Diabetes & Metabolic Syndrome: Clinical Research & Reviews 3 (2009) 35–39

Original paper

Inter-relationship between low-density lipoprotein phenotype and carotidintima-media thickness in North Indian type 2 diabetic subjects

Jamal Ahmad *, Khalid Jamal Farooqui, Abdur Rahman Khan

Centre for Diabetes and Endocrinology, Faculty of Medicine, J.N. Medical College, Aligarh Muslim University, Aligarh 202002, India

A R T I C L E I N F O

Keywords:

Small dense LDL

Phenotype B

Carotid IMT

Type 2 diabetes

A B S T R A C T

Aims: Diabetic dyslipidemia is characterized by a preponderance of small dense LDL which is highly

atherogenic. The aim of this study was to examine the interrelationship between LDL Phenotype and

atherosclerosis; to determine the factors determining LDL phenotype; and evaluate LDLc:apo-B ratio as a

surrogate for the assessment of LDL phenotype in a group of North Indian Type 2 diabetic subjects.

Methods: 285 diabetic subjects attending the outpatient Endocrine Clinic were subjected to detailed

anthropometry and fasting serum lipid and apo-B was measured. The carotid intima-media thickness

(IMT) was determined using a high resolution B-mode Ultrasonography. LDLc:apo-B ratio was taken as a

surrogate index for LDL size.

Results: 29.5% patients with normal triglyceride levels and 52.1% patients with normal LDLc levels

showed the presence of small dense LDL or Phenotype B as estimated by the LDL cholesterol/apo-B ratio.

The mean IMT in Phenotype B group was higher (0.88 mm vs. 0.68 mm). Triglycerides was the most

important predictor variable predicting carotid IMT (R2 = 0.15, b = 0.376) as well as LDL phenotype B

(R2 = 0.28, b = 0.561).

Conclusions: Triglycerides and HDLc contribute independently to the variability in LDL particle size, and

LDL particle size was associated with preclinical atherosclerosis as determined by carotid IMT in North

Indian Type 2 diabetic subjects. LDL cholesterol/apo-B ratio serves as an easy clinical tool to determine the

elevated small dense LDL.

� 2008 Diabetes India. Published by Elsevier Ltd. All rights reserved.

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1. Introduction

Diabetic dyslipidemia is characterized by elevated triglyceride,low HDL cholesterol (HDLc), and a preponderance of small denseLDL phenotype or Phenotype B [1,2]. LDL cholesterol (LDLc)lowering is the primary lipid target in current guidelines but it doesnot fully account for the cardiovascular risk associated withdiabetes, either alone or in combination with triglycerides andHDLc [3,4]. More than 50% of the subjects with CAD have normalLDLc levels, thus the calculated LDLc fails to be an adequate indexof lipid associated risk. Measurements beyond traditional lipids,such as measurements of the presence of small dense LDL inpatients with diabetes, may help to identify cardiovascular risksubgroups and individualize hypolipidemic treatments [5].

In several cross-sectional studies subjects with coronary arterydisease (CAD) have had smaller and denser LDL particles thancontrols [6–8]. The determination of LDL size with density gradient

* Corresponding author. Tel.: +91 571 2721544; fax: +91 571 2721544.

E-mail address: jamalahmad11@rediffmail.com (J. Ahmad).

1871-4021/$ – see front matter � 2008 Diabetes India. Published by Elsevier Ltd. All r

doi:10.1016/j.dsx.2008.10.006

ultracentrifugation and gradient gel electrophoresis [9], is difficult,time consuming and requires specialized instruments. Electro-phoresis quantifies just the size of the predominant LDL species orthe average size of LDL. NMR which is another rapid andconvenient method for determining LDL size and subfractionsconcentration is limited by lack of published data on detailedprocedures, calibration, and validation. LDLc:apo-B ratio can beused as a surrogate for the assessment of LDL phenotype as shownin the AMORIS study [10]. Several reports have shown that a higherLDLc:apo-B ratio identifies subjects with predominantly largebuoyant LDL particles, whereas a low value indicates the presenceof predominantly small dense LDL particles [11–13]. It has beensuggested that the intima-media thickness (IMT) of the commoncarotid artery may be the most sensitive marker for the earlieststages of atherosclerosis [14].

