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Indian Journal for the Practising Doctor

A Correlation of Common Carotid Intima Media Thickness with Risk Factors for Atherosclerosis in Type 2 Diabetes Mellitus Patients

Author(s): Aftab Sas, Sudha V, Dixit US, Bairy KL

Vol. 5, No. 6 (2009-01 - 2009-02)

Aftab Sas, Sudha V, Dixit US, Bairy KL

Dr Aftab Sas, MD, Dr V Sudha, MD, Dr US Dixit, MD, Department of Medicine Dr KL Bairy, MD,PhD, Department of Pharmacology, Kasturba Medical College and Hospital, Manipal, India

Correspondence:
Dr. K. L. Bairy
MD, PhD, Professor of Pharmacology, Kasturba Medical College, Manipal-576104.
[Phone: +91 820 2922554, Fax: +01 820 2571999, Email: klbairy(at)yahoo.com]

Abstract

Objective: To correlate common carotid intima media thickness (CCIMT) with risk factors for atherosclerosis in patients with Type 2 Diabetes Mellitus and thereby assess the strongest determinants. Design: The CCIMT in ninety type 2 diabetes patients with and without atherosclerotic events was assessed with the aim of individually correlating various risk factors for atherosclerosis with the CCIMT.
Results: In our study the strongest significant positive correlation and independent association of CCIMT turned out to be with Age (r = + 0.2948, p = 0.0493, β/SE = 2.4474) and Proteinuria (r = + 0.4083, p = 0.0054, β/SE = 2.2205). Whereas waist/hip ratio, duration of diabetes mellitus, systolic blood pressure, glycosylated hemoglobin, triglyceride, and Total Cholesterol/HDL Cholesterol showed a positive but statistically insignificant correlation with CCIMT. However, the patients who had higher CCIMT values and high odds ratios for atherosclerotic events had significantly higher durations of diabetes, hypertension and presence of dyslipidemias.
Conclusion: Age and proteinuria were the strongest correlates and independent associates of the CCIMT. Further studies on a larger number of patients are needed to confirm the correlation of duration of diabetes mellitus, hypertension, central obesity, HbA1c and triglyceride levels with CCIMT, which is the trend emerging from our study.

Key words: Type 2 diabetes mellitus, risk factors for atherosclerosis, common carotid intima media thickness, strongest determinants, prompt intervention, prevention

Introduction

By enabling the assessment of atherosclerosis through direct visualization at the anatomical vascular level, the Common Carotid Intima Media Thickness (CCIMT) provides us an immense opportunity to assess the modulation of in situ pan-atherosclerosis via control of risk factors for atherosclerosis.

Diabetes mellitus itself accelerates atherosclerosis but the immense impetus comes from the in concert interaction with various risk factors for atherosclerosis. Once the strongest correlates and associates of the CCIMT are uniformly unraveled in patients with diabetes, we would have immense modifying power in our hands to prevent atherosclerotic vascular events. The key word and the beacon behind the purpose of our study is the word ”uniformly” because the astute reviewer of this topic will realize that more the studies conducted and reported, the more the variability of risk factors correlating with CCIMT.

When it was suggested by the International Atherosclerosis Project that the atherosclerotic process occurs at the same time in the carotid, the cerebral and the coronary arteries1, the assessment of carotid atherosclerosis by ultrasonographic measurement of CCIMT took over as being the marker of atherosclerosis2,3. A highly accurate, reproducible, reliable and valid estimate of the arterial wall thickness and a useful tool for detecting and monitoring changes in intima media thickness and assessing sub clinical atherosclerosis4-6 was now available. Today the progression of CCIMT is an independent predictor of atherosclerotic events and a useful surrogate marker for coronary and other atherosclerotic events.7-9, and numerous studies have shown that CCIMT is higher in type 2 diabetes mellitus patients than in non-diabetic patients.10-12

As the value of CCIMT in judging atherosclerosis and it’s association with diabetes have become clearer, the next natural step is to evaluate the determinants of CCIMT and to evaluate the association of risk factors with panatherosclerosis reflected by CCIMT.

Keeping the implications of the above in mind, the present study was undertaken to know the relationship of CCIMT with risk factors for atherosclerosis in type 2 diabetes mellitus patients.

