Dyslipidemia in type 2 diabetes mellitus: more atherogenic lipid profile in women

Abstract

Previous studies have shown that diabetes mellitus (DM) increases the risk of cardiovascular disease in women to a greater extent than in men. It seems that DM may alter lipid profiles more adversely in women compared to men. In this study we evaluated serum lipoprotein differences in type 2 diabetic men and women. The study included 350 type 2 diabetic patients (100 men and 250 women), aged 19-82 years. Demographic data were and biochemistry tests including serum lipoproteins were measured. There was no difference between men and women with respect to duration of DM and type of treatment. Body mass index (BMI), systolic and diastolic blood pressures were significantly higher in women than age matched men. Women also had significantly higher plasma levels of total cholesterol (233.7 vs. 190.3 mg/dl, P < 0.001), triglycerides (219.7 vs. 180.6 mg/dl, P < 0.05), low-density lipoprotein cholesterol (LDL-C) (141.2 vs. 116.1 mg/dl, P < 0.001), high-density lipoprotein cholesterol (HDL-C) (47.1 vs. 39.4 mg/dl, P < 0.001), non-HDL cholesterol (186.1 vs. 150.8 mg/dl, P < 0.05), Lp(a) (50.7 vs. 38.2 mg/dl, P < 0.05) and apo-B (117.6 vs. 101.2 mg/dl, P < 0.001). All types of dyslipidemia were significantly more prevalent in females. Women had higher plasma levels of HDL-C compared to men. Higher prevalence of hypertriglyceridemia in females was due to their higher BMI, and sex was not an independent risk factor for hypertriglyceridemia. Type 2 diabetic women are exposed more profoundly to risk factors including atherogenic dyslipidemia and higher BMI, systolic and diastolic blood pressures compared to men.

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DYSLIPIDEMIA IN TYPE 2 DIABETES MELLITUS:
MORE ATHEROGENIC LIPID PROFILE IN WOMEN
M. Nakhjavani*, A. R. Esteghamati , F. Esfahanian and A. R. Heshmat
Endocrinology and Metabolism Research Center (EMRC), Vali-e-Asr Hospital, Tehran University
of Medical Sciences, Tehran, Iran

Abstract- Previous studies have shown that diabetes mellitus (DM) increases the risk of cardiovascular
disease in women to a greater extent than in men. It seems that DM may alter lipid profiles more
adversely in women compared to men. In this study we evaluated serum lipoprotein differences in type
2 diabetic men and women. The study included 350 type 2 diabetic patients (100 men and 250 women),
aged 19-82 years. Demographic data were and biochemistry tests including serum lipoproteins were
measured. There was no difference between men and women with respect to duration of DM and type
of treatment. Body mass index (BMI), systolic and diastolic blood pressures were significantly higher
in women than age matched men. Women also had significantly higher plasma levels of total
cholesterol (233.7 vs. 190.3 mg/dl, P < 0.001), triglycerides (219.7 vs. 180.6 mg/dl, P < 0.05), low-
density lipoprotein cholesterol (LDL-C) (141.2 vs. 116.1 mg/dl, P < 0.001), high-density lipoprotein
cholesterol (HDL-C) (47.1 vs. 39.4 mg/dl, P < 0.001), non-HDL cholesterol (186.1 vs. 150.8 mg/dl, P <
0.05), Lp(a) (50.7 vs. 38.2 mg/dl, P < 0.05) and apo-B (117.6 vs. 101.2 mg/dl, P < 0.001). All types of
dyslipidemia were significantly more prevalent in females. Women had higher plasma levels of HDL-C
compared to men. Higher prevalence of hypertriglyceridemia in females was due to their higher BMI,
and sex was not an independent risk factor for hypertriglyceridemia. Type 2 diabetic women are
exposed more profoundly to risk factors including atherogenic dyslipidemia and higher BMI, systolic
and diastolic blood pressures compared to men.
Acta Medica Iranica, 44(2): 111-118; 2006
© 2006 Tehran University of Medical Sciences. All rights reserved

Key words: Diabetes mellitus, hypertriglyceridemia, dyslipidemia


INTRODUCTION

Type 2 diabetes mellitus (DM) increases the risk
of coronary heart disease (CHD) more markedly in
women than men (1). However, the reported
magnitudes of the diabetes-related CHD risk in men
and women vary widely between different studies
(2-6). The cause of the greater relative risk of CHD
in diabetic women still remains incompletely