Very few studies have examined the interrelationship betweenLDL Phenotype and atherosclerosis and the factors determining ofLDL phenotype in North Indian Type 2 diabetic subjects. The aim ofthis study was to evaluate the interrelationship between LDLparticle size, insulin resistance and atherosclerosis thus identifyingdiabetic subjects with high cardiovascular risk.

ights reserved.

J. Ahmad et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 3 (2009) 35–3936

2. Methods

2.1. Study population

The study population consisted of 285 diabetic subjects (153men and 132 women) attending the outpatient Endocrine Clinic atthe Centre for Diabetes and Endocrinology. The mean age ofdiabetic subjects was 50.6 � 9.6 years (Range 40–70 years). Patientswith recent myocardial infarction or acute coronary syndrome;cerebrovascular accidents; inherited or acquired disorders of lipid/lipoprotein metabolism and/or family history of such diseases;deranged liver function; or medications known to affect lipidmetabolism (other than a sulfonylurea) were excluded from thestudy. Informed consent was obtained from all subjects. The localmedical ethics committee approved the study, which was carried outin accordance with the Declaration of Helsinki.

2.2. Anthropometric measurements

Physical examination included height and weight measure-ments and the body mass index (BMI) were calculated. Waistmeasurement was done in the standing position [15]. Bloodpressure (BP) was recorded to the nearest 2 mmHg in the sittingposition in the right arm with a mercury sphygmomanometer.

2.3. Laboratory measurements

Measurements of total cholesterol, triglycerides, HDLc, andLDLc were performed on serum collected after the subject’s fastedovernight, using enzymatic methods (Pointe Scientific Inc., MI,USA). LDLc was calculated using the Friedewald formula [16].Hemoglobin A1C (HbA1C) was measured by cation exchange resinas per directives of the supplier of the kit, Pointe Scientific Inc., MI,USA with normal values ranging from 4.6% to 5.8%. ApolipoproteinB (apo-B) was estimated by immune-turbidometry as per thedirectives of SPINREACT diagnostic systems; SPAIN.

2.4. Low-density lipoprotein subtypes

LDLc:apo-B ratio was taken as a surrogate index for LDL size asin the updated analysis of the AMORIS study [10]. LDLc:apo-B ratio<1.20 and�1.20 constituted Phenotype B/small dense LDL particleand Phenotype A/large buoyant LDL particle, respectively [17].

Table 1Patient characteristics according to LDLc phenotype.

Variables Whole cohort n = 285

Age (years) 50.6 � 9.6

Systolic BP (mmHg) 137.8 � 19.8

Diastolic BP (mmHg) 86.9 � 11.3

Body mass index (kg/m2) 26.1 � 4.4

Waist:hip ratio 0.94 � 0.10

Fasting PG (mg%) 130.3 � 43.4

Post-prandial PG (mg%) 186.4 � 59.4

HBA1C (%) 8.7 � 0.6

Urinary albumin (mg/l) 31.4 � 82.7

VLDL cholesterol (mg/dl) 32.5 � 12.1

HDL cholesterol (mg/dl) 42.6 � 6.6

Trigycerides (mg/dl) 153.3 � 56.6

LDL cholesterol (mg/dl) 108.6 � 25.5

Total cholesterol (mg/dl) 182.2 � 32.0

Non-HDL Cholesterol (mg/dl) 139.6 � 30.4

apo-B (mg/dl) 110.6 � 37.9

LDL:apo-B ratio 1.24 � .28

Mean IMT (mm) 0.78 � .13

PG = plasma glucose; IMT = intima-medial thickness.

2.5. Ultrasonographic evaluation of carotid arteries

The intima-media thickness of the carotid arteries wasdetermined using a high resolution B-mode Ultrasonographysystem (Logic 500 Proseries; Wipro GE) having an electricallinear transducer (multi-frequency probe of 5–9 MHz). An IMTmore than 0.8 mm represents early changes of atherosclerosis[18–20]. Undulation and thickening of the internal line indicateplaque deposition which is echogenic. Focal depression, break inplaque surface or anechoic area within the plaque or slowmoving eddies of colour within an anechoic region suggestplaque ulceration.

2.6. Statistical analysis

Statistical analysis was performed using SPSS version 11.0statistical package for Windows (SPSS, Chicago, IL). Continuousvariables are expressed as mean � S.D. (Gaussian distribution) orrange, and qualitative data is expressed in percentages. Forcontinuous variables, and depending on normality distribution,unpaired t tests were used if comparing two groups. The associationbetween continuous variables was tested by linear correlation. Alltests were two-tailed, and a P value of �0.05 was consideredsignificant. Stepwise multiple linear regression models were per-formed with LDL phenotype and carotid IMT as the dependentvariable.

3. Results

3.1. Characteristics of the study subjects

The clinical and biological features of the 285 type 2 diabeticsubjects (153 men and 132 women) included in the study areshown in Table 1. 183 (64.2%) patients were found to behypertensive. Hypercholesterolemia, hypertriglyceridemia andlow HDLc was present in 69 (24.2%), 102 (35.5%) and 96 (33%)subjects, respectively. High IMT (0.8 mm and above) was seen in102 (35.8) subjects whereas LDLc:apo-B ratio less than 1.20(Phenotype B) was found in 126 (44.2%) subjects. The meanIMT in Phenotype B group was higher (0.88 mm vs. 0.68 mm).LDL cholesterol/apo-B ratio was significantly lower in men thanin women. The LDLc:apo-B ratio in pattern B group was1.16 � 0.25.

Phenotype A n = 159 Phenotype B n = 126

50.5 � 9.2 50.7 � 10.1

137.4 � 18.6 138.4 � 21.3

85.5 � 12.2 88.6 � 9.8

25.8 � 5.0 26.3 � 3.5

0.94 � 0.06 0.94 � 0.14

132.7 � 48.2 127.4 � 36.6

186.3 � 58.8 186.5 � 60.2

8.7 � 0.6 8.6 � 0.6

31.2 � 96.0 31.6 � 62.4

25.9 � 8.5 40.9 � 10.7

43.18 � 5.24 41.9 � 8.0

117.86 � 26.80 197.9 � 52.6

103.37 � 21.14 115.2 � 28.8

171.1 � 26.5 196.3 � 32.9

127.1 � 20.8 155.3 � 33.2

91.2 � 27.9 135.1 � 34.6

1.31 � 0.23 1.16 � 0.25

0.68 � 0.12 0.88 � 0.14

Table 2Fasting lipid profile and mean IMT in study subjects as per LDLc phenotype.

Phenotype A Phenotype B P

Female n = 81 (mean � S.D.) Male n = 78 (mean � S.D.) Female n = 51 (mean � S.D.) Male n = 75 (mean � S.D.)

VLDLc 23.8 � 7.9 27.9 � 8.5 39.6 � 12.4 42.7 � 7.1 .00HDLc l 42.6 � 4.5 43.7 � 5.8 43.5 � 8.0 39.4 � 7.4 .10

Triglyceride 111.9 � 24.4 123.5 � 27.8 189.3 � 61.5 210.4 � 32.4 .00LDLc 103.1 � 20.0 103.6 � 22.3 110.5 � 30.5 122.0 � 24.8 .00Total cholesterol 169.0 � 27.9 173.0 � 24.8 191.2 � 36.0 203.6 � 26.4 .00Non-HDLc 123.5 � 20.0 130.4 � 21.0 149.3 � 35.9 164.1 � 26.5 .00apo-B 85.1 � 21.7 97.0 � 31.7 133.4 � 39.7 137.6 � 25.4 .00LDLc:apo-B ratio 1.35 � 0.27 1.27 � 0.20 1.18 � .22 1.14 � .18 .00Mean IMT 0.66 � .11 0.70 � .13 0.86 � .14 0.90 � .14 .00

Values are mean � S.D. P-Value indicate difference (independent sample t-test). NS, not significant.

Table 3Pearson’s correlation of intima-medial thickness and LDL phenotype with glycemic

parameters and components of insulin resistance in diabetic subjects.

Variables Mean IMT

(mm) r

LDL

phenotype B r

LDL

phenotype A r

Mean IMT (mm) 1.000 0.172* 0.035

Systolic BP (mmHg) 0.040 0.077 0.032

Diastolic BP (mmHg) 0.079 0.068 0.031

Body mass index (kg/m2) 0.030 0.033 0.170

Waist:hip ratio 0.058 0.022 0.118

Fasting PG (mg%) 0.074 0.002 0.037

Post-prandial PG (mg%) 0.144 0.061 0.040

HbA1C (%) 0.024 0.012 0.107

Urinary albumin creatinine ratio 0.175 0.143 0.036

HDL cholesterol (mg/dl) �0.182* �0.202* �0.018

Trigycerides (mg/dl) 0.394* 0.265* 0.078

LDL cholesterol (mg/dl) 0.300* 0.304* 0.018

Total cholesterol (mg/dl) 0.361* 0.171* 0.137

Total cholesterol HDL ratio 0.453* 0.288* 0.081

Non-HDLc (mg/dl) 0.401* 0.196* 0.156

apo-B (mg/dl) 0.712* 0.547* 0.281*

LDL:apo-B ratio �0.409* 1.00 1.00

r is Pearson’s correlation coefficient.* Indicates significant correlation. Correlation is significant at the 0.01 level (2-

tailed).

J. Ahmad et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 3 (2009) 35–39 37

3.2. Carotid IMT and its association with lipoproteins and LDL

phenotype

The mean IMT level was higher in subjects belonging tophenotype B in various age groups and gender. Also the malesubjects belonging to phenotype B had a higher mean IMT levelwhen compared to females belonging to phenotype B (P < 0.05)(Table 2). Subjects belonging to phenotype B had higher meanlevels of VLDLc, LDLc, total cholesterol, non-HDLc, triglycerides andapo-B and lower levels of HDLc (Table 2) with the males exhibitingLDL phenotype B displaying higher values as compared to thefemales.

Mean IMT significantly correlated with LDLc, serum cholesterol,triglycerides, non-HDLc, Apolipoprotein B, LDL:apo-B ratio and thetotal cholesterol:HDL cholesterol ratio (Table 3).

Table 4Stepwise multiple regression analyses with average carotid IMT as a dependent

variable.

b coefficienta P value

Trigycerides 0.376 0.008

LDL phenotype B 0.179 0.000

apo-B 0.138 0.000

HDLc �0.215 0.008

LDLc 0.139 0.009

a b-Partial regression coefficient.

Stepwise multiple regression analysis using carotid IMT asdependent variable showed that Triglycerides, LDL:apo-Bratio < 1.20, apo-B, HDLc, LDLc were the most significantpredictors of mean IMT Table 4. Triglycerides was the mostimportant predictor variable (R2 = 0.15, b = 0.376) Fig. 1.

3.3. LDL phenotype and its association with lipoproteins and other

risk factors

LDL phenotype B was significantly correlated with triglycerides,HDLc, non-HDLc, mean IMT, total cholesterol:HDLc ratio, LDLc,total cholesterol and apo-B (Table 3). An inverse relation betweenplasma triglyceride levels and LDL particle size as estimated by theLDL cholesterol/apo-B ratio was seen.

Stepwise multiple regression analysis showed that Triglycerides,HDLc, and mean IMT contribute the most towards the variance ofLDL phenotype B (Table 5). Trigycerides alone accounts for 28%(R2 = 0.28) of the total variance in LDL phenotype and is the singlemost important predictor of LDL Phenotype B (b = 0.561) Fig. 2.

More importantly 54/183 (29.5%) patients with normaltriglyceride levels and 114/219 (52.1%) patients with normal LDLclevels showed the presence of small dense LDL or Phenotype B asestimated by the LDL cholesterol/apo-B ratio.

4. Discussion

Diabetic dyslipoproteinemia substantially increases the risk ofdeveloping macro-vascular disease especially coronary arterydisease [21]. This study demonstrated that 52.1% of patients withnormal LDLc levels showed the presence of small dense LDL orPhenotype B as estimated by the LDL cholesterol/apo-B ratio. LDLcholesterol levels generally under-represent the number of LDLparticles in patients with high triglycerides as they have cholesterol-poor LDL particles, which are smaller, have a core lipid contentenriched in triglycerides and are depleted of cholesterol ester, orboth [22,23]. The role of small dense LDL as an importantatherogenic risk factor is a very well established fact [24,25].

Plasma triglyceride levels have been identified as the singlebest metabolic correlate of LDL particle size in several populations

Table 5Stepwise multiple regression analyses with LDL phenotype as the dependent

variable.

b coefficienta P value

Trigycerides �0.561 0.000

Carotid IMT �0.172 0.000

HDLc 0.215 0.008

a b-Partial regression coefficient.

Fig. 1. Regression curve showing the relationship of mean IMT with trigycerides.

Fig. 2. Regression curve showing the relationship of LDLc ApoB ratio with

trigycerides.

J. Ahmad et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 3 (2009) 35–3938

[26,27]. In our study also, triglyceride emerged as the mostsignificant variable predicting LDL phenotype B. Carotid IMT wasalso significantly associated with circulating levels of trigyceridesand HDLc. Ahmad et al. investigated the role of post-prandialtriglyceride levels in atherosclerosis in diabetic subjects of Asian-Indian origin and found that age and post-prandial triglyceridelevels had the strongest statistical influence with carotid IMT [28].In this study, using the regression equation the cut-off point oftriglycerides to match an LDL:apo-B ratio of�1.2, was determinedas 130 mg%. This is lower when compared to the values reportedby Wagner et al. (180 mg%) [29] and the European policy group(152 mg%) [30]. The triglyceride level of 130 mg% had sensitivityof 79.2% and specificity of 63.8%. In this study, the cut-off pointobtained for triglyceride to distinguish between phenotypes Aand B is lower than the goal recommended by the NationalCholesterol Education Program and the American DiabetesAssociation. Thus the lower levels of triglycerides at which smalldense LDL phenotype appears in the Indian population could

account for the high rates of premature CAD. Insulin resistance;which is reported to be highly prevalent in Asian-Indians [31]; isclosely associated with high plasma triglyceride levels [32] andreduced LDL particle size [33]. A negative relationship betweenLDL particle size and intima-media thickness has been found in aprevious study by Skoglund-Andersson et al. [34]. We found asignificant negative correlation between mean IMT and smalldense LDLc phenotype (r = �0.172 and P < 0.004). The presentstudy also demonstrated that the severity of carotid IMT thicknessis significantly associated with small LDL particle size orphenotype B.

To conclude, triglycerides and HDLc contribute independentlyto the variability in LDL particle size, and LDL particle size wasassociated with preclinical atherosclerosis as determined bycarotid IMT in North Indian Type 2 diabetic subjects. However,estimating small dense LDL still remains a challenge, as methodssuch as quantification, nuclear magnetic resonance or use of non-denaturing polyacrylamide gel electrophoresis methods arerequired. Moreover all these procedures are time-consuming,labor intensive and expensive and these factors restrict the use ofsmall dense LDL as a cardiovascular marker. In this context, LDLcholesterol/apo-B ratio serves as an easy clinical tool to determinethe elevated small dense LDL. Further studies in Indian subjects areneeded to determine the triglyceride cut-off levels at whichintervention may be initiated.

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