The detailed study of the risk factors determining the point status and progression of atherosclerosis with its attendant events in patients with diabetes aims at reducing the mortality and morbidity in these patients and also decreasing the fiscal burden on both patients and health institutions.

Materials and Methods

A total of 90 cases were studied over a period of 3 years from August 2001 to August 2004. The inclusion and exclusion criteria were as follows.

Inclusion Criteria: Type 2 Diabetes mellitus patients.

Exclusion Criteria:
1. Type 1 Diabetes mellitus patients
2. Patients with Secondary Diabetes

All the patients studied underwent:

  • Detailed history with special emphasis on a systematic quantification of risk factors for atherosclerosis and on atherosclerotic events.
  • Thorough general physical examination including anthropometric measurements and systemic examination.
  • Biochemical investigations with standard laboratory techniques: Fasting, postprandial blood glucose estimation, urine analysis, renal function tests, fasting lipid profile glycosylated hemoglobin estimation, chest X-ray and ECG.
  • Measurement of common carotid intima media thickness. This was done by B-mode ultrasonography using high frequency linear transducer with the help of a specialist radiologist.

Individuals were categorized as:

  1. Type 2 Diabetics as per the American Diabetic Association (ADA), 2000, Criteria (based on consensus of experts from the National Diabetic Data Group and WHO) and absence of ketosis and adequate insulin reserve.
  2. Hypertensives were the patients who met the criteria of 6th report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Blood Pressure (JNC VIth report) (Systolic BP>140mm Hg or Diastolic BP > 90mm/Hg) or on antihypertensive medications excluding secondary hypertension.
  3. Hyperlipidemia was defined using the National Cholesterol Education Programme (NCEP) ATP III guidelines.
    • LDL cholesterol <100mg / dl optimal 100-129 mg/dl near optimal 130- 159 mg/dl borderline high 160-189 mg/dl high
    • >190 mg/dl very high
    • Total Cholesterol <200 mg/dl desirable 200-239 mg/dl borderline high >240mg/dl high
    • HDL Cholesterol <40mg/dl low (higher risk) > 60mg/dl high (lower risk)
    • Triglycerides <150mg/dl Normal 150-199 mg/dl Borderline high 200-499 mg/dl High > 500 mg/dl very high
  4. Anthropometric measurements:
    1. Body Mass Index (BMI) was calculated as:
      BMI= (Weight in Kg) /
      Height in Meters2
      <25 Normal
      25-30 Overweight
      >30 Obese
    2. Waist Hip Ratio (W/H ratio) (at increased risk)
      Women >0.85; Men > 0.95
  5. Smoking was assessed from history and quantified using pack years.
  6. The common carotid intima media thickness (CCIMT) was measured by B-mode ultrasonography using high frequency linear transducer (probe) on a “GE LOGIQ 700” machine with the help of a specialist radiologist. Intima plus media thickness (IMT) as defined by Pignoli et al 4 was measured as the distance from the leading edge of the first echogenic line (lumen intima interface) to the second echogenic line (the collagen containing upper layer of the intimal adventitia).The common carotid arteries of both sides were visualized in the neck and at each longitudinal projection the point of maximum thickness by visual inspection was measured. At two more points, one at 1cm upstream and the other 1cm downstream from the point of maximum thickness, the CCIMT was measured. The total of 6 values (3 from right and 3 from left common carotid artery) were averaged to give mean CCIMT value for the patient.

The ninety (90) patients of Type 2 Diabetes Mellitus were thus enrolled to have an evaluation by history, general physical and systemic examination, investigations and CCIMT measurements. They were classified into two groups of 45 each Group I) with and Group II) without atherosclerotic events.

Various risk factors were then correlated with the CCIMT values in both the groups to get a clearer idea of the determinants of CCIMT actually translating into events.

Statistical Analysis: SPSS package was used for statistical analysis.

  • Student’s t test was used for independent groups to compare the significance of difference between two means.
  • Chi-square test and Fisher exact test were used to compare proportions. Statistical significance was assumed if p<0.05.
  • Pearson’s correlation coefficient® analysis was carried out to determine the correlation of CCIMT with different variables.
  • Multivariate regression analysis was done to study the independent effect of various risk factors and co-morbidities on CCIMT.

Results

There was no significant difference in mean age, sex distribution and physicochemical characteristics of the two groups except for the duration of diabetes mellitus and of hypertension (Table 1 and 2).

Table 1: Comparison of patient’s clinical characteristics in those with Atherosclerotic risk factors (group 1) and those with Atherosclerotic events (group 2)

(View all tables here)

All values are mean ± SD; ٭ p < 0.05

Table 2: Comparison of patient’s biochemical characteristics in those with Atherosclerotic risk factors (group 1) and those with Atherosclerotic events (group 2)

(View all tables here)

All values are mean ± SD

Comparison of distribution of risk factors amongst the two groups, the number of patients having hypertension and dyslipidemias was significantly higher in Group II as compared to Group I (Table 3); the same group showed significantly higher values of CCIMT as compared to those in Group I. (Table 4).

Table 3: Distribution of co-morbidities and risk factors in group 1 and group 2

(View all tables here)

٭ p < 0.05

Table 5 shows that in Group I patients, age had statistically significant correlation with CCIMT (p<0.05), while in Group 2 patients, proteinuria had a statistically significant correlation with CCIMT (p<0.05).

Table 4: CCIMT in patients with Risk Factors for Atherosclerosis but no events (group 1) and Atherosclerotic events (group 2)

(View all tables here)

٭ Statistically highly significant (p<0.0001) as compared with group 1

In both the groups, waist/hip ratio, duration of diabetes mellitus, systolic blood pressure, glycosylated hemoglobin, triglyceride, total cholesterol: HDL cholesterol ratio had positive correlation with CCIMT, however, did not assume statistical significance (Table 5). The only variables that were found to have a statistically significant association with CCIMT were age in Group 1 and proteinuria in Group 2 patients. (Table 6)

Discussion

The Common carotid intima media thickness (CCIMT), an established indicator of atherosclerosis and an important functional predictor of cardiovascular system3,9 can effectively be used to measure progress of atherosclerosis and also to assess the success of interventions 2,8.

What is known is that measurement of CCIMT by non-invasive B-mode ultrasonography can detect atherosclerosis at the earliest preclinical stage and help in the prediction and diagnosis of asymptomatic vascular disease.3,14,15

Our study demonstrates the factors which have the strongest correlation with CCIMT and hence with pan-atherosclerosis.

In the present study, comparison of the cases (Group I) with the age- and sex-matched controls (Group II), revealed a higher duration of diabetes, hypertension and dyslipidaemia in the latter Group 2. These patients also had a significantly higher mean CCIMT value. With these points in mind let us consider the correlation of risk factors with CCIMT in our patients.

In our analysis, age showed a significant positive correlation and independent association (by multivariate regression analysis) with CCIMT in Group 1 patients who did not have atherosclerotic events. (r=0.2948, p=0.0493). Such a positive correlation of intima media thickness with age has also been reported by Kraml et al12 and Guvener et al.13

A linear positive correlation of age with intima-media thickness was also observed by Mohan et al.10

In fact in the latter study correlation of age with IMT was true for diabetic as well as non diabetic patients. The fact that age did not correlate with CCIMT in group 2 was explained by the presence of certain skew observations which had some statistical impact. We included these cases since it not only minimised bias but pointed towards a very important and novel concept of the genetic predisposition to higher CCIMTs irrespective of risk factors. Such studies proposing the role of genetic factors have been reported by Lange et al16, Diamontopoulos et al 17 and also veryrecently by Moskau S et al 18.

Table 5: Coefficient of correlation (r values) for different variables with CCIMT in group 1 and 2 patients

(View all tables here)

Apart from age, proteinuria had correlation with increased CCIMT in our study. Proteinuria showed a positive correlation with CCIMT in group 2 patients (ie those with atherosclerotic events) (r=0.4083, p=0.0054). Also, in multivariate regression analysis using CCIMT as dependent variable, proteinuria showed an independent association with CCIMT. Similar correlation of proteinuria with increased CCIMT was reported by Visona et al19 and Mykannen et al.20

Table 6: Multivariate regression analysis using CCIMT as dependent variable

(View all tables here)

٭ Statistically significant (p<0.05) β/SE (Regression coefficient / standard error of coefficient ratio ≥2, indicates statistical significance) patients. It also reflects the role of hypertension possibly both directly and indirectly in influencing CCIMT. The same may hold good for other risk factors that were significantly higher in group 2 patients as mentioned above. In both the groups 1 and 2, waist/hip ratio, duration of diabetes mellitus, systolic blood pressure, glycosylated hemoglobin, triglyceride, and total Cholesterol/HDL Cholesterol ratio had positive correlation with CCIMT but could not assume statistical significance (p>0.05). However a higher incidence and duration of hypertension, duration of diabetes and hyperlipidemia was seen in group 2. At the same time the mean value of CCIMT in group 1 was 0.798+0.12mm, while in group 2 it was significantly higher 1.005+0.17mm (p < 0.0001). This strongly suggests an effect of these parameters on CCIMT, however, we would suggest further studies with a larger numbers of patients to confirm the statistical significance of the above associations.

This correlation in group 2 patients is understandable because of an overall longer duration of the disease and co-morbidities in this group. Besides, in our diabetic patients with atherosclerotic events, there was a statistically significant positive correlation of proteinuria with the systolic blood pressure (r=0.4615, p=0.0014). This is another interesting example of the ever puzzling link between hypertension, proteinuria (microvascular event), carotid atherosclerosis and attendant macrovascular events in diabetic

The risk factors for increased CCIMT in patients with diabetes seem to be variable in various studies. While certain risk factors correlate with CCIMT in one study the others don’t and so on. Kanters et al72 showed that none of the variables of their study was associated with CCIMT in type 2 diabetics. Geroulakos et al21 also found that none of the potential risk factors was associated with IMT in patients with diabetes. With respect to the above mentioned parameters our findings are similar to these studies except for the age and proteinuria. On the other hand, in the study conducted by Guvener et al 13 even though age, body mass index (BMI), duration of diabetes, smoking, lipid profile, fasting insulin levels, serum fibrinogen, hypertension and coronary artery disease were all assessed as determinants of carotid artery intimamedia thickness, multivariate analysis showed that age and BMI were the most important independent determinants of carotid intima-media thickness.

Temelkova-Kurktschiev et al22 noticed increased CCIMT in diabetic patients with hyperlipidaemia, Jadhav and Kadam23 with hypertension and, very recently, Karim et al24 found that the association between carotid IMT and duration of diabetes increases with both the frequency and duration of smoking.

In another recent study Kablak- Ziembicka et al25 concluded that hypertension, hyperlipidemia and non-insulin-dependent diabetes mellitus are related to a greater IMT, whereas other risk factors didn’t reveal any such correlation. Folsom et al26 showed that carotid artery intima-media thickness was also positively associated with coronary calcification; the findings reaffirmed the established role of traditional risk factors in the etiology of coronary artery disease, as assessed by computed tomography, but did not identify any important nontraditional risk factors.

McDonald et al27 remarked that, in a multivariate model, age, smoking, waist circumference and the highest quartile of CRP concentrations (> or =14 mg/l) remained significant predictors of IMT > or =0.72 mm. Our findings are different from the findings of these workers with except in case of age and proteinuria. According to Yokoyama et al28, a slight elevation of albuminuria is a significant determinant of IMT and PWV (pulse wave velocity), independent of conventional cardiovascular risk factors in type 2 diabetic patients with no clinical nephropathy or any vascular diseases. Tatsukawa et al29 from Japan concluded that in a section of their subjects, BMI was not a cardiovascular risk factor, although LDL cholesterol was a common important risk factor. In this way it is clear that there is a lot of variability in the correlation of risk factors with CCIMT. Once a uniform set of the strongest correlates and independent associates is established, a tight control of the risk factors will enable a tight control over the atherosclerotic process. This in turn will ensure a good quality of life and freedom from the morbidity and mortality associated with atherosclerotic events in patients with diabetes mellitus.

To conclude, in our study the value of CCIMT showed a significant positive correlation and independent association with age and proteinuria in type 2 diabetes mellitus patients. Hypertension, duration of diabetes, and dyslipidaemia may actually have a correlation with CCIMT either directly or by influencing other parameters like proteinuria, even though these risk factors did not attain statistical significance in our study. We would therefore suggest studies with larger number of patients to confirm such associations statistically and also to propose, from among the numerous inconsistent correlates, a uniform set of the strongest correlates of CCIMT which may then be dealt with in a most thorough manner.

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