Received: 3 Dec. 2005, Revised: 3 May 2005, Accepted: 2 July 2006

* Corresponding Author:
M. Nakhjavani, Endocrinology and Metabolism Research Center,
Vali-e-Asr Hospital, School of Medicine, Tehran University of
Medical Sciences, Tehran, Iran
Tel: +98 21 88830323
Fax: +98 21 88823885
E-mail: nakhjavanim@sina.tums.ac.ir
understood, but several explanations can be offered.
First, adverse changes induced by type 2 DM in
some cardiovascular risk factors, such as high-
density lipoprotein (HDL) cholesterol, triglycerides
(TG), low-density lipoprotein (LDL) particle size
and blood pressure have been found to be more
pronounced in women than in men (7-9). In addition,
DM in women may interfere with protective
mechanisms in the vascular wall and thereby lead to
enhanced atherogenesis. Patients with type 2 DM
have two to fourfold increase in cardiovascular
disease (CVD) (10, 11) and dramatically higher risk
of accelerated cerebral and peripheral vascular
disease (12, 13).
Although DM is a well-known independent risk
factor for vascular disease, abnormalities in insulin
and glucose do not seem to account entirely for high

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Dyslipidemia in type 2 diabetes
112 Acta Medica Iranica, Vol. 44, No. 2 (2006)
frequency of macrovascular disease in patients with
type 2 DM. In the UK Prospective Diabetes Study
(UKPDS) the typical lipid pattern in the population
with DM compared with no DM showed a pattern of
hypertriglyceridemia, low
unaltered total cholesterol and an increased LDL-C
in women (14).
Type 2 DM is associated with a cluster of
interrelated plasma lipid and lipoprotein (Lp)
abnormalities that are all recognized as predictors for
coronary heart disease, including reduced plasma
levels of high density lipoprotein cholesterol (HDL-
C), a predominance of small and dense, low density
lipoprotein cholesterol (LDL-C) particles and
elevated plasma levels of TG (15). Elevated levels of
Lp(a), a well known independent predictor of CVD
(6, 7), has also been reported in diabetic patients
compared to control groups (16, 17).
The purpose of this study was to evaluate the
effect of sex on lipid abnormalities in patients with
type 2 DM, to determine the prevalence of
dyslipidemia in these patients and to evaluate its
coexistence and correlation with other known CVD
risk factors.


MATERIALS AND METHODS

Patients’ Data
This study recruited 600 type 2 diabetic
outpatients who consecutively presented to the
Diabetes Clinic of Emam Khomeini Hospital,
affiliated to Tehran University of Medical Science
and Health Services (TUMS), from Oct. 2002 to Oct.
2003. The diagnosis of DM was based on the
American Diabetes Association criteria for type 2
DM (fasting plasma glucose level higher than 126
mg/dl and/or glucose level exceeding 200 mg/dl at 2
hours in the 75 g oral glucose tolerance test). A total
of 350 patients (100 males and 250 females), aged
19-82 years (54.3 ± 10.9, mean ± SD) completed the
study. Patients had been treated by diet, exercise
and/or oral hypoglycemic agents (i.e.; biguanides
and/or sulfonylureas) and/or insulin. For each patient
a questionnaire including epidemiologic data such as
age, gender, occupation, duration of DM and history
of smoking was completed. Information was
HDL-C, relatively
obtained about demographic characteristics and
medical history of all patients concerning their age,
sex, history and duration of DM, hypertension,
smoking, medications and co-morbidities. Patients’
drug history such as taking anti-hypertensive and
lipid lowering drugs was not considered as a
restriction for inclusion.
All subjects underwent physical examination,
including measurements of height, weight, waist
circumference and blood pressure (sitting position
after at least 10 min rest). Patient with elevated
serum creatinine (1.3 mg/dl for women and 1.5
mg/dl for men), clinical evidence of congestive heart
failure (CHF) or liver insufficiency, poor blood
glucose control, and systemic or local infections
were excluded. We obtained informed consent from
all participants.

Anthropometric Data
Patients’ heights were measured in centimeters
with shoes off and weights were measured in
kilograms in indoor clothing. Body mass index
(BMI) was calculated using the formula BMI=
weight (kg)/ height2 (m).

