 1845 (36.3%) 98 (5.4%) 1747 (53.7%) <0.001
Blood pressure component 5000 (97.8%) 1728 (94.5%) 3272 (99.7%) <0.001
Glucose component 2600 (51.3%) 266 (14.7%) 2334 (71.6%) <0.001
Waist component 3392 (67.6%) 529 (29.5%) 2863 (88.9%) <0.001
Total number of metabolic 3.0 ± 1.33 [2, 4] 1.6 ± 0.52 [1, 2] 3.8 ± 0.84 [3, 4] <0.001
syndrome components
Comorbidities at baseline
Diabetes 1842 (36.0%) 146 (8.0%) 1696 (51.6%) <0.001
Hypertension 4924 (96.3%) 1682 (92.0%) 3242 (98.8%) <0.001
Systolic blood pressure 139.5 ± 20.4 137.1 ± 19.9 140.8 ± 20.4 <0.001
(mm Hg)
Diastolic blood pressure 79.3 ± 11.8 80.2 ± 11.3 78.7 ± 12.0 <0.001
(mm Hg)
Prevalent cardiovascular 1566 (30.6%) 360 (19.7%) 1206 (36.7%) <0.001
disease
Laboratory parameters
eGFR-CKD-EPI 49.4 ± 18.2 53.7 ± 20.2 47 ± 16.5 <0.001
(ml/min/1.73 m2 )
Serum albumin (mg/L) 38.3 ± 4.4 38.7 ± 4.4 38.2 ± 4.4 <0.001
Urine albumin–creatinine 432 ± 96151 429 ± 92365 432 ± 98246 [9, 0.005
ratio (UACR; mg/g) [10, 392] [11, 459] 357]
Total cholesterol (mg/dl) 211 ± 53 215 ± 51 209 ± 54 <0.001
HDL cholesterol (mg/dl) 52.0 ± 18.1 63.1 ± 18.2 45.6 ± 14.8 <0.001
LDL cholesterol (mg/dl) 118 ± 44 125 ± 43 114 ± 44 <0.001
Triglycerides (mg/dl) 199 ± 128168 130 ± 63120 238 ± 139207 [152, <0.001
[117, 238] [90, 154] 281]
Glycated haemoglobin 6.3 ± 1.06.0 5.8 ± 0.65.7 6.6 ± 1.16.3 [5.9, <0.001
(HbA1c; %) [5.7, 6.6] [5.5, 5.9] 7.1]
High-sensitivity C-reactive 4.8 ± 8.42.3 3.6 ± 9.21.5 5.4 ± 7.72.82 [1.4, <0.001
protein (hs-CRP; mg/L) [1.0, 5.0] [0.7, 3.4] 6.1]
Note: Values are provided as mean ± standard deviation and [25th, 50th (median) and 75th percentiles] or a number of
patients, n (%) eGFR-CKD-EPI, estimated glomerular filtration rate calculated according to the CKD-EPI formula. p-Values
are given for the comparison between patients with and without metabolic syndrome.

1222 © 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Journal of Internal Medicine, 2021, 290; 1219–1232
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Association of the metabolic syndrome / L. M. Pammer et al.

