Prevalence of peripheral arterial disease in a cohort of diabetic patients.

Background: The aim of this study was to determine the prevalence of peripheral diseases in diabetics of different age groups, the role of color Doppler in peripheral arterial disease in diabetics, and to compare the prevalence of peripheral arterial disease (PAD) in diabetics taking different therapy modalities.

Methods: In a hospital-based prospective study conducted over 19 months, we screened 100 consecutive type 2 diabetic patients and 50 consecutive nondiabetic patients matched for demographics and ethnicity. History, physical examination and color Doppler results were analyzed. The degree of stenosis in PAD was graded according to Jager's criteria.

Result: The prevalence of PAD was 8% in controls and 24% in diabetics. There were 60 subjects (60%) greater than 50 years of age in the diabetic population and 36 (72%) subjects in the nondiabetic group. There was male preponderance with 70% of diabetic patients and 60% of nondiabetic patients being male. According to mode of therapy, the prevalence of PAD was found to be 20% in diabetics taking oral hypoglycemic agents and insulin, 27.2% on oral hypoglycemic agents, and 25% on insulin therapy.

Conclusion: This study suggests that there is a higher prevalence of PAD in diabetics as compared with controls. The prevalence of PAD is directly proportional to the duration of diabetes and age of the person. The prevalence of PAD is not a function of treatment modality. The stenosis associated with PAD in diabetics is generally infrapopliteal.

Key Words: peripheral arterial disease, color Doppler, diabetes mellitus, atherosclerosis

**********

Peripheral arterial disease (PAD) is a common presentation of atherosclerosis and is also a strong independent predictor of future cardiovascular ischemic events. (1-3) Several studies have shown a relationship of age, duration of diabetes, hypertension, smoking, obesity and urine albumin excretion rate with PAD. (2-5) The diagnosis of PAD in diabetics is evidence of more widespread atherothrombotic disease, with substantial risks of subsequent cardiovascular events and death. (6, 7)

In diabetics, PAD is commonly under diagnosed and results in increased morbidity complicated by peripheral neuropathy and susceptibility to infection, which leads to foot ulceration, gangrene and amputation of the affected extremity. PAD accounts for half of all amputations among diabetics. (6)

To ascertain the prevalence of PAD in different populations, many studies have been performed. Most epidemiologic and clinical studies have used a noninvasive measurement, the ankle-brachial index (ABI), to diagnose PAD which involves measuring the systolic blood pressure in the ankles (dorsalis pedis and posterior tibial arteries) and arms (brachial artery) using a handheld Doppler and then calculating a ratio. (8-10) Limitations in the measurement of ABI include patients with calcified, poorly compressible vessels, most often found in the elderly, and diabetic patients, who may have apparently elevated values. ABI may also be falsely negative in symptomatic patients with moderate aortoiliac stenosis. (10)

The present study was undertaken to examine the utility of color Doppler in peripheral arterial disease in type 2 diabetics, the prevalence of peripheral arterial disease in diabetics in different age groups and to compare the prevalence of PAD in diabetics on different therapies.

Materials and Methods

Written informed consent was taken from the patients and the protocol approved by the ethics committee of our institution.

Subjects

In a hospital-based prospective study, we screened 100 consecutive type 2 diabetic patients with no previous clinical manifestation of cardiovascular disease (CVD), peripheral arterial disease (PAD) or cerebrovascular accident (CVA) admitted to the medicine ward of our institution between June 2003 to December 2004. The control group included 50 nondiabetic patients admitted to medical wards for other illnesses, matched for age, gender, and ethnicity. A detailed clinical history and physical examination, which focused on the lower extremities, was performed in all patients. Anthropometric measurements included height and weight measurements and BMI was determined according to kg/[m.sup.2]. The blood pressure was recorded using a mercury sphygmomanometer in the right arm in the sitting position. Two readings were taken 5 minutes apart, and the mean was taken. Individuals were classified as nonsmokers (never smoked) and smokers (ex-smokers and current smokers). No subjects had a history of ketoacidosis. Intermittent claudication was taken as a PAD symptom when the exercise-pain-rest cycle was constant. Leg pain that occurred at rest was also diagnosed as a PAD symptom, because it was difficult to distinguish them from symptoms of peripheral neuropathy. Orthopaedic diseases in the lumbar spine were also excluded. Among the subjects, 44 patients were on oral hypoglycemic agents, 16 had been on insulin therapy for at least 5 years and 40 were on oral hypoglycemics as well as insulin therapy.

Exclusion criteria in the control group were presence of overt hyperglycemia of 7.0 mmol/L (126 mg/dL) or higher. In addition, we excluded patients taking pharmacological therapy for diabetes mellitus.

Biochemical Investigations

Blood was drawn in the morning after an overnight fast. These assays were done by standard laboratory methods. A fasting blood sample was taken, 75 g of glucose was given orally with 200 mL of water to all of the individuals excluding known diabetic subjects, and a 2 hour post glucose sample was then collected. Fasting and 2 hour plasma glucose (glucose oxidase method), serum cholesterol (cholesterol oxidase method), serum triglycerides (glycerol phosphate oxidase method), serum urea and serum creatinine (modified kinetic method of Jaffe) were measured. HDL cholesterol was estimated by the cholesterol oxidase method after precipitating LDL and chylomicron fractions by the addition of phosphotungstic acid in the presence of magnesium ions and VLDL. Microalbuminuria (MA) was diagnosed when subjects had a urinary albumin concentration greater than the assay threshold (6.2 mg/L)

Peripheral Doppler Studies

An operator who was blinded to subject conditions performed the arterial Doppler study on 100 type 2 diabetic patients and 50 controls. All the Doppler studies were performed by a single observer using the color Doppler machine (Hewlett Packard HP, Sonos 2000 Cardiac/ Vascular Ultrasound System 2000, USA.). Information on the presence and grade of stenosis, post stenotic turbulence, peak systolic velocity, end diastolic velocity, presence of collaterals and their flow characteristics, and presence of flow in any extravascular collection were collected in color Doppler imaging. The degree of stenosis was graded according to the criteria of Jager et al: Normal: Triphasic waveform with thin spectral band. Grade I: 1 to 19% stenosis: Normal triphasic flow with normal peak systolic velocity (PSV) with spectral broadening. Grade II: 20 to 49% stenosis: Triphasic waveform with PSV increased by more than 30% with respect to proximal recording site. Marked spectral broadening. Grade III: 50 to 99% stenosis: Monophasic waveform with PSV increased by more than 100% with marked spectral broadening. Distal waveform is abnormal. Grade IV: 100% stenosis: No forward flow detected with altered flow patterns both proximal and distal to stenosis. (11)

Definitions and Diagnostic Criteria

Diabetes was diagnosed in the study participants based on the past medical history, pharmacological therapy for diabetes (oral hypoglycemic agents or insulin), and/or criteria outlined by the World Health Organization. (12) Diabetes was diagnosed if fasting plasma glucose level was [greater than or equal to] 126 mg/dL (7.0 mmol/L) and/or the 2-hour plasma glucose was [greater than or equal to]200 mg/dL (11.1 mmol/L). Hypertension was diagnosed based on a history of drug treatment for hypertension or if blood pressure was >140/90 mm Hg. (13) Hypercholesterolemia and hypertriglyceridemia were diagnosed if serum cholesterol or triglycerides were > 5.2 mmol/L (200 mg/dL) and >2.26 mmol/L (200 mg/dL), respectively, according to National Cholesterol Education Program guidelines. (14) Subjects were classified as having pre-existent ischemic heart disease (IHD) when they had an ECG with Minnesota code 1.1 to 1.3, 4.1 to 4.3, 5.1 to 5.3, or 7.1 and/or had undergone coronary bypass surgery or angioplasty; as having cerebrovascular disease when they had evidence of a past transient ischemic attack or stroke according to the WHO cardiovascular questionnaire. (15)

Statistical Analysis

Data analysis was performed using SPSS statistical analysis software (version 10). Differences in continuous variables were analyzed by independent sample t test. Categorical variables were analyzed by chi-square cross tabulations. All p values are two sided with values <0.05 considered significant.

Results

The overall age and gender distribution of the patients is depicted in Table 1. The predominant age group in the diabetic population was 41 to 60 years (mean: 55.9 year, standard deviation [SD] 9.3 years) comprising 68 patients (68%) with 48 males (71.6%). The predominant age group in the nondiabetic population was 51 to 70 years (mean: 59.5 years, SD of 10.1 years), comprising 32 patients (64%) with 18 females (56.3%). There were 60 (60%) subjects over 50 years of age in the diabetic population and 36 (72%) in the nondiabetic population. There was a definite male preponderance with 70% of diabetic patients and 60% of nondiabetic patients being male.

Among the biochemical parameters in both the diabetics and controls, fasting and postprandial blood sugar, glycosylated hemoglobin, blood urea, serum creatinine, cholesterol, triglycerides, and percentages of patients with albuminuria and microalbuminuria were significantly higher (P < 0.05) in diabetics as compared with controls. Mean fasting blood sugar, mean postprandial blood sugar, and mean glycosylated hemoglobin in the diabetic population were 160 mg%, 189 mg%, 9.2 g%, while in the control population, the values were 85 mg%, 127 mg%, and 6.1 g%, respectively (P < 0.05). Mean serum cholesterol and serum triglycerides were 218 mg% and 314.2 mg% in diabetics, and 169.2 mg% and 138.2 mg% in the control group (P < 0.05). However, serum HDL was not significantly lower in the diabetic population, with a mean of 41.6 mg%, as compared with 57.8 mg% in the control group. There were significant numbers of diabetics with microalbuminuria as compared with controls (P < 0.05).

Duration of diabetes mellitus included in the study group was 13.2 years with a standard deviation of [+ or -]8.3 years. Seventy-six patients (76%) had a diabetes duration of 0 to 10 years. The minimum duration was 3 years, and the maximum duration was 30 years. The diabetics as well as controls showed male predominance with a male/female ratio of 2.3:1 in diabetics and 1.5:1 in controls.

There were 54% hypertensive patients in the diabetic group as compared with 34% in the control group (P < 0.05).

There were a significant number of asymptomatic patients in regards to leg pain in the diabetic group as well as in the nondiabetic group. Forty six percent of diabetics and 52% of nondiabetics were asymptomatic, while 38% of diabetics and 40% of nondiabetics presented with typical leg symptoms. Only 16% of diabetic patients and 8% of the control group patients presented with classic claudication. This was similar to the cardiovascular health study done by Newman et al in 2001 who observed 59% subjects to be asymptomatic, 32% with exertional leg symptoms other than intermittent claudication and only 9% of patients with intermittent claudication.

A total of 24 of 100 diabetics and 4 out 50 controls were found to have PAD using the Jager's criteria by color Doppler method (P < 0.05). Eighteen of 24 (75%) diabetic patients with PAD were in the 41 to 60 year age group (mean) while 4 of 4 (100%) nondiabetic patients with PAD were in the 51 to 70 year age group. The number of patients > 50 years of age having PAD was 14 of 24 (58.33%) in the diabetic group and 4 of 4 (100%) in the control group. There was a definite male preponderance with 70% of diabetic patients and 60% of nondiabetic patients being male.

The prevalence of PAD in diabetic patients was correlated according to pharmacological therapy. In our study, 44 (44%) diabetic patients were on oral hypoglycemic agents, 40% were taking oral hypoglycemic agents and insulin, and 16 patients (16%) were on insulin alone. Twelve of 44 patients on oral hypoglycemic agents were found to have PAD with a prevalence of 27.3%. Four out of 16 diabetic patients on insulin therapy for at least 5 years were found to have PAD with a prevalence of 25%. Of the 40 patients who were receiving oral hypoglycemics as well as insulin, 20% had PAD. It was found that pharmacological therapy in diabetics was not statistically significant (P = NS) with relation to prevalence of PAD.

[FIGURE OMITTED]

The prevalence of PAD increased with the duration of diabetes mellitus. The prevalence of PAD was 5.3% with duration of 0 to 10 years. The prevalence of PAD increased to 42.9% with a diabetic duration of between 11 to 20 years. The prevalence of PAD increased to 50% if the duration was 21 to 30 years. There was a statistically significant increase (P < 0.001) in the prevalence of PAD with the increasing duration of diabetes mellitus.

The involvement of arterial segments in the lower extremities was seen in 48 patients in the diabetic group and in 8 patients in the control group (P < 0.05). The external iliac artery was involved in 2 patients in the diabetic group, and there was significant involvement of the anterior tibial, posterior tibial, popliteal, and dorsalis pedis arteries in this group. There was multisegmental involvement in 16 patients in the diabetic subjects, but none in the controls. (Fig.)

Discussion

PAD is a manifestation of atherosclerotic disease that leads to a narrowing of the arteries in the legs. (16) About half of the patients with PAD (defined as abnormal ankle brachial pressure index) have associated symptomatic coronary or cerebrovascular disease. (17) Atherosclerosis of the peripheral arterial system contributes to significant morbidity and mortality in patients. (18) Coronary artery disease and PAD are still under diagnosed. Only 20% of patients with PAD are aware of the disease.

The combination of diabetes and PAD is ominous, because PAD rapidly progresses to ischemic pain at rest and ulceration. Patients with claudication and diabetes mellitus have an overall amputation risk of 20% and a 5-year mortality rate of almost 50%. Among risk factors for amputation in diabetics are neuropathic symptoms and lack of outpatient diabetic education. (8)

Advances in radiographic imaging of the lower limb in recent years have provided details of its pathology, both vascular and nonvascular, particularly with the advent of ultrasonography, CT and MR imaging, conventional angiography and radio nucleotide scanning. (10) The advent of color Doppler imaging has added to our armamentarium as an important vascular imaging technology because of its noninvasive nature. (10)

In large population-based studies conducted in the United States, Europe and the Middle East, the prevalence of PAD based on an abnormal ABI ranges from 4.6% to 19.1%. (10) In this study, the prevalence of PAD was 8% in the control population, and 24% in the diabetic subjects by color Doppler analysis.

A study by Collins et al, (19) which included Caucasian, African-American, Latino, and Spanish-speaking Latino-American patients, concluded that after adjusting for atherosclerotic risk factors and level of education, ethnicity was not an independent risk factor for PAD. But the prevalence of PAD in various studies using ABI, in comparison to our study (Table 2) (7, 8, 11, 21-23) clearly suggests a different prevalence of PAD in different regions and groups; thus emphasizing the need for more efforts to better understand the role of the primary care setting in reducing the burden of social inequality on health.

In a large study in a free-living population participating in a lipid research clinic protocol, PAD was detected in less than 3% of those younger than 60 years but in more than 20% of those 75 years and older, and was 27% more prevalent in men than women. (6) In the present study, the youngest diabetic patient was 34 years old, and the oldest was 78. The youngest patient in the nondiabetic population was 36 years old, and the oldest was 76. The predominant age group in the diabetic population was 41 to 60 years comprised of 68 patients (68%) and in the nondiabetic population, a total of 32 patients (64%) were between 51 to 70 years old. There were 60 (60%) subjects in the diabetic population who were greater than 50 years of age and 36 (72%) subjects in the nondiabetic group. There was a definite male preponderance with 70% of diabetic patients and 60% of nondiabetic patients being male. A study of Greek patients also supports the present study that male sex (P < 0.001) has a higher prevalence of PAD. (8)

In 2003, the American Diabetes Association stated that in diabetic patients, the risk of PAD is increased by age, duration of diabetes mellitus, and presence of peripheral neuropathy. (10)

The limitations of our study are a small sample size and therefore might not be representative of the whole population. Also, the study did not match the homocysteine levels in both groups. In previous studies it is well documented that homocysteine is an independent risk factor for the development of peripheral arterial disease. (10, 20) Peroneal arteries could not be appropriately studied in the present study because of technical difficulties. Previous studies have documented that peroneal arteries are commonly involved, especially in diabetics. The present study did not confirm color Doppler findings by other methods like peripheral angiography, which is considered the gold standard for confirming PAD.

Conclusions

In a cohort of type 2 diabetic patients, PAD has a high prevalence as compared with controls when assessed by color Doppler method. The prevalence of PAD was directly proportional to the duration of diabetes mellitus and the age of the patients. The prevalence of PAD was not limited by the treatment modality in diabetics. In diabetics, stenosis usually occurs in the bilateral infrapopliteal arteries, with greater involvement of the anterior tibial, posterior tibial and dorsalis pedis arteries. There is also multisegmental involvement of lower limb arteries in diabetes mellitus, which is unlike the nondiabetics. In addition, PAD occurs at a younger age in diabetic patients.

References

1. SoRelle Ruth. Keeping the pressure down in patients with type 2 diabetes and peripheral artery disease: cardiovascular news. Circulation 2003;107:E9008-E9009.

2. Kallino M, Forsblom C. Groop PH, et al. Development of new peripheral arterial occlusive disease in patients with type 2 diabetes during a mean follow up of 11 years. Diabetes Care 2003;26:1241-1245.

3. Khan S, Cleanthis M. Smout J, et al. Life-style modification in peripheral arterial disease. Eur J Vase Endovasc Surg 2005;29:2-9.

4. Fine JJ, Hall PA, Richardson JH. Predictive power of cardiovascular risk factors for detecting peripheral vascular disease. South Med J 2004;97:951-954.

5. Willigendael EM, Teijink JA, Bartelink ML, et at. Influence of smoking on incidence and prevalence of peripheral arterial disease J Vasc Surg 2004;40:1158-1165.

6. Caro J, Migliaccio-Walle K, Ishak KJ, Proskorovsky I. The morbidity and mortality following a diagnosis of peripheral arterial disease: long term follow-up of a large database. BMC Cardiovasc Disord 2005;5:14.

7. Beks PJ, MacKaay AJC, De Neeling JN, et al. Periphral arterial disease in relation to glycaemic level in an elderly Caucasian population: the Hoorn Study. Diabetologia 1995;38:86-96.

8. Antonopoulos S, Kokkoris S, Stasini F, et al. High prevalence of subclinical peripheral artery disease in Greek hospitalized patients. Eur J Intern Med 2005; 16:187-191.

9. Raman PC, Bhagwat A. Ankle brachial index in peripheral vascular disease in diabetes mellitus. JAPI 1997;45:440-442.

10. Borssen B, Bergenheim T, Lithner F. The epidemiology of foot lesions in diabetic patients. Diabet Med 1990;7:438-444.

11. Jager KA, Phillips DJ, Martin RL, et al. Noninvasive mapping of lower limb arterial lesions. Ultrasound Med Biol 1985;11:515-521.

12. Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications, I: diagnosis and classification of diabetes mellitus: provisional report of a WHO consultation. Diabet Med 1998;15:539-553.

13. Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993;153:154-183.

14. Goodman DS. The National Cholesterol Educational Program: Guidelines, status and issues. Am J Med 1991;90:32S-35S.

15. Rose GA, Blackburn H. World Health Organ Monogr Ser. 1968;56:1-188.[Medline] [Order Article via Infotrieve].

16. Olson KW, Treat-Jacobson D. Symptoms of peripheral arterial disease: a critical review. J Vasc Nurs 2004;22:72-77.

17. Norman PE, Eikelboom JW, Hankey GJ. Peripheral arterial disease: prognostic significance and prevention of atherothrombotic complications. Med J Aust 2004;181:150-154.

18. Murabito JM, Evans JC, Nieto K, et al. Prevalence and clinical correlates of peripheral arterial disease in the Framingham Offspring Study. Am Heart J 2002; 143:961-965.

19. Collins TC, Petersen NJ, Suarez-Almazor M, Ashton CM. Ethnicity and peripheral arterial disease. Mayo Clin Proc 2005;80:48-54.

20. Taylor Jr, LM Moneta GL, Sexton GJ, Schuff RA, et al. Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease. J Vase Surg 1999;29:8-19.

21. Beach KW, Bedford GR, Bergelin RO, et al. Progression of lower-extremity arterial occlusive disease in type 2 diabetes mellitus. Diabetes Care 1998;11:464-472.

22. Fowkes FGR, Housley E, Cawood EHH, et al. Edinburgh Artery Study prevalence asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol 1991;20:384-392.

23. Katsilambros NL, Tsapogas PC, Arvanitis MP, et al. Risk factors for lower-extremity arterial disease in non-insulin-dependent diabetic persons. Diabet Med 1996;13:243-246.

The real art of conversation is not only to say the right thing at the
right place but to leave unsaid the wrong thing at the tempting moment.
--Dorothy Nevill

Vishwajeet Bembi, MD, Sarabjeet Singh, MD, Paramjeet Singh, MD, G. K. Aneja, MD, DM, T. V. S. Arya, MD, DM, and Rohit Arora, MD, FACC 

From the Department of Medicine, Chicago Medical School, Chicago, IL, and the Department of Medicine, Lala Lajpat Rai Memorial Medical College and Sardar Vallabh Bhai Patel and associated hospitals, Meerut, India.

Reprint requests to Rohit Arora, MD, FACC, Department of Cardiology, Chicago Medical School/NCVAMC-133 B, 3001 Green Bay Road, North Chicago, IL 60064. Email: [e-mail]

Accepted March 3, 2006.

RELATED ARTICLE: Key Points

* Peripheral arterial disease (PAD) is more prevalent in diabetics compared with nondiabetics.

* The prevalence of PAD is directly proportional to the duration of diabetes and age of the person.

* The prevalence of PAD is not a function of treatment modality.

* The stenosis associated with PAD is generally infrapopliteal.

Table 1. Demographics of diabetic and control population

                                                Control           P
Characteristic                 Diabetics        group             value

Age (years)                     55.86            59.5             NS
                                  [+ or -] 9.3     [+ or -] 10.1
Duration of diabetes (years)    13.24             -               -
                                  [+ or -] 8.3
Sex distribution male/female    70/30            30/20
Percentage of hypertensive      54%              34%              -
  patients
Percentage of smokers           40%              46%              NS
Mean fasting blood sugar       159.9             84.8             < 0.05
  (mg%)
Mean postprandial blood sugar  189.2            127.4             < 0.05
  (mg%)
Mean glycosylated hemoglobin     9.2              6.1             < 0.05
  (gm%)
Mean blood urea (mg%)           34.2             23.6             < 0.05
Mean serum creatinine (mg%)      1.2              0.9             < 0.05
Mean serum cholesterol (mg%)   218.1            169.2             < 0.05
Mean serum triglyceride (mg%)  314.2            138.2             < 0.05
Mean serum HDL (mg%)            41.6             57.8             NS
Percentage of patients with     40%               0%              -
  urine albumin
Microalbuminuria                20/60             4/50            < 0.05
Percentage of patients with     39%               0%              -
  urine sugar
Type of treatment
  OHA                           44 (44%)          -
  Insulin                       16 (16%)          -
  OHA + insulin                 40 (40%)          -

NS, not significant; OHA, oral hypoglycemic agent.

Table 2. Prevalence of peripheral arterial disease (PAD) in various
studies

Reference          City, country           Age (years)

Beach et al (22)   Washington, USA         50-70
  (1998)
Fowkes et al (23)  Edinburgh, UK           55-74
  (1991)
Katsilambros et    Athens, Greece          All age groups
  al (24) (1996)
Antonopoulos S et  Piraeus, Greece         50-80
  al (8) (2005)
Beks et al (7)     Amsterdam, Netherlands  50-74
  (1996)
Present study      Meerut, India           30-70

                                  Prevalence
Reference          Category       of PAD (%)  Diagnostic criteria

Beach et al (22)   Diabetes       22.0        ABI<0.95
  (1998)           NGT             3.0
Fowkes et al (23)  General        18.0        ABI<0.9 and/or
  (1991)             population                 intermittent
                                                claudication
Katsilambros et    Diabetes       42.0        ABI<0.9 and/or
  al (24) (1996)                                intermittent
                                                claudication
Antonopoulos S et  Hospitalized   36%         ABI<0.9
  al (8) (2005)      general pts
Beks et al (7)     NGT             7.0        ABI<0.9
  (1996)           IGT             9.5
                   NDD            15.1
                   KD             20.9
Present study      Diabetes       24.0        Color Doppler
                   Control         8.0        (Jager et al (11)
                                                criteria)

KD, known diabetes; NDD, newly diagnosed diabetes; NGT, normal glucose
tolerance; IGT, impaired glucose tolerance; ABI, ankle brachial index;
pts, patients.