Laboratory Data
Blood samples were drawn after at least 12.00
hours of overnight fasting. Fasting blood samples
were obtained for measuring fasting blood glucose
(FBG), total cholesterol, LDL-C, HDL-C, TG,
Lp(a), apoprotein B (apo-B) and HbA1c. Total
cholesterol was measured by Trinder method. HDL-
C was measured by immunoinhibitory method. Lp(a)
and apo-B were measured by immunoturbidimetery.
TG was measured by
Commercially available kit (Lipid, Pars Azmoon
Co., Karaj, Iran) were used for measurements. LDL-
C was calculated using Friedewald formula.

Statistical Analyses
Statistical analysis was carried out using the
Statistical Package for Social Sciences (SPSS 12.0
for windows). Independent t test was used to
compare quantitative data in groups. Pearson
correlation coefficient was used to determine the
correlation between quantitative data. P value < 0.05
was considered significant.
enzymatic method.

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M. Nakhjavani et al.
Acta Medica Iranica, Vol. 44, No. 2 (2006) 113
RESULTS

A total of 350 type 2 DM patients (100 males and
250 females) were studied. Table 1 shows
demographic data of the patients. Female patients
had higher level of BMI (28.57 kg/m2 vs. 25.37
kg/m2, P < 0.05), systolic BP (132.93 mm Hg vs.
128.24 mm Hg, P = 0.05) and diastolic BP (81.40
mm Hg vs. 76.87 mm Hg, P < 0.05). Patients’ lipid
profiles are also demonstrated in table 1.
Prevalence of different types of dyslipidemia in
all of the patients and in males and females are
shown in table 2. Apo-B levels were more than 110
mg/dl in 56% and Lp(a) levels were more than 40
mg/dl in 49% of patients. Apo-B, LDL-C and Lp(a)
had positive correlation with each other (P < 0.05)
(Fig. 1). Non-HDL cholesterol (total cholesterol-
HDL-C) levels higher than 160 mg/dl were present
in 61% of patients. Non-HDL-C had positive
correlation with apo-B, Lp(a), LDL-C and TG. There
was no correlation between duration of diabetes and
lipid profile. Forty percent of patients were smokers.
No significant difference was detected regarding
lipid profile between smoker and non-smoker
patients. Obese patients (BMI > 30) had higher
levels of systolic BP (135.08 mm Hg vs. 130.25 mm
Hg, P < 0.05), diastolic BP (83.30 mm Hg vs. 78.63
mm Hg, P < 0.05) and longer duration of diabetes
(7.14 years vs. 9.24 years, P < 0.05).

APOB
600 400
100
500
200
300
400
300
TG LDL
300200
200
100
100

Fig. 1. Triglycerides, low-density lipoprotein cholesterol and
apo-B had positive correlation with each other.


Furthermore, there was no significant difference
in lipid profile between obese (BMI > 30) and non-
obese patients.
Female patients had higher plasma level of total
cholesterol (233.67 mg/dl vs. 190.30 mg/dl, P <
0.05), TG (219.7 mg/dl vs. 180.6 mg/dl, P < 0.05),
LDL-C (141.23 mg/dl vs. 116.10 mg/dl, P < 0.05),
HDL-C (47.14 mg/dl vs. 39.44 mg/dl, P value <
0.05), non-HDL cholesterol (186.18 mg/dl vs.
150.76 mg/dl, P < 0.05), Lp(a) (50.67 mg/dl vs.
38.18 mg/dl, P < 0.05) and apo-B (117.61 mg/dl vs.
101.17 mg/dl, P value < 0.05) compared to age
matched male patients ( Fig. 2).

Table 1. Demographic characteristics and serum lipoprotein levels of the studied patients
All Patients
Mean SD
54.4 10.9
Duration of diabetes (yr) 8.7 7.2
BMI (kg/m2) 27.67 5.17
SBP (mm Hg) 132
DBP (mm Hg) 80
HDL (mg/dl) 45 14.2
LDL (mg/dl) 133
Total cholesterol (mg/dl) 221
TG (mg/dl) 208
Lp(a) 47
Apo-B 112.8 30.2
Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL, high density lipoprotein; LDL, low density
lipoprotein; TG, triglycerides.

Characteristic
Age (yr)













Female












Male
Mean
53.7
8.5
28.58
133
81
39.4
116.1
190
181
38
101
SD
10.6
6.9
5.18
21
12
14.2
40.96
52
96
33
28
Mean
56.1
9.0
25.38
128
77
47.1
141.23
234
219
51
117.6
SD
11.3
7.8
4.39
16
10
14
43
63
121
38
30
20
11
44
63
96
37

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Dyslipidemia in type 2 diabetes
114 Acta Medica Iranica, