Journal of Vascular Surgery
Volume 50, Issue 1 , Pages 61-69, July 2009

Metabolic syndrome and vascular risk in patients with peripheral arterial occlusive disease

  • Anne L.M. Vlek, MD

      Affiliations

    • Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
    • ,
  • Yolanda van der Graaf, MD, PhD

      Affiliations

    • Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
    • Corresponding Author InformationReprint requests: Yolanda van der Graaf, MD, PhD, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Str. 6.131, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
    • ,
  • Maayke A. Sluman, MD

      Affiliations

    • Department of Internal Medicine, St Antonius Hospital Nieuwegein, Utrecht, The Netherlands
    • ,
  • Frans L. Moll, MD, PhD

      Affiliations

    • Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
    • ,
  • Frank L.J. Visseren, MD, PhD

      Affiliations

    • Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
    • ,
  • SMART Study Group

Received 24 October 2008; accepted 29 December 2008. published online 17 February 2009.

Article Outline

Objectives

Peripheral arterial occlusive disease (PAOD) is associated with a high risk of cardiovascular events. The metabolic syndrome is a frequent condition among patients with manifest vascular disease, but the influence of the metabolic syndrome on cardiovascular events in patients with PAOD is unknown. Also, progression and regression of the metabolic syndrome after follow-up are not extensively studied.

Methods

The study population consisted of 461 patients with symptomatic PAOD from the Second Manifestations of Arterial Disease study (SMART). Patients underwent vascular screening at baseline and after a mean follow-up of 5.5 ± 1.3 years. Hazard ratios (HRs) for vascular events according to metabolic syndrome status (updated National Cholesterol Education Program [NCEP] criteria) were calculated using Cox regression analysis. The course of the metabolic syndrome during follow-up and the influence of body mass index (BMI) on development or disappearance of the syndrome were assessed.

Results

During follow-up, 91 first vascular events were recorded. Cumulative 3-year survival free from vascular events was 84.7% in metabolic syndrome patients compared to 92.1% in participants without the syndrome. The metabolic syndrome was associated with an increased risk of vascular events (HR 1.51; 1.01-2.30, age- and gender-adjusted). During follow-up, 128 patients died or were lost to follow-up, and of 333 remaining patients, 221 participated in follow-up measurements. The metabolic syndrome disappeared in 16% of patients and was incident in 14% of patients during follow-up. Waist circumference increased with 10 ± 8 cm in those developing the syndrome. A BMI decrease of 1 kg/m2 significantly decreased the risk of metabolic syndrome development by 23% (odds ratio [OR] 0.77; 0.62-0.96), and increased the chance to revert to a non-metabolic syndrome state by 32% (OR 1.32; 1.03-1.71).

Conclusion

The metabolic syndrome is associated with a 1.5-fold increase in risk of vascular events in PAOD patients. Weight control reduces metabolic syndrome incidence and increases metabolic syndrome resolution during follow-up.

 

Peripheral arterial disease (PAOD) is most often the result of atherosclerosis in the arteries of the lower extremities and is associated with a high risk of vascular events at other sites of the vasculature (myocardial infarction, stroke) and death.1, 2, 3, 4 Risk factors for developing vascular complications in PAOD patients are hypertension, hypercholesterolemia, diabetes, smoking, and atherosclerotic vascular diseases in other vascular beds.4 Often vascular risk factors cluster in single patients as the result of central obesity, referred to as metabolic syndrome.

The metabolic syndrome is defined as the clustering of at least three risk factors such as abdominal obesity, hypertension, hyperglycemia, hypertriglyceridemia, and low high-density lipoproteins (HDL)-cholesterol levels. The age-dependent prevalence of the metabolic syndrome is between 20% and 40% in healthy subjects,5 whereas the metabolic syndrome is present in 45% of patients with manifest vascular disease.6 In particular, in patients with PAOD, the condition is remarkably frequent, with prevalences of 52% and 58% reported for this population.6, 7 Presence of metabolic syndrome in PAOD patients is associated with advanced vascular damage.8

In populations free of cardiovascular disease at baseline, cardiovascular morbidity and mortality increased 1.5 to 3-fold in the presence of the metabolic syndrome.9, 10 Also, in patients with a history of myocardial infarction or coronary heart disease, the metabolic syndrome was associated with increased risks of cardiovascular events or death.9, 11, 12, 13, 14

Considering the high absolute risk of vascular morbidity and mortality in PAOD patients, the high prevalence of the metabolic syndrome in this population, as well as the increased vascular risk accompanied by the metabolic syndrome, might be an important condition in patients with PAOD.

Given the high prevalence of the metabolic syndrome in PAOD patients, it is also important to gain understanding about how the metabolic syndrome develops over time. No information is currently available on the course of the metabolic syndrome or on possible improvements or worsening in individual metabolic syndrome characteristics in patients with PAOD.

The aim of this prospective cohort study was to quantify the risk of vascular events associated with the metabolic syndrome in PAOD patients. Second, we studied determinants of the incidence of metabolic syndrome and its disappearance during follow-up as well as the changes in individual metabolic syndrome components.

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Methods 

Study population 

The patients included in this study originated from the Second Manifestations of ARTerial disease (SMART) study. The SMART study is an ongoing single-center prospective cohort study that was designed to establish the presence of additional arterial disease and risk factors for atherosclerosis in patients with manifest vascular disease or a vascular risk factor. Since 1996, more than 8000 patients aged 18-80 years with atherosclerotic vascular disease (cerebrovascular disease, coronary heart disease, PAOD, or abdominal aortic aneurysm [AAA]) or risk factors for atherosclerosis (hyperlipidemia, diabetes, or hypertension) have been included. The study was approved by the local ethics committee and all patients gave written informed consent. Rationale and design of the SMART study have been described previously.15

The current study was based on the data of SMART participants included because of PAOD. These patients were referred to the Department of Vascular Surgery of the University Medical Center Utrecht with symptomatic PAOD (intermittent claudication, non-healing ulcers, or gangrene) and had a resting ankle brachial pressure index (ABI) less than or equal to 0.90. The data of 461 consecutive patients included in the screening program between September 1996 and December 2000 were available for analysis.16 Patients were invited to visit the hospital again for a follow-up measurement in the period between September 2003 and March 2005. In the intervening period, patients received usual care from their own general practitioner or vascular specialist.

Vascular screening 

Patients underwent standardized screening for detection of manifestations of atherosclerotic disease and vascular risk factors both at baseline and after follow-up. Participants completed a questionnaire on cardiovascular history, medication use, and risk factors. Severity of PAOD was classified according to the Fontaine classification.17 After an overnight fast, patients visited the hospital where a physical examination was carried out, consisting of measurements of weight, height, waist and hip circumferences, and blood pressure (BP). Measurements were performed according to a standardized protocol. Fasting blood was sampled to ascertain levels of glucose, total cholesterol, HDL-cholesterol, triglycerides, creatinine, and homocysteine. Low-density lipoprotein (LDL)-cholesterol levels were calculated with Friedewald's formula. Morning urine samples were collected to measure albumin and creatinine concentrations. All assessments were performed at a single laboratory. An ABI was assessed for each leg by calculating ratios of the highest systolic BP measured at the ankle to the highest systolic BP in both arms with the patient in the supine position. Systolic BP in the posterior tibial and dorsal pedal arteries (left and right) was measured with an 8-MHz continuous-wave Doppler probe connected to an IMEXLAB 9000 Vascular Diagnostic System (Imex Medical Systems Inc, Golden, Colo). Systolic BP in both brachial arteries was determined with a semiautomatic oscillometric device (Omega 1400, Invivo Research Laboratories Inc, Broken Arrow, Okla). Screening also included duplex scanning of the carotid arteries, electrocardiography, and ultrasonography of the abdomen with measurements of the anteroposterior aortic and juxtarenal diameter. Results of the screening and recommendations for treatment, formulated by a team of medical specialists, were reported to the general practitioner and other treating specialists. The techniques of the baseline examinations have been published formerly.15

Definitions 

Metabolic syndrome was defined as the presence of 3 or more of the following: (1) waist circumference ≥88 cm in women and ≥102 cm in men; (2) fasting triglycerides ≥1.70 mmol/L (150 mg/dL) or drug treatment for elevated triglycerides; (3) HDL-cholesterol <1.30 mmol/L (50 mg/dL) in women and <1.03 mmol/L in men (40 mg/dL) or drug treatment for reduced HDL-cholesterol; (4) BP ≥130/85 mm Hg or use of BP-lowering medication; and (5) fasting glucose ≥5.6 mmol/L (100 mg/dL) or use of glucose-lowering medication, according to the American Heart Association/National Heart, Lung, & Blood Institute (AHA/NHLBI) updated National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) criteria.18 If waist circumference was not available, a body mass index (BMI) ≥30 kg/m2 was used as a determinant for abdominal obesity.19 Hypertension was defined as diastolic BP ≥90 mm Hg, systolic BP ≥140 mm Hg, or self-reported use of BP-lowering.20 Type 2 diabetes mellitus was defined as self-reported type 2 diabetes, use of glucose-lowering agents, or fasting glucose ≥7.0 mmol/L at screening.21 In this way, diabetes mellitus also included newly diagnosed patients with diabetes mellitus. Patients were classified as smoking when currently smoking or stopped smoking in the year of inclusion in the SMART study.

The four-variable Modification of Diet in Renal Disease (MDRD) equation was used to calculate estimated glomerular filtration rate (eGFR). At follow-up, the homeostatic model assessment (HOMA) for insulin sensitivity was added to the measurements to estimate insulin resistance.22

Follow-up and outcome evaluation 

Patients provided information on hospitalization and out-patient clinic visits in response to a short questionnaire every 6 months. When a cardiovascular event was reported, original source documents were retrieved and reviewed to determine the occurrence of cardiovascular disease. All possible events were audited independently by three members of the Endpoint Committee. Patients were followed until death or refusal of further participation. The main outcome of interest for this study was a composite of first occurrence of stroke, myocardial infarction, or vascular death. Definitions of events are shown in Table I.

Table I. Definitions of events
Vascular death
−Sudden death (unexpected cardiac death occurring within 1 hour after onset of symptoms, or within 24 hours given convincing circumstantial evidence).


−Death from ischemic stroke, intracerebral hemorrhage, myocardial infarction, congestive heart failure, or AAA rupture.

Stroke
−Definite: relevant clinical features causing an increase in impairment of at least one grade on the modified Rankin scale, accompanied by an infarction or hemorrhage on a repeat CT scan.


−Probable: clinical deficits causing an increase in impairment of at least one grade on the modified Rankin scale, without CT documentation.

Myocardial infarction
−At least two of the following criteria: (1) chest pain for at least 20 minutes, not disappearing after administration of nitrates; (2) ST-elevation >1 mm in two following leads or a left bundle branch block on the electrocardiogram; (3) CK elevation of at least two times the normal value of CK and a myocardial band-fraction >5% of the total CK.

AAA, Abdominal aortic aneurysm; CK, creatine kinase; CT, computed tomography; ST, xxx.

Statistical analysis 

Results are expressed as means with standard deviations or as percentages unless otherwise stated. Crude overall cumulative survival after 1 and 3 years was calculated using the Kaplan Meier method. Age- and gender-adjusted cumulative incidence of vascular events and of vascular interventions according to the presence or absence of the metabolic syndrome at baseline was evaluated with the use of the Cox proportional hazards model. Results are presented as hazard ratios (HRs) with 95% confidence intervals (95% CIs). Patients without the metabolic syndrome served as the reference category in the analyses. The presence and extent of confounding was assessed by comparing the crude HR with the adjusted HR derived from the model containing the potential confounding variable. Potential confounders were factors related to the determinant (metabolic syndrome) as well as to the outcome (occurrence of vascular events), but not part of the causal chain of the metabolic syndrome. No adjustment was made for variables, part of the metabolic syndrome, or highly correlated to (components of) the metabolic syndrome.

Patients who underwent follow-up measurements were classified into four categories according to the presence of metabolic syndrome at baseline and at follow-up: (1) patients without metabolic syndrome at baseline and at follow-up; (2) patients with metabolic syndrome at baseline but not at follow-up; (3) patients with metabolic syndrome at follow-up but not at baseline; (4) patients with metabolic syndrome at baseline and at follow-up. Changes in metabolic syndrome components are presented according to these groups. Logistic regression analysis was performed to evaluate the effect of baseline BMI and of change in BMI on development and losing of the metabolic syndrome during follow-up. Adjustments were made for age and gender, and additionally for baseline BMI when a change in BMI was studied. All statistical analyses were performed with SPSS 14.0 for Windows (SPSS, Chicago, Ill).

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Results 

Study population 

In the period between September 1996 and December 2000, 461 patients were included based on a recent diagnosis of PAOD. The baseline characteristics of these patients are shown in Table II. Of the 461 patients, 20 (4%) were lost to follow-up and 108 (23%) had died before the time of the follow-up visit. Of the remaining 333 patients, 112 (34%) refused further participation and 221 (66%) underwent follow-up measurements (Fig 1). Differences in baseline characteristics between patients who did and did not participate in the follow-up measurements are presented in Table III. The largest differences were found between those who participated in the follow-up examination and those who died before the follow-up examination, but differences were also present between those who agreed and those who refused to participate. Participants were more often male (67% vs 61%), were generally younger (57 vs 60 years), less often had a history of cerebrovascular disease (9.5% vs 19.7%) or diabetes mellitus (14.9% vs 34.6%), and had lower mean glucose levels (6.0 vs 7.0 mmol/L). The proportion of patients using medication was lower in participants compared with non-participants.

Table II. Baseline characteristics of 461 patients with PAOD according to metabolic syndrome presence
Metabolic syndrome−Metabolic syndrome+
n = 234n = 227
Male gender (%)67.967.4
Age (years)60±1160±11
Fontaine classification 2 (%)8784
Fontaine classification 3 or 4 (%)1316
Ankle-brachial index0.83±0.200.82±0.21
Additional cerebrovascular disease (%)12.420.7
Additional coronary heart disease (%)28.227.3
Additional AAA (%)6.47.0
Diabetes mellitusa (%)9.940.4
Smoking (%)6354
Pack years of smoking27.2±19.528.4±20.3
Physical activityb (%)22.717.5
Body mass index (kg/m2)24.0±2.927.4±4.1
LDL-cholesterol (mmol/L)3.8±1.03.9±1.0
Homocysteine (μmol/L)15.4±11.314.5±5.8
eGFR (ml/min/1.73m2)76±2074±21
Albuminuria (%)c17.323.1
Subcutaneous fat (cm)2.6±2.52.8±1.5
Intra-abdominal fat (cm)8.5±2.010.6±2.1
Metabolic syndrome components
Waist circumference (cm)90±899±11
Systolic BP (mm Hg)143±22151±21
Diastolic BP (mm Hg)78±1181±11
HDL-cholesterol (mmol/L)1.3±0.41.0±0.2
Triglycerides (mmol/L)1.6±1.02.7±1.6
Fasting glucose (mmol/L)5.7±1.57.2±2.6
Treatment at baseline
Glucose-lowering agents (%)7.324.2
Lipid-lowering agents (%)24.933.5
Blood pressure-lowering agents (%)24.840.4
Antithrombotic agents (%)42.741.9

AAA, Abdominal aortic aneurysm; LDL, low-density lipoprotein; eGFR, estimated glomerular filtration rate, calculated with MDRD equation; BP, blood pressure; HDL, high-density lipoproteins; MDRD, Modification of Diet in Renal Disease.

aDefined as self-reported type 2 diabetes, use of glucose lowering agents or fasting glucose ≥7.0 mmol/L.

bSelf-reported exercising.

cAlbumin-to-creatinine rate >3 mg/mmol. Waist circumference was measured in 179 individuals, and measurements of intra-abdominal and subcutaneous fat were present for 51 patients. Continuous variables are expressed as means with standard deviations.

Table III. Differences in baseline characteristics between participants and non-participants in the follow-up examination
Participants follow-upNon-participants and lost to follow-upDied before follow-up
n=221n=132n=108
Male gender (%)67.061.476.9⁎
Age (years)57±1060±1167±10⁎
Fontaine classification 2 vs 3 or 4 (%)87.8vs12.285.1vs14.981.0vs19.0
Ankle-brachial index0.85±0.190.79±0.190.80±0.23⁎
Additional cerebrovascular disease (%)9.519.726.9⁎
Additional coronary heart disease (%)23.522.742.6⁎
Additional AAA (%)5.04.513.0⁎
Diabetes mellitusa (%)14.934.633.6⁎
Smoking (%)58.660.855.1
Pack years of smoking26.6±18.728.9±21.929.0±19.9
Body mass index (kg/m2)25.6±3.726.1±4.225.2±3.8
LDL-cholesterol (mmol/L)4.0±1.03.8±1.13.8±1.0
Waist circumference (cm)95±1196±1295±12
Systolic BP (mm Hg)144±21149±21152±24⁎
Diastolic BP (mm Hg)80±1080±1178±12
HDL-cholesterol (mmol/L)1.1±0.31.2±0.41.1±0.4
Triglycerides (mmol/L)2.1±1.42.4±1.32.0±1.4
Fasting glucose (mmol/L)6.0±1.57.0±2.76.7±2.4⁎
Glucose-lowering agents (%)8.222.322.4⁎
Lipid-lowering agents (%)28.833.324.5
Blood pressure-lowering agents (%)26.833.143.0⁎
Antithrombotic agents (%)38.041.751.9

AAA, abdominal aortic aneurysm; LDL, low-density lipoprotein; BP, blood pressure; HDL, high-density lipoproteins.

Waist circumference was measured in 179 individuals. Continuous variables are expressed as means with standard deviations.

aDefined as self-reported type 2 diabetes, use of glucose-lowering agents or fasting glucose ≥7.0 mmol/L.

⁎Indicates P value <.05.

Metabolic syndrome and vascular events 

The metabolic syndrome was present in 49% of the study population. Of the individual metabolic syndrome components, the BP criterion was most frequent and was present in 83% of patients, followed by the criterion for HDL-cholesterol (54%), triglycerides (53%), and glucose (42%). The criterion for waist circumference was present in 19% of subjects.

During a mean follow-up of 5.6 ± 1.4 years, 91 patients experienced one or more vascular events (first event: 23 myocardial infarctions, 22 strokes, and 46 vascular deaths). Crude cumulative 1-year survival free from vascular events was 94.6% (92.4-96.8%) and declined to 88.4% (85.5-91.3%) after 3 years. In patients without the metabolic syndrome, crude survival free from vascular events was 96.1% (93.6-98.6%) after 1 year and 92.1% (88.6-95.6%) after 3 years of follow-up, compared to 92.9% (89.6-96.2%) and 84.7% (80.0-89.4%) in patients with the metabolic syndrome. Fig 2 shows the cumulative incidence of vascular events according to the presence or absence of the metabolic syndrome, resulting from an age- and gender-adjusted Cox regression analysis. The metabolic syndrome increased the risk of vascular events after adjustment for age and gender (HR 1.51; 1.01-2.30). There was no relation between presence of individual metabolic syndrome components and the occurrence of vascular events (Table IV).

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  • Fig 2. 

    Cumulative incidence of vascular events according to presence or absence of the metabolic syndrome at baseline, adjusted for age and gender. MS absent, Without metabolic syndrome; MS present, with metabolic syndrome; HR, hazard ratio; CI, confidence interval.

Table IV. Effect of metabolic syndrome and its components on the occurrence of vascular events
Prevalence HR (95% CI)
Metabolic syndrome49%I1.51(1.00-2.30)
Blood pressure criteriona83%I0.79(0.46-1.35)
II0.75(0.45-1.25)
HDL criterionb54%I1.09(0.72-1.65)
II1.00(0.63-1.60)
Triglycerides criterionc53%I1.13(0.75-1.71)
II1.06(0.67-1.70)
Waist criteriond19%I1.07(0.92-1.25)
II1.07(0.91-1.24)
Glucose criterione42%I1.14(0.89-1.47)
II1.18(0.90-1.56)

HR, Hazard ratio; CI, confidence interval; HDL, high-density lipoproteins.

Model I adjusted for age and gender; model II additionally adjusted for other metabolic syndrome components.

aBlood pressure (BP) ≥130/85 mm Hg or use of BP-lowering medication.

bHDL cholesterol <1.29 mmol/L (50 mg/dL) in women and <1.04 mmol/L in men (40 mg/dL).

cFasting triglycerides ≥1.70 mmol/L (150 mg/dL).

dWaist circumference >88 cm in women and >102 cm in men.

eFasting glucose ≥6.1 mmol/L (110 mg/dL) or use of glucose-lowering agents.

In additional analyses, no association was found between the metabolic syndrome and the occurrence of revascularization procedures to the legs during follow-up (age- and gender-adjusted HR 0.99; 95% CI 0.65-1.49) and between the metabolic syndrome and the occurrence of lower limb amputations (age- and gender-adjusted HR 1.59; 0.84-3.01). The metabolic syndrome also did not influence the occurrence of surgical and endovascular aortic interventions (age- and gender-adjusted HR 1.11; 0.59-2.10) or the occurrence of interventions to the carotid arteries (age- and gender-adjusted HR 1.20; 0.49-2.95).

Change in metabolic syndrome status 

Mean follow-up among the 221 PAOD patients with follow-up measurements was 5.5 ± 1.3 years. Metabolic syndrome was diagnosed in 45% of the population at baseline and in 43% at follow-up. The majority of patients (70%) remained at the same status: 91 patients (41%) did not meet the metabolic syndrome criteria at baseline and at follow-up, and 64 patients (29%) had the metabolic syndrome at both measurements. In Table V, baseline characteristics, change in metabolic syndrome components, and medication use is shown according to four groups of metabolic syndrome status at baseline and follow-up.

Table V. Baseline characteristics and changes in metabolic syndrome components and medication use according to metabolic syndrome status at baseline and after follow-up
Metabolic syndrome
Baseline
✓
✓
Follow-up
✓✓
n = 91n = 35n = 31n = 64P value
Baseline characteristicsa
Male gender (%)63.777.174.262.5.34
Age (years)56±1055±1061±860±10.08
Smoking (%)58.262.967.752.4.63
Diabetes mellitus (%)1.125.719.426.6<.01
Waist circumference (cm)88±799±1096±6100±12<.01
Systolic BP (mm Hg)139±20147±19138±22150±19<.01
Diastolic BP (mm Hg)79±1084±876±982±9<.01
HDL-cholesterol (mmol/L)1.3±0.31.0±0.21.3±0.30.9±0.2<.01
Triglycerides (mmol/L)1.5±1.02.5±2.01.9±1.12.8±1.4<.01
Fasting glucose (mmol/L)5.3±0.56.9±2.75.9±1.36.5±1.4<.01
Glucose-lowering agents (%)1.114.316.111.1.01
Lipid-lowering agents (%)22.220.038.738.1.06
Blood pressure-lowering agents (%)15.425.725.844.4<.01
Changes in metabolic syndrome components and medication useb
Waist circumference (cm)+3±9+1±9+10±8+6±5.01
Systolic BP (mm Hg)+9±20+11±21+8±25+9±22.94
Diastolic BP (mm Hg)+4±12+1±10+4±12+2±10.45
HDL-cholesterol (mmol/L)+0.3±0.3+0.3±0.2+0.2±0.4+0.2±0.2.08
Triglycerides (mmol/L)−0.2±0.9−1.0±1.3+0.2±1.0−0.4±1.5<.01
Fasting glucose (mmol/L)+0.1±0.5−0.8±2.1+1.1±3.8−0.1±1.2<.01
Glucose-lowering agents+1.1+0+3.3+23.3<.01
Lipid-lowering agents+38.2+54.3+29.0+36.9.06
Blood pressure-lowering agents+17.6+17.2+29.0+18.1.15
ACE-inhibitors/AT II antagonists+4.4+14.3+19.3+26.6.12
Follow-up measurement
HOMA-IRc1.5 (1.1-2.3)1.9 (1.6-3.2)2.7 (2.0-6.4)4.1 (3.1-5.8)<.01

BP, Blood pressure; HDL, high-density lipoproteins; ACE, angiotensin-converting enzyme; AT II, angiotensin II; HOMA-IR, homeostatic model assessment insulin resistance.

aContinuous variables are expressed as means with standard deviations.

bContinuous variables are expressed as differences in mean±standard deviation, categorical variables are expressed as differences in percentages.

cMedian with interquartile range.

Patients with the metabolic syndrome at baseline and at follow-up were older and showed highest values of waist circumference (100 ± 12 cm), systolic BP (150 ± 19 mm Hg), and triglycerides (2.8 ± 1.4) as well as the lowest HDL-cholesterol level (0.9 ± 0.2 mmol/L). Change in metabolic syndrome components according to metabolic syndrome status at baseline and follow-up is shown in Fig 3. Homeostatic model assessment insulin resistance (HOMA-IR) measured at follow-up correlated well with metabolic syndrome status and was highest among patients with persistent metabolic syndrome. HOMA-IR was also high in patients with incident metabolic syndrome.

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  • Fig 3. 

    Changes in the metabolic syndrome components according to metabolic syndrome status at baseline and at follow-up. White bars represent patients without metabolic syndrome at baseline and follow-up; light grey bars represent patients with metabolic syndrome at baseline but not at follow-up; dark grey bars represent patients with metabolic syndrome at follow-up but not at baseline; black bars represent patients with metabolic syndrome at baseline and follow-up. HDL, High-density lipoproteins.

HDL-cholesterol was the criterion most frequently lost. A total of 53.7% of patients fulfilling the HDL criterion at baseline lost it after follow-up. Also the triglycerides criterion was frequently lost (39.6%). The glucose criterion was no longer present in 21.8% of the baseline cases. Fewer patients were able to get their waist circumference below the metabolic syndrome cut-off (10.8%) and almost none lost the BP criterion (2.3%). Of the patients without the BP criterion at baseline, 84% did meet the BP criterion at follow-up and of patients without the HDL criterion at baseline, 46% had the HDL criterion at follow-up. A total of 36% of patients without the criterion for waist circumference at baseline did have the criterion for waist circumference at follow-up, and 20% of those without the triglycerides criterion and 16% of those without the glucose criterion at baseline fulfilled these criteria at follow-up.

Both baseline BMI and change in BMI during follow-up were significantly associated with the development or disappearance of the metabolic syndrome. Baseline BMI was related to incident metabolic syndrome (odds ratio [OR] 1.53; 1.23-1.90) and to the disappearance of metabolic syndrome at follow-up (OR 0.87; 0.77-0.98) after adjustment for age and gender. Per kg/m2 decrease in BMI during follow-up, patients without the metabolic syndrome at baseline decreased their risk to acquire the syndrome during follow-up by 23% (OR 0.77; 0.62-0.96). Subjects with the metabolic syndrome at baseline showed a 32% (OR 1.32; 1.03-1.71) increase in chance to lose the syndrome during follow-up when they lowered their BMI by 1 kg/m2 (adjusted for age, gender, and baseline BMI).

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Discussion 

The metabolic syndrome is a frequent condition in symptomatic PAOD patients with a prevalence of 49%. Cumulative 3-year survival free from vascular events was 84.7% in metabolic syndrome patients compared to 92.1% in participants without the metabolic syndrome. In the present study, it was shown that the metabolic syndrome is associated with a 1.51-fold increased risk for the development of vascular events in patients with symptomatic PAOD. The metabolic syndrome was not associated to future vascular interventions and presence of individual metabolic syndrome components was not associated with an increased vascular risk. BMI at baseline as well as change in BMI during follow-up had a large influence on incident metabolic syndrome and on disappearance of metabolic syndrome during follow-up.

The prevalence of metabolic syndrome in patients with PAOD is high in the present study (49%), and is comparable with other studies.6, 7 In general, it is thought that abdominal obesity is the driving force for the development of insulin resistance resulting in the metabolic changes seen in the metabolic syndrome.23, 24 As exercise has beneficial effects on insulin resistance25, 26 and symptomatic PAOD reduces the ability to ambulate, a decrease in physical activity might be an important cause of insulin resistance in this population. Other possible causes of insulin resistance in this population include genetic predisposition27 and low birth weight.28

In the present study, with 5.5 years of follow-up, it is shown that presence of the metabolic syndrome significantly increased the risk of vascular events in patients with PAOD by 51%. This is comparable with results from other studies among patients with coronary artery disease where the metabolic syndrome increased the risk of future vascular events by 23-63%.9, 11, 29 In a previous study, we showed that in patients with a history of vascular disease the metabolic syndrome induced increased vascular risks. The metabolic syndrome was associated with a considerable vascular risk increment in patients with a history of PAOD or coronary heart disease, and to a lesser extent in patients with a history of AAA or cerebrovascular disease.30 In patients without diabetes or overt cardiovascular disease at baseline, the risk of cardiovascular events was 2-3 times higher in the presence of the metabolic syndrome.31 In our study, the individual metabolic syndrome components alone were not associated with future vascular events. In line with this observation, a number of studies found that most components of the syndrome were not or only marginally associated with vascular events,9 coronary heart disease32 or carotid stenosis32 when considered individually, whereas the metabolic syndrome was associated with the outcomes examined. Also, the clustering of metabolic risk factors had excess influence on carotid intima-media thickness beyond what would have been expected from merely additive effects.33 The results of the present study point towards an additional value of identifying the metabolic syndrome beyond recognition of its component traits. Probably cardiovascular risk increment is also caused by other factors associated with insulin resistance, like elevated inflammation, hypoadiponectinemia, and coagulation disorders all seen in metabolic syndrome.34, 35

Although the prevalence of abdominal obesity at baseline was fairly low, in this study, the development from a non-metabolic syndrome state to a metabolic syndrome state was associated with a marked increase in waist circumference. This may suggest that an increase in insulin resistance is underlying the development to a metabolic syndrome state, supported by the high HOMA-IR values in patients developing the metabolic syndrome. However, since baseline HOMA-IR values were not available, conclusions on an increase in insulin resistance cannot be drawn. Although the obesity criterion at baseline was the least frequent of the metabolic syndrome criteria, baseline BMI as well as change in BMI during follow-up significantly influenced the risk of development of the metabolic syndrome or reversion to a non-metabolic syndrome state. In parallel, a 1.22-fold increased risk of development of the syndrome was shown for every kg gained over 6 years among subjects from the DESIR cohort.36 Maintaining stable weight from young adulthood into middle age has also been shown to prevent development of the metabolic syndrome.37

In cardiovascular risk prevention in PAOD patients, the importance of weight control should be emphasized, and specific interventions directed towards modulation of insulin resistance, such as increasing physical activity, may positively alter vascular prognosis in these patients at very high risk for cardiovascular events. Emphasis on weight control and physical activity are most important, as the present study showed a large effect of BMI decrease on the course of the metabolic syndrome during follow-up. Apart from lifestyle changes, treatment with insulin sensitizing agents, like metformin or thiazolidinediones, can also be considered in PAOD patients with metabolic syndrome,38 although the benefit of these interventions in this population should first be investigated in randomized controlled trials.

A reduction in the number of individual metabolic syndrome components in this study was mainly due to loss of the HDL-cholesterol or triglycerides criteria. These patients had lower HOMA-IR levels at follow-up compared to patients who kept the metabolic syndrome throughout the study. Possibly these changes in HDL-cholesterol and plasma triglyceride concentrations may be the result of increased insulin sensitivity, but information on HOMA-IR levels at baseline would be necessary to conclude on this possibility.

Alternatively, the increased use of statins may also have affected plasma lipids, although statins only marginally influence HDL-cholesterol (+5%) and triglycerides (−15%).39, 40

Changes in metabolic syndrome components over time have also been studied in the French DESIR cohort.41 Among 4293 healthy participants aged 30-64 years, the metabolic syndrome was present in 14% of the population. A quarter of patients with the metabolic syndrome at baseline were no longer classified as having the syndrome after 3 years of follow-up in that study, compared to 35% after 5.5 years in our study. This indicates that even in a high-risk population of patients with PAOD, it is possible to rid oneself of the metabolic syndrome. In the DESIR cohort, fasting glucose was the component that normalized most frequently (40%) after follow-up, whereas in our study this was the case for HDL-cholesterol and triglycerides, while the glucose criterion was only lost in 22% of patients. This difference might be caused by the baseline differences in glucose abnormalities: 10% in DESIR vs 42% in our study.

In the present cohort, vascular risk factors were not optimally treated. For example, less than half of the 221 patients were on statin therapy and the average BP was high. Many patients did not reach treatment goals for vascular risk factors. This is in line with studies by others also showing suboptimal treatment of risk factors in patients with PAOD and coronary heart disease.42, 43 Optimal treatment leads to a better cardiovascular prognosis in these high-risk patients. Patients with clinically-evident coronary heart disease and the metabolic syndrome benefited the most from aggressive lipid-lowering therapy compared to patients without the metabolic syndrome, irrespective of the presence of diabetes.44

We acknowledge limitations in our study. Adequate measures for insulin resistance (eg, fasting insulin) at baseline are lacking. It is therefore not possible to draw conclusions as to how insulin resistance is associated with cardiovascular prognosis in this study and development of insulin resistance over time could not be estimated. Also, changes in physical activity may have influenced the results. As we utilized measures of BMI instead of waist circumference in those patients who did not have their waist circumference measured, it is possible we may have misclassified some individuals that would have been classified differently based on waist circumference measures that constitute the accepted criterion for the metabolic syndrome. Because the survivors of the cohort were invited and only part of them agreed to participate in the follow-up examination, possibly only the less severely affected and younger PAOD patients participated in the follow-up measurement. This could have led to an underestimation of the worsening of vascular risk factors and metabolic syndrome components during follow-up. As only symptomatic PAOD patients were included in this study, we were not able to pronounce upon the vascular risk in asymptomatic patients with PAOD.

In conclusion, patients with PAOD and the metabolic syndrome have a 51% higher risk of developing a vascular event compared to PAOD patients without the metabolic syndrome. Incident metabolic syndrome is associated with an increase in abdominal obesity, and a decrease in BMI was associated with the disappearance of metabolic syndrome in PAOD patients. It may be speculated that weight control in order to reduce incident metabolic syndrome may add to the prevention of new vascular events in these high-risk patients.

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Author contributions 


Conception and design: AV, YG, FM, FV

Analysis and interpretation: AV, MS, FV

Data collection: AV

Writing the article: AV, YG, MS, FV

Critical revision of the article: AV, YG, FM, FV

Final approval of the article: AV, YG, MS, FM, FV

Statistical analysis: AV, MS

Obtained funding: Not applicable

Overall responsibility: AV

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Members of the SMART Study Group are Ale Algra, MD, PhD; Pieter A. Doevendans, M.D, PhD; Yolanda van der Graaf, MD, PhD; Diederick E. Grobbee, MD, PhD; L. Jaap Kappelle, MD, PhD; Willem P.Th.M. Mali, MD, PhD; Frans L. Moll, MD, PhD; Guy E.H.M. Rutten, MD, PhD; and Frank L.J. Visseren, MD, PhD.

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 Competition of interest: none.

PII: S0741-5214(08)02374-4

doi:10.1016/j.jvs.2008.12.070

Journal of Vascular Surgery
Volume 50, Issue 1 , Pages 61-69, July 2009

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