Table 2. Distribution of endpoints during the 6.5 years prospective follow-up stratified by the presence or absence of metabolic
syndrome at baseline
Total N = 5110 No metabolic syndrome Metabolic syndrome N
Endpoint (100%) N = 1826 (35.7%) = 3284 (64.3%) p-Value
All-cause mortality 605 11.8% 137 7.5% 468 14.3% <0.001
3-Point MACE 473 9.3% 102 5.6% 371 11.3% <0.001
4-Point MACE 649 12.7% 137 7.5% 512 15.6% <0.001
Main causes of death
Cardiovascular death 183 3.6% 28 1.5% 155 4.7% <0.001
Death due to cancer 90 1.8% 26 1.4% 64 1.9% 0.17
Death due to infection 140 2.7% 26 1.4% 114 3.5% <0.001
Death due to other cause 62 1.2% 20 1.1% 42 1.3% 0.57
Death due to unknown 130 2.5% 37 2.0% 93 2.8% 0.08
cause
Note: 3-Point MACE (Major Adverse Cardiovascular Events) includes death from cardiovascular causes including myocar-
dial infarction, coronary heart disease, sudden cardiac death, and ischemic stroke as well as acute non-fatal myocardial
infarction (STEMI and NSTEMI) and non-fatal stroke. 4-Point MACE comprised all endpoints included in 3-point MACE
plus fatal peripheral ischemia, amputation due to peripheral vascular disease, and surgical or percutaneous revascular-
ization due to peripheral vascular disease.

disease, sudden cardiac death and ischaemic test <0.0001). Cox regression models with different
stroke as well as acute non-fatal myocardial infarc- degrees of adjustment for confounders are summa-
tion (STEMI and NSTEMI), non-fatal stroke. Six- rized in Table 3. In the age- and sex-adjusted model
hundred forty-nine patients experienced a 4-point 1, the presence of a metabolic syndrome increased
MACE additionally including besides the 3-point the probability to die of any cause during the obser-
MACE events, fatal peripheral ischemia, amputa- vation period by 1.47-fold (95% confidence inter-
tion due to peripheral vascular disease and sur- val [CI]: 1.21–1.78, p < 0.0001). Estimates were
gical or percutaneous revascularization due to slightly attenuated when adjusted for kidney func-
peripheral vascular disease. Table 2 provides a tion parameters (model 2) and by extended adjust-
summary of the events and causes of death for the ment for current smoking, prevalent CVD at base-
entire patient group and stratified for the presence line and LDL cholesterol (model 3). Only when we
and absence of a metabolic syndrome. In patients additionally adjusted for hs-CRP in model 4, the
with metabolic syndrome all-cause mortality, 3- association was no longer significant (Table 3).
point MACE and 4-point MACE were approximately
twice as frequent as in patients without metabolic The estimates for 3-point MACE and 4-point MACE
syndrome (p < 0.001). When we analyzed the main were higher than that for all-cause mortality in the
causes of death, we observed cardiovascular death extended adjustment model 3: HR = 1.43 (95% CI:
and death due to infections a 3-fold and 2.5-fold 1.14–1.79; p = 0.002) for 3-point MACE and HR =
higher relative frequency, respectively, in patients 1.48 (95% CI: 1.22–1.79; p = 0.0001) for 4-point
compared to those without metabolic syndrome MACE (Table 3). The associations remained signif-
(Table 2). icant even after further adjustment for hs-CRP in
model 4 (Table 3).
Presence of metabolic syndrome at baseline and risk for In order to avoid potential overestimation of the
endpoints HRs for 3-point MACE and 4-point MACE, we addi-
Kaplan–Meier-curves were constructed for the out- tionally performed a competing risk analysis. The
comes of all-cause mortality, 3-point MACE and 4- corresponding cumulative incidence curves are
point MACE, stratified by metabolic syndrome sta- provided in Fig. S1, and the results from the com-
tus (Fig. 1). Significant differences between the two peting risk regression are provided in Table 3 (right
groups for all three endpoints were observed, with columns). The subdivision hazard ratios remained
higher endpoint-free survival rates for those with- almost unchanged and highly significant in all
out metabolic syndrome (all p-values of log-rank models.

© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. 1223
Journal of Internal Medicine, 2021, 290; 1219–1232
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© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
log-rank test.
Fig. 1 Kaplan–Meier-curves and cumulative event tables for all-cause mortality, 3-point MACE and 4-point MACE. p-values were calculated using the
Association of the metabolic syndrome / L. M. Pammer et al.

Journal of Internal Medicine, 2021, 290; 1219–1232

1224
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Association of the metabolic syndrome / L. M. Pammer et al.

Table 3. Association of metabolic syndrome with all-cause-mortality, 3-point MACE and 4-point MACE during the prospective
follow-up of 6.5 years using Cox proportional hazards regression models with various adjustments for confounders. For
3-point MACE and 4-point MACE, both cause-specific hazard ratio (HR) and subdivision HR (SHR) are given
HR 95% CI p-Value SHR 95% CI p-Value
All-cause mortality
Model 1 1.47 [1.21–1.78] <0.0001 – – –
Model 2 1.37 [1.13–1.67] 0.002 – – –
Model 3 1.26 [1.04–1.54] 0.021 – – –
Model 4 1.11 [0.91–1.35] 0.325 – – –
3-Point MACE
Model 1 1.68 [1.35–2.10] <0.0001 1.66 [1.32–2.07] <0.0001
Model 2 1.59 [1.27–1.98] <0.0001 1.57 [1.25–1.97] <0.0001
Model 3 1.43 [1.14–1.79] 0.002 1.42 [1.13–1.78] 0.003
Model 4 1.31 [1.04–1.64] 0.020 1.32 [1.05-1.66] 0.019
4-Point MACE
Model 1 1.74 [1.44–2.10] <0.0001 1.72 [1.42–2.08] <0.0001
Model 2 1.67 [1.38–2.02] <0.0001 1.66 [1.37–2.01] <0.0001
Model 3 1.48 [1.22–1.79] 0.0001 1.47 [1.21-1.78] 0.0001
Model 4 1.36 [1.12–1.65] 0.0022 1.36 [1.12-1.66] 0.002
Note: HR: hazard ratios derived from Cox models; SHR: subdivision HR derived from competing for risk regression.
Model 1: adjusted for sex and age; Model 2: Model 1 + eGFR, log(urine albumin–creatinine ratio); Model 3: Model 2 +
current smoking, prevalent cardiovascular disease, log(LDL cholesterol); Model 4: Model 3 + log(hs-CRP).
For definitions of 3-point MACE and 4-point MACE, see footnotes of Table 2.

We furthermore investigated whether the metabolic MACE and 4-point MACE, Fig. 2), we also used
syndrome is a predictor for each of the main causes the number of components as a linear predic-
of death. This was the case for cardiovascular tor. When data were adjusted for age, sex, eGFR,
death and death due to infections but not for death UACR, current smoking, prevalent CVD and LDL
due to cancer or death due to other causes (Fig. S2 cholesterol (model 3 in Table 4), the risk for all-
and Table S1). cause mortality, 3-point MACE and 4-point MACE
increased significantly per component by 9%, 24%
and 23%, respectively. Additional adjustment for
Number of metabolic syndrome components and risk for
hs-CRP weakened the association only for all-
endpoints
cause mortality (model 4 in Table 4).
In the next step, we investigated whether the total
number of metabolic syndrome components in
each individual has an influence on outcomes. Due
Associations of individual metabolic syndrome
to the high frequency of the blood pressure com-
components and risk of endpoints
ponent (97.8%), at least one metabolic syndrome
component was fulfilled by close to all patients. To elucidate how strongly each component con-
Therefore, patients who had either none or one tributes to the risk for reaching an endpoint,
component were combined and used as the ref- individual models for each of the components
erence group. Figure 2 shows a linear increase of were calculated (Fig. 3 and Table S3). The glu-
HRs for each additional metabolic syndrome com- cose component consistently conferred higher risk
ponent reaching significance at three components for all endpoints (HR = 1.68 for all-cause mor-
for all-cause mortality and 4-point MACE. For 3- tality, HR = 1.73 for 3-point MACE and HR =
point MACE, significance was reached with four 1.81 for 4-point MACE). Additionally, for both
components (Fig. 2 and Table S2). 3-point MACE and 4-point MACE, HDL choles-
terol, waist circumference, and triglyceride compo-
Since the risk increase for each additional com- nents were associated with increased risk. For all-
ponent was rather linear (especially for 3-point cause mortality, high triglyceride concentrations

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Journal of Internal Medicine, 2021, 290; 1219–1232
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Association of the metabolic syndrome / L. M. Pammer et al.

Fig. 2 Forest plots of hazard ratios for

all-cause-mortality, 3-point MACE, and 4-point MACE,
grouping by the sum of metabolic syndrome
components. All models are adjusted for sex, age,
estimated glomerular filtration rate (eGFR), log(urine
albumin–creatinine ratio), smoking status, log(LDL
cholesterol) and prevalent cardiovascular disease.

Table 4. Association of the number of metabolic syndrome components (HR refers to increase by one additional component)
with all-cause-mortality, 3-point MACE and 4-point MACE during the prospective follow-up period using Cox proportional
hazards regression models with various adjustments for confounders. For 3-point MACE and 4-point MACE, both cause-
specific hazard ratio (HR) and subdivision HR (SHR) are given
HR 95% CI p-Value SHR 95% CI p-Value
All-cause mortality
Model 1 1.18 [1.10,1.26] <0.001 – – –
Model 2 1.14 [1.07,1.22] <0.001 – – –
Model 3 1.09 [1.02,1.17] 0.011 – – –
Model 4 1.04 [0.98,1.12] 0.189 – – –
3-Point MACE
Model 1 1.32 [1.22,1.42] <0.001 1.31 [1.21,1.42] <0.001
Model 2 1.29 [1.19,1.40] <0.001 1.29 [1.19,1.40] <0.001
Model 3 1.24 [1.15,1.35] <0.001 1.24 [1.14,1.35] <0.001
Model 4 1.21 [1.11,1.31] <0.001 1.22 [1.12,1.33] <0.001
4-Point MACE
Model 1 1.31 [1.23,1.40] <0.001 1.31 [1.23,1.40] <0.001
Model 2 1.30 [1.21,1.38] <0.001 1.30 [1.21,1.39] <0.001
Model 3 1.23 [1.15,1.32] <0.001 1.23 [1.15,1.32] <0.001
Model 4 1.20 [1.12,1.28] <0.001 1.20 [1.12,1.29] <0.001
Note: HR: Hazard ratios derived from Cox models; SHR: subdivision HR, derived from competing risk regression.
Model 1: adjusted for sex and age; Model 2: Model 1 + eGFR, log(urine albumin–creatinine ratio); Model 3: Model 2 +
current smoking, prevalent cardiovascular disease, log(LDL cholesterol); Model 4: Model 3 + log(hs-CRP).
For definitions of 3-point MACE and 4-point MACE, see footnotes of Table 2.

were associated with lower risk (HR = 0.82, Combinations of metabolic syndrome components and
p = 0.019). risk of endpoints

Results only slightly changed when all compo- Finally, we investigated which combinations of
metabolic syndrome components were most fre-
nents were included in one model simultaneously,
thereby also adjusting all components for each quent and whether any of these combinations were
other (see Fig. S3 and Table S4). associated with a markedly different increase of

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Association of the metabolic syndrome / L. M. Pammer et al.

Fig. 3 Forest plots of hazard ratios (HRs) for individual

components for all-cause mortality, 3-point MACE and
4-point MACE. All models were adjusted for sex, age,
estimated glomerular filtration rate (eGFR), log(urine
albumin–creatinine ratio), smoking status, log(LDL) and
prevalent cardiovascular disease. Multivariate HRs are
from five different models only including the component
under investigation alongside the variables for
adjustment. TG: triglyceride, HDL: HDL cholesterol, BP:
blood pressure.

Table 5. Frequency of combinations of metabolic syndrome components and associations with main outcomes. The hazard
ratios (HRs) and 95% confidence intervals (95% CIs) are given for each combination in comparison to the combination with
the lowest risk (except the binned group), separately for the patients with three and four metabolic syndrome components,
respectively
All-cause mortality 3-Point MACE 4-Point MACE
BP Glucose Waist TG HDL n HR (95% CI) HR (95% CI) HR (95% CI)
Patients with three metabolic syndrome components present (N = 1394)
BP Glucose Waist – – 590 1.70 (1.06–2.74) 1.58 (0.65–3.82) 2.07 (0.93–4.60)
BP – Waist TG – 322 1.00 1.21(0.47–3.12) 1.38(0.59–3.22)
BP – Waist – HDL 129 1.42 (0.70–2.90) 1.68 (0.60–4.67) 1.74 (0.68–4.47)
BP – – TG HDL 114 1.03 (0.45–2.35) 1.00 1.00
BP Glucose – TG – 108 1.37 (0.69–2.75) 2.08 (0.77–5.60) 2.54 (1.06–6.10)
Binned remaining rarer combinations 131 1.89 (1.00–3.58) 1.29 (0.44–3.81) 1.72 (0.68–4.37)

BP Glucose Waist TG HDL n HR (95% CI) HR (95% CI) HR (95% CI)

Patients with four metabolic syndrome components present (N = 1153)
BP Glucose Waist TG – 462 1.70 (1.03–2.82) 1.57 (0.96–2.56) 1.39 (0.91–2.11)
BP – Waist TG HDL 333 1.00 1.00 1.00
BP Glucose Waist – HDL 219 3.22 (1.91–5.40) 1.86 (1.06–3.24) 1.64 (1.02–2.62)
BP Glucose – TG HDL 96 1.94 (1.01–3.74) 1.67 (0.85–3.26) 1.43 (0.80–2.55)
Binned remaining rarer combinations 43 0.57 (0.13–2.47) 0.57 (0.13–2.46) 0.36 (0.09–1.53)
Note: Hazard ratios derived from Cox models adjusted for sex, age, eGFR, log(urine albumin–creatinine ratio), current
smoking, prevalent cardiovascular disease and log(LDL cholesterol).
Metabolic syndrome components: BP, high blood pressure; glucose, high glucose; waist, high waist circumference; TG,
high triglycerides; HDL, low HDL cholesterol.

risk in individuals with the same number of com- with blood pressure, glucose and waist showed
ponents (Table 5). In the 1394 patients with exactly the highest risk for all-cause mortality. For 4-
three components, the most common combination point MACE, it was blood pressure, glucose and
included blood pressure, glucose and waist (n = triglycerides. Triglycerides or HDL in any other
590), followed by blood pressure, waist and triglyc- combinations did not seem to drive the risk for
erides (n = 322) and blood pressure, waist and those with three components. In the 1153 patients
HDL (n = 129). The combination of components with exactly four components, the most frequent

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Association of the metabolic syndrome / L. M. Pammer et al.

combination contained blood pressure, glucose, One of the explanations for the lack of studies
waist, and triglycerides (n = 462), followed by might be that most definitions of a metabolic syn-
blood pressure, waist, triglycerides and HDL (n = drome require blood collection in a fasting state.
333) and blood pressure, glucose, waist, and HDL This is not easy to accomplish in a standardized
cholesterol. In the groups with four components, way especially when many recruitment centres are
the glucose component was always included when involved and the rate of patients with diabetes is
the risk for outcomes was increased. However, high. However, many studies in non-CKD popula-
waist and HDL contributed to the increase in risk tions faced the same problem and used surrogate
(TABLE 5). parameters such as substituting HbA1c for fasting
glucose, a higher threshold for non-fasting triglyc-
erides or BMI for waist circumference measure-
Discussion ments. Since GCKD study participants were not
This prospective observational study provides necessarily fasting, we had to use a threshold for
evidence that the presence of a metabolic triglyceride concentrations of 175 mg/dl instead of
syndrome in CKD patients with moderately 150 mg/dl as recommended by a recent consensus
reduced eGFR and/or increased albuminuria is statement [14].
independently associated with increased all-cause
mortality and more cardiovascular endpoints More studies are available in CKD patients that
during an observation period of 6.5 years. The investigated associations of single metabolic syn-
association became stronger with an increas- drome components with outcomes. For example,
ing number of metabolic syndrome components. impaired glucose metabolism is a well-known risk
Especially the glucose component drives the factor for cardiovascular disease and all-cause
association followed by the lipid and waist cir- mortality in the general population [19–21]. In the
cumference component. These associations were GCKD study, the glucose component showed the
stronger for cardiovascular outcomes than that for strongest association with both, all-cause mor-
all-cause mortality. tality and cardiovascular disease, independent of
the other metabolic syndrome components. This
Our findings might have been expected from is in line with data from Neves et al. [22] who
investigations in the general population [1, 15–17], investigated 3701 CKD patients with normogly-
while studies investigating metabolic syndrome caemia, prediabetes, and diabetes. Patients with
in patients with moderate CKD are surprisingly pre-diabetes had a higher risk of a composite car-
sparse [6, 7, 18]. The largest study to date by Nava- diovascular outcome and a trend towards higher
neethan et al. [6] is an electronic health record- risk for all-cause mortality. Participants with dia-
based CKD registry with 43,546 patients in stages betes had increased risk for both outcomes when
3 and 4. Metabolic syndrome data were available compared to normoglycaemic patients.
from 25,868 (59%) patients with a mean follow-up
period of 2.3 years. They observed an association of A recent systematic review and meta-analysis
metabolic syndrome with progression to end-stage using BMI as a measure of obesity in CKD stage
kidney disease but no association with all-cause G3–5 patients [23] found only five studies includ-
mortality [6]. A further study, the African-American ing 10,443 patients for all-cause mortality and two
Study of Kidney Disease and Hypertension in 842 studies including 2101 patients for cardiovascu-
hypertensive individuals with CKD found no lar mortality. There was a minuscule association
association of metabolic syndrome with a com- of BMI with all-cause mortality and no associa-
posite endpoint of progression of CKD and death tion with cardiovascular mortality. The authors
without giving detailed data for each of the out- concluded that the number of studies were not
comes [7]. Interestingly, no sufficiently powered enough to reach definite conclusions. Data from
prospective studies investigated the association of the REGARDS study with 5805 patients with CKD
metabolic syndrome with cardiovascular outcomes stages 1–4 and with a median follow-up of 4 years
in non-dialyzed CKD patients. This is worri- described a graded and increased mortality risk
some since it is generally claimed that metabolic across increasing waist circumference categories
syndrome is associated with cardiovascular end- after adjustment for BMI and other covariates [24].
points in CKD patients, a conclusion extrapolated
from the general population not backed up by In our study, elevated triglyceride concentrations
data. were associated with a lower risk for all-cause

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Journal of Internal Medicine, 2021, 290; 1219–1232
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Association of the metabolic syndrome / L. M. Pammer et al.

mortality which even remained significant when mation due to metabolic syndrome may account
adjusted for other metabolic syndrome compo- for some of the risk increases. When we modelled
nents as well as other risk factors. For the car- the association between metabolic syndrome and
diovascular endpoints, this trend reversed but lost outcomes we started with a simple age- and sex-
significance as soon as we adjusted also for the adjusted model 1 followed by additional adjust-
other metabolic syndrome components. The pro- ment for the main kidney function parameters
tective association of triglycerides seems to be eGFR and UACR in model 2 and finally adjusted for
counterintuitive in light of its association in the major cardiovascular risk factors not yet included
general population, where elevated triglycerides in the metabolic syndrome definition (i.e. prevalent
are a well-known cardiovascular risk factor [25, CVD, smoking and LDL cholesterol) in model 3.
26]. A recent study by Soohoo et al. [27] in The associations with all endpoints were slightly
over two million patients from the United States attenuated but still remained significant. This was
Veterans Affairs databases showed that the risk also the case for both MACE definitions when we
increase conferred by triglyceride levels is increas- additionally adjusted for hs-CRP as a measure
ingly attenuated with declining kidney function of systemic inflammation. For all-cause mortal-
which might be related to an increasing preva- ity, however, the association was no longer signifi-
lence of inflammation and malnutrition. The risk cant. It might be discussed controversially whether
for all-cause mortality was significantly increased an adjustment for hs-CRP is appropriate. Some
for triglyceride levels <80mg/dl in all groups of might argue that elevated CRP levels, as well as
CKD and non-CKD patients. For levels ≥240mg/dl, pro-inflammatory cytokines, are a consequence
risk for all-cause mortality was increased for all rather than a cause of the metabolic syndrome.
groups except for those with end-stage kidney The expansion of adipose tissue results in fur-
disease, suggesting a possibly U-shaped relation- ther insulin resistance by disruption of insulin sig-
ship between triglycerides and all-cause mortal- nalling with further metabolic derangements [37].
ity in kidney patients. Lee et al. [28] studied It is likely a complex vicious cycle further escalat-
CKD patients with diabetes and no prevalent CVD ing with decreasing kidney function.
at baseline and found lower TG/HDL cholesterol
ratios to be associated with decreased risk for all- A joint statement from the American Diabetes
cause mortality and major cardiac adverse events. Association and the European Association for the
Study of Diabetes has raised several critical ques-
The pathways that lead to cardiovascular disease tions on the imprecise definition of the metabolic
in either metabolic syndrome or chronic kidney dis- syndrome, the lack of certainty regarding the
ease may have common endpoints. Changes in car- pathogenesis and its value as a marker for CVD
diac structure occur in both metabolic syndrome risk [38]. A dichotomized variable such as the pres-
[29] and CKD [30]. Similarly, vascular endothelial ence of a metabolic syndrome likely mirrors the
dysfunction is present in both metabolic syndrome heterogeneous pathogenesis of the disease inad-
[31] and CKD [32]. This could explain why our anal- equately. This statement questioned whether the
yses showed the additive risk for those patients metabolic syndrome on its own conveys greater
who have both disorders. information than the sum of its component risk
factors [38]. This was one of the reasons why we
analysed our data on a per-component basis to
Pathophysiological consideration see whether the sum of the components may bet-
The underlying mechanisms for the association of ter reflect the risk of certain outcomes. We showed
metabolic syndrome with outcomes are not fully that there was a linear increase in risk with the
elucidated. They might include misguided immune number of metabolic syndrome components which
system activity [33], dysregulation of haemostasis resulted in HRs between 1.50 and 2.50 in case of
[34] and excess intra-abdominal fat [35]. Excess four to five components present, a lot higher than
visceral adipose tissue might trigger a cascade of considering a binary variable with HRs between
metabolic changes, leading to changes in insulin, 1.26 and 1.48 (model 3) for various outcomes. Fur-
leptin and adiponectin signalling [36]. Besides thermore, the extent of the association for each of
metabolic activity, visceral adipose tissue has a the components with various outcomes was also
higher relative percentage of inflammatory cells explored. The weight of the glucose component is
and produces pro-inflammatory cytokines. There- highest followed by the lipid and by waist circum-
fore, systemic, vascular and endothelial inflam- ference component. In addition, we investigated

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Journal of Internal Medicine, 2021, 290; 1219–1232
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Association of the metabolic syndrome / L. M. Pammer et al.

whether there was a markedly different risk for out- endpoints, even if it did not contribute to the risk
comes among combinations of metabolic syndrome discrimination in our models.
components. However, these latter analyses were
not fully conclusive but supported the impression Since more than 71.6% of our patients with
that the glucose component may carry the greatest metabolic syndrome were diagnosed by fulfilling
weight for adequate risk estimation (Table 5). the glucose component but only 51.6% of these
patients had a documented diagnosis of diabetes,
the question arises whether the diagnosis of a
metabolic syndrome may provide earlier identifica-
Clinical implications tion of high-risk patients than is the case if only
We found an association between the binary con- single component was diagnosed. Furthermore,
dition of a metabolic syndrome with outcomes. distinct components of the syndrome such as
As an umbrella term, it may ease communication waist circumference, low HDL cholesterol or hyper-
between physicians and their patients. However, it triglyceridemia are often missed when the screen-
may not reflect the entire information behind this ing, diagnosis, and management of dyslipidaemia
label. The finding of a graded association between is mostly centred around measuring LDL concen-
the number of metabolic syndrome components tration as the primary lipid analysis method [40].
and the outcomes as described in the general popu-
lation [39] is an easily transmittable information to Strengths and limitations of the study
the patient (the higher the number the higher the Strengths of the study include the large sample size
danger). This could be a motivating factor for the of a well-defined homogeneous study population
individual patient in the sense that each metabolic with a median follow-up of 6.5 years with a very low
syndrome component successfully avoided might loss to follow-up. Limitations include that blood
decrease the risk for a cardiovascular endpoint was not necessarily drawn in a fasting state. We,
or premature death. Hence not all metabolic syn- therefore, had to use HbA1c instead of fasting glu-
dromes are created equally and individual analy- cose for the estimation of the glucose component
sis of each of the metabolic syndrome components which, however, has the advantage that it does
should guide the search to find the most promis- not simply reflect a single measurement of glu-
ing target for therapeutic intervention on a case-by- cose. For triglycerides, we used a threshold of 175
case basis. In this context, it may be worth consid- mg/dl instead of 150 mg/dl to define the triglyc-
ering that the association between the single com- eride component. A further limitation was that the
ponents of a metabolic syndrome with outcomes study population was restricted to Caucasian eth-
might be far more pronounced than estimated by nicities and thus the findings are not generalizable
epidemiological studies: these studies count the to other ethnicities.
singular components as a metabolic component
to be present even if successfully treated (e.g. Conclusions
lipids, blood pressure or blood glucose) and thereby
underestimate the risk for those who are not suc- This study demonstrates a strong association
cessfully treated yet. between metabolic syndrome and cardiovascular
disease as well as an increased risk for mortality
In terms of prioritizing therapeutic approaches, in patients with moderately severe CKD, which up
targeting the glucose component including insulin to now has only been anticipated from data in the
resistance might be the most promising therapeu- general population.
tic approach. A combination of drug treatment with
lifestyle changes (physical activity and diet) will Conflict of interest
also have an influence on other metabolic syn-
The authors have no conflict of interest to declare.
drome components including lipids, central obe-
sity and increased blood pressure. One should not
Acknowledgements
be misguided by the observation that the blood
pressure component was not predictive for any of We are grateful for the willingness of the patients
the outcomes. This can be explained by the simple to participate in the GCKD study. The enor-
fact that the increased blood pressure component mous effort of the study personnel of the various
was present in 97.8% of all patients. Thus, it may regional centres is highly appreciated. We thank
have contributed to the pathogenesis of the clinical the nephrologists who provide routine care for the

1230 © 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Journal of Internal Medicine, 2021, 290; 1219–1232
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Association of the metabolic syndrome / L. M. Pammer et al.

patients and collaborate with the GCKD study (the of Regensburg, Institute of Functional Genomics:
list of nephrologists currently collaborating with Peter Oefner, Wolfram Gronwald; University of
the GCKD study is available at http://www.gckd. Bonn, Institute of Medical Biometry, Informat-
org). ics and Epidemiology, Medical Faculty: Matthias
Schmid, Jennifer Nadal.
This study was supported by the Austrian
Research Fund to Florian Kronenberg (FWF, W-
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