OBJECTIVE— To assess the occurrence and development of new peripheral arterial occlusive disease (PAOD), its risk factors, and the outcome in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS— A total of 130 type 2 diabetic patients (mean age 58 years) were examined at baseline and after a mean follow-up of 11 years (range 7–14). The ankle-brachial index (ABI) and toe-brachial index were used to detect PAOD. Blood and urine samples were taken at baseline, and a history of cardiovascular events was recorded during follow-up.

RESULTS— PAOD was diagnosed in 21 (16%) patients at baseline. During follow-up, 21 of 89 (24%) patients developed new PAOD. There were 29 patients who died, 21 (72%) of them from cardiovascular disease. Patients with PAOD suffered an excess mortality compared with patients without PAOD (58 vs. 16%; P < 0.001). Logistic regression analysis showed that PAOD at baseline was associated with age, duration of diabetes, smoking, and urinary albumin excretion rate. Patients who developed new PAOD during follow-up had higher serum LDL cholesterol concentrations and lower HDL cholesterol concentrations and were older than the patients who remained free of PAOD.

CONCLUSIONS— Objectively measured PAOD is frequent in type 2 diabetic patients. It presents the early clinical signs of atherosclerosis and is strongly associated with cardiovascular death. The risk factor pattern for PAOD was different at baseline and after a mean follow-up of 11 years. We consider routine ABI measurements and modification of risk factors necessary also in patients with asymptomatic PAOD.

In patients with type 2 diabetes, peripheral arterial occlusive disease (PAOD) is a major contributor to diabetic foot problems. Identification of PAOD is essential because, in many cases, appropriate treatment saves the diabetic foot (1). Further, prevention of foot problems may be easier than treating foot problems. For this purpose, specific risk factors for the development of PAOD need to be recognized.

Follow-up studies on risk factors for objectively measured PAOD in patients with type 2 diabetes are few, and the follow-up times are short (2–4 years) (2–4). Some evidence suggests that general risk factors of atherosclerosis such as systolic hypertension, smoking, dyslipidemia, and age are also risk factors for progression of PAOD (2,4). A recent study proposed that HbA1c, LDL cholesterol, and smoking are risk factors for development of new PAOD in patients with type 1 diabetes (5), but no similar data are available for type 2 diabetes.

Objectively measured PAOD predicts cardiovascular death and morbidity both in the general population and the diabetic population (2,6,7). Therefore, the following question arises: Could objectively measured PAOD be the first clinical sign of cardiovascular disease?

The diagnosis of PAOD is critical. Palpation of pulses and a history of claudication detect PAOD inadequately; therefore, PAOD should be assessed by objective noninvasive measurements (8). The ankle-brachial index (ABI) is the most documented of these methods, but in diabetic patients, calcification of artery walls (medial sclerosis) frequently causes falsely elevated ankle pressure values (9,10). A complementary method might be necessary to exclude medial sclerosis.

Our aim was to study the occurrence and development of new PAOD, its risk factors, and the outcome in patients with type 2 diabetes using objective noninvasive methods.

We randomly selected 134 patients with type 2 diabetes (42–69 years of age) from the register of the Helsinki Diabetes Association. Type 2 diabetes was defined using 1985 World Health Organization criteria (11). Patients with malignancies or nephropathy were excluded, and the remaining 130 patients (66 men and 64 women) were first studied from 1983 to 1985, and all available patients (n = 93) were studied again from 1992 to 1995 (Fig. 1). Of the patients, 29 died, 6 did not want to participate, and 2 were lost to follow-up. The mean follow-up time was 11 years (range 7–14). Information on current medical status of the six nonparticipating patients was obtained from their medical records. Death causes were obtained from death certificates and medical records. All patients gave their informed consent, and the protocol was approved by the local ethics committee.

At baseline, all patients underwent a clinical examination with careful assessment of macrovascular (coronary heart disease, PAOD) and microvascular (neuropathy, albuminuria) disease. C-peptide concentrations were measured in serum samples taken before and 6 min after an intravenous injection of 1 mg glucagon by radioimmunoassay (12,13). Fasting blood samples were drawn for measurement of HbA1c and serum lipoprotein concentrations. HbA1 was measured by microcolumn cation exchange chromatography (Isolab, Akron, OH). Lipoprotein fractions were separated by sequential ultracentrifugation from blood samples taken after an overnight (12-h) fast (14). The concentrations of cholesterol and triglycerides in total plasma and separate lipoprotein fractions were determined by enzymatic methods using commercial kits (Boehringer Mannheim, Mannheim, Germany). At baseline, three 24-h urine collections, and at follow-up, three timed overnight urine collections were used for the measurement of urinary albumin excretion rate (UAER) by radioimmunoassay (Pharmacia, Uppsala, Sweden). Microalbuminuria was defined as an UAER of 30–300 mg/24 h or 20–200 μg/min and macroalbuminuria as an UAER of >300 mg/24 h or >200 μg/min in at least two of three urine collections. BMI was calculated as weight in kilograms/height in meters squared (Table 1).

Assessment of PAOD

PAOD was diagnosed based on an ABI of <0.9 on either side, calculated by dividing ankle blood pressure by brachial blood pressure. The ankle blood pressure was measured in a resting position with a 12-cm–wide occluding cuff and a Doppler device as the distal sensor (15–18).

To improve the detection of true PAOD in patients with possible medial sclerosis, we used a toe-brachial index (TBI) value of <0.64 for the patients with an ABI exceeding 1.15 (16,19). TBI was calculated by dividing toe blood pressure by brachial blood pressure. Toe blood pressure was measured using a 24-mm–wide occluding cuff and a mercury strain gauge as the distal sensor. Measurements were performed by a specialized nurse in a vascular laboratory. Eight patients were unable to visit the outpatient clinic at follow-up and their ABI was measured at home by M.K.

Single low values of ABI and TBI at baseline that normalized during follow-up were not considered to indicate PAOD. Progression was defined as a 15% decrease of ABI during follow-up. In addition, a history of claudication was recorded.

Assessment of cardiovascular disease

A cardiovascular event was defined as a history of a verified myocardial infarction or stroke. Coronary heart disease and stroke were recorded as cardiovascular causes of death. Electrocardiograms were taken from each patient. The presence of probable myocardial infarction (codes 1.1–1.2) was recorded according to the Minnesota Coding system (20).

Blood pressure was measured in the sitting position after a 15-min rest using a mercury sphygmomanometer. The mean value of three measurements obtained at 5-min intervals was calculated. Hypertension was defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥95 mmHg or the use of antihypertensive drugs.

Statistical analysis

All data are expressed as means ± SE unless otherwise stated. Categorical data were analyzed with the χ2 test (Fisher two-tailed) and continuous data with the Mann-Whitney U test. Independent variables associated with the presence or development of PAOD were identified with backward stepwise logistic regression analysis.

Frequency and development of PAOD

At baseline, 21 of 130 patients (16%) had PAOD (Table 1). After a mean follow-up of 11 years (range 7–14), 21 of the 89 (24%) patients free of PAOD at baseline developed new PAOD (Fig. 1). Of the 21 patients with PAOD at baseline, 11 were deceased (52%), and progression was seen in 4 of the remaining 10 patients (19%). In total, PAOD was observed in 31 of 99 patients (31%) at follow-up. In three patients, ABI normalized during follow-up.

PAOD was bilateral in 13 of 21 patients (62%) at baseline. Objectively verified PAOD was seen in 59% of the 22 patients reporting claudication, whereas a history of claudication was reported by 62% of 21 patients with verified PAOD. ABI alone identified one patient less with PAOD at baseline and three patients less at follow-up compared with combined TBI and ABI criteria.

Six patients suffered from severe PAOD that required a major amputation. Five of these patients died during follow-up.

Cardiovascular events

During follow-up, 29 of 130 (22%) patients died, 21 (72%) of them from cardiovascular causes. The mortality during a mean follow-up of 11 years was significantly higher in patients with PAOD than without PAOD (52 vs. 17%, P < 0.001). The cause of death was cardiovascular in 91% of patients with PAOD and 61% of patients without PAOD (P < 0.001).

Baseline PAOD was strongly associated with cardiovascular mortality in patients with no history of cardiovascular events or electrocardiogram changes suggestive of a probable myocardial infarction (P < 0.001).

Risk factors for PAOD

At baseline, patients with PAOD were older, had a longer duration of diabetes, and had microalbuminuria more frequently than patients without PAOD (Table 1). Logistic regression analysis showed that the strongest predictor of PAOD was smoking in addition to age, duration of diabetes, and UAER (Table 2).

At follow-up, a different risk factor cluster was associated with new PAOD: high serum triglyceride, serum total and LDL cholesterol, and low HDL cholesterol concentrations (Table 3). In a logistic regression analysis, these risk factors predicted PAOD when tested in separate models. When all lipids were entered into the model simultaneously, the concentrations of LDL and HDL cholesterol as well as the age of the patients and the follow-up time remained significant predictors of PAOD (Table 4).

In this study, 16% of the patients with diabetes had PAOD at baseline and 24% of the patients developed new PAOD during follow-up. The factors associated with objectively measured PAOD at baseline were smoking, microalbuminuria, age, and duration of diabetes. Lipids were associated with development of new PAOD. The mortality during a mean follow-up of 11 years was significantly higher in patients with PAOD than without PAOD.

In our study, the long mean follow-up of 11 years and a well-characterized group of patients with type 2 diabetes provide certain advantages. Further, few studies have so far used objective methods to assess the development of new PAOD in patients with type 2 diabetes. In this respect, ABI is a widely used noninvasive diagnostic tool both in clinical practice and epidemiological studies. It correlates well with the intra-arterial pressure and angiographical findings and is reproducible (15,21–23). However, falsely high ABI values caused by medical sclerosis and incompressible arterial walls are seen in patients with diabetes. Such calcification is rare in the walls of small arterioles; therefore, toe blood pressure measurements are used to detect PAOD in patients with medial sclerosis (9,16,19).

In our material, 16% of patients with type 2 diabetes had PAOD. This figure is similar to the prevalence reported in other studies (2,24,25), although higher percentages (30–40%) are also published (16,26). In comparison, the prevalence of objectively measured PAOD is between 4 and 18% in the general population aged 50–75 years (26–28).

Data regarding development of new PAOD are somewhat conflicting, but it is noteworthy that available studies cannot be directly compared. In two earlier studies, the 2-year incidence of PAOD in patients with diabetes was 14 and 11% in the age-group 50–70 years (2,4). On the other hand, a lower 9% incidence was reported in a study with a 4-year follow-up (29). After a mean follow-up of 11 years, our data showed new PAOD in 24% of the patients, which is in line with a longer follow-up period.

Our study confirmed that a decreased ABI is a strong predictor of increased risk of cardiovascular morbidity and mortality in patients with diabetes, with little additional benefit of toe pressure measurement. Because ABI is one of the first obvious indicators of atherosclerosis, some have proposed using it to screen for atherosclerotic disease to direct more aggressive treatment in patients with the highest risk of cardiovascular events (7,17). ABI could easily be measured at the yearly control visits recommended for diabetic patients (30).

Interestingly, two different risk factor patterns associated with PAOD were observed. Selective mortality could explain the different risk factor profiles because risk factors strongly predictive of death, such as smoking and microalbuminuria, were closely associated with PAOD at baseline (31,32). The effect of lipids may become unmasked only after the most morbid patient group has been removed by death.

Four previous follow-up studies assess risk factors for objectively measured PAOD in diabetes, all using different designs (2–5). The most recent 6-year follow-up in patients with type 1 diabetes showed that metabolic control, LDL cholesterol, and smoking predict development of new PAOD (5). Beach et al. (2) observed that smoking, duration of diabetes, HDL and total cholesterol, blood pressure, and low obesity index were associated with the progression, but not with the development, of new PAOD in patients with type 2 diabetes followed for 2 years. On the other hand, Bendick et al. (4) found that age, duration of diabetes, low body weight, systolic blood pressure, and cholesterol predicted both development and progression of PAOD in patients with diabetes. In general, all studies suggest that general risk factors for atherosclerosis are operative in the process leading to PAOD. However, in the previous studies, the patients were not followed for more than 6 years. The main reason for the two distinct risk patterns for PAOD in our study may be because of the longer follow-up period and thereby the possibility to detect both short- and long-term effects of risk factors.

Patients with type 2 diabetes generally have an atherogenic lipid pattern characterized by high triglyceride and low HDL cholesterol concentrations. However, the atherogenic influence of lipids in patients with diabetes is not necessarily linked to the degree of dyslipidemia only, but also to altered, particularly atherogenic, particles in patients with type 2 diabetes (33).

Microalbuminuria is a risk factor for microvascular complications and premature death in patients with diabetes. Evidence is emerging that PAOD is more frequent in patients with type 2 diabetes with abnormal UAER than with normal UAER (34). In our study, microalbuminuria was associated with PAOD at baseline, but it did not predict the development of new PAOD, possibly because of the selective mortality of microalbuminuric diabetic patients during follow-up (31,32).

In conclusion, objectively measured PAOD is frequent in patients with type 2 diabetes. It presents the early clinical signs of atherosclerosis and is strongly associated with cardiovascular death. The risk factor pattern for PAOD was different at baseline and after a mean follow-up of 11 years. We consider routine ABI measurements and modification of risk factors necessary in patients with asymptomatic PAOD.

Figure 1—
Figure 1—. Fate of the patients during the follow-up period.
View largeDownload slide

Fate of the patients during the follow-up period.

Figure 1—
Figure 1—. Fate of the patients during the follow-up period.
View largeDownload slide

Fate of the patients during the follow-up period.

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Table 1—

Characteristics of the 130 patients at baseline

PAOD (21 patients)No PAOD (109 patients)P
Age (years) 61 ± 0.8 57 ± 0.6 0.01 
Sex (% male) 57 50  
History of smoking (%) 71 50  
BMI (kg/m2) 27 ± 0.5 27 ± 0.4  
Insulin treatment (%) 19 22  
Duration of diabetes (years) 12 ± 1.0 9 ± 0.4 0.01 
HbA1 (%) 10.6 ± 0.4 9.9 ± 0.2  
C-peptide (nmol/l) 0.48 ± 0.06 0.47 ± 0.03  
Systolic blood pressure (mmHg) 156 ± 7 153 ± 2  
Diastolic blood pressure (mmHg) 87 ± 3 88 ± 1  
Hypertension (%) 67 51  
Total cholesterol (mmol/l)* 6.5 ± 0.3 6.3 ± 0.1  
LDL cholesterol (mmol/l)* 4.4 ± 0.3 4.3 ± 0.1  
HDL cholesterol (mmol/l)* 1.3 ± 0.05 1.4 ± 0.04  
Triglycerides (mmol/l)* 2.8 ± 0.5 2.3 ± 0.2  
Microalbuminuria (%) 52 11 <0.0001 
UAER (mg/24 h)† 61 ± 19 12 ± 2 0.0003 
Electrocardiogram changes (%) 5 10  
History of myocardial infarction (%) 1 8  
History of stroke (%) 2 1  
PAOD (21 patients)No PAOD (109 patients)P
Age (years) 61 ± 0.8 57 ± 0.6 0.01 
Sex (% male) 57 50  
History of smoking (%) 71 50  
BMI (kg/m2) 27 ± 0.5 27 ± 0.4  
Insulin treatment (%) 19 22  
Duration of diabetes (years) 12 ± 1.0 9 ± 0.4 0.01 
HbA1 (%) 10.6 ± 0.4 9.9 ± 0.2  
C-peptide (nmol/l) 0.48 ± 0.06 0.47 ± 0.03  
Systolic blood pressure (mmHg) 156 ± 7 153 ± 2  
Diastolic blood pressure (mmHg) 87 ± 3 88 ± 1  
Hypertension (%) 67 51  
Total cholesterol (mmol/l)* 6.5 ± 0.3 6.3 ± 0.1  
LDL cholesterol (mmol/l)* 4.4 ± 0.3 4.3 ± 0.1  
HDL cholesterol (mmol/l)* 1.3 ± 0.05 1.4 ± 0.04  
Triglycerides (mmol/l)* 2.8 ± 0.5 2.3 ± 0.2  
Microalbuminuria (%) 52 11 <0.0001 
UAER (mg/24 h)† 61 ± 19 12 ± 2 0.0003 
Electrocardiogram changes (%) 5 10  
History of myocardial infarction (%) 1 8  
History of stroke (%) 2 1  

Data are means ± SE or %. PAOD/no PAOD

*

22/104,

†

21/103.

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Table 2—

Factors associated with PAOD at baseline

Log likelihood ratio POdds ratio (95% CI)
Age 0.03 1.15 (1.00–1.32) 
Smoking 0.04 3.69 (0.98–13.84) 
Duration of diabetes 0.05 1.13 (1.00–1.27) 
UAER 0.002 1.02 (1.00–1.04) 
Log likelihood ratio POdds ratio (95% CI)
Age 0.03 1.15 (1.00–1.32) 
Smoking 0.04 3.69 (0.98–13.84) 
Duration of diabetes 0.05 1.13 (1.00–1.27) 
UAER 0.002 1.02 (1.00–1.04) 

Included in the logistic regression model were age, sex, smoking, BMI, hypertension, treatment of diabetes (insulin/oral agents), duration of diabetes, HbA1, cholesterol, and UAER.

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Table 3—

PAOD at follow-up: baseline characteristics of the 89 patients with no PAOD at baseline who participated in the follow-up study

PAOD (21 patients)No PAOD (68 patients)P
Age (years) 58.6 ± 1.0 56.6 ± 0.7  
Sex (% male) 38 49  
Smoking history (%) 57 44  
BMI (kg/m2) 27 ± 1 27 ± 1  
Systolic blood pressure (mmHg) 158 ± 5 153 ± 3  
Diastolic blood pressure (mmHg) 88 ± 2 88 ± 1  
Hypertension (%) 48 52  
Insulin treatment (%) 14 24  
Diabetes duration (years) 9.9 ± 0.6 8.5 ± 0.6  
HbA1 (%) 10.3 ± 0.5 9.6 ± 0.2  
Fs C-peptide (nmol/l) 0.49 ± 0.05 0.44 ± 0.05  
Total cholesterol (mmol/l)* 7.2 ± 0.4 6.1 ± 0.2 0.002 
LDL cholesterol (mmol/l)* 4.8 ± 0.3 4.1 ± 0.1 0.03 
HDL cholesterol (mmol/l)* 1.3 ± 0.1 1.5 ± 0.1 0.04 
Triglycerides (mmol/l)* 3.5 ± 0.6 1.8 ± 0.2 0.0002 
Microalbuminuria (%) 10 7  
UAER (mg/24 h)† 10 ± 3 10 ± 3  
PAOD (21 patients)No PAOD (68 patients)P
Age (years) 58.6 ± 1.0 56.6 ± 0.7  
Sex (% male) 38 49  
Smoking history (%) 57 44  
BMI (kg/m2) 27 ± 1 27 ± 1  
Systolic blood pressure (mmHg) 158 ± 5 153 ± 3  
Diastolic blood pressure (mmHg) 88 ± 2 88 ± 1  
Hypertension (%) 48 52  
Insulin treatment (%) 14 24  
Diabetes duration (years) 9.9 ± 0.6 8.5 ± 0.6  
HbA1 (%) 10.3 ± 0.5 9.6 ± 0.2  
Fs C-peptide (nmol/l) 0.49 ± 0.05 0.44 ± 0.05  
Total cholesterol (mmol/l)* 7.2 ± 0.4 6.1 ± 0.2 0.002 
LDL cholesterol (mmol/l)* 4.8 ± 0.3 4.1 ± 0.1 0.03 
HDL cholesterol (mmol/l)* 1.3 ± 0.1 1.5 ± 0.1 0.04 
Triglycerides (mmol/l)* 3.5 ± 0.6 1.8 ± 0.2 0.0002 
Microalbuminuria (%) 10 7  
UAER (mg/24 h)† 10 ± 3 10 ± 3  

Data are means ± SE or %. Number of patients with PAOD/no PAOD;

*

20/66,

†

19/65.

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Table 4—

Factors associated with development of new PAOD in 89 patients with no PAOD at baseline

P for log likelihood ratioOdds ratio (95% CI)
Age 0.002 1.25 (1.06–1.48) 
HDL cholesterol 0.0003 0.009 (0.0003–0.23) 
LDL cholesterol 0.002 2.97 (1.33–6.66) 
Follow-up time 0.008 1.62 (1.09–2.41) 
P for log likelihood ratioOdds ratio (95% CI)
Age 0.002 1.25 (1.06–1.48) 
HDL cholesterol 0.0003 0.009 (0.0003–0.23) 
LDL cholesterol 0.002 2.97 (1.33–6.66) 
Follow-up time 0.008 1.62 (1.09–2.41) 

Included in the logistic regression model were age, sex, smoking, BMI, hypertension, treatment of diabetes (insulin/oral agents), duration of diabetes, HbA1, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, AER, and follow-up time.

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This study was supported by the Finnish Medical Society, the Foundation for Life and Health, the Sigrid Juselius Foundation, and the Perklén Foundation.

We thank Marita von Bell, Päivikki Määttälä, and Jukka Ollgren, MSc.

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Address correspondence and reprint requests to Per-Henrik Groop, MD, DMSc, Folkhälsan Research Centre, Biomedicum Helsinki (C318b), POB 63, University of Helsinki, FIN-00014, Finland. E-mail: [email protected].

Received for publication 17 March 2002 and accepted in revised form 13 December 2002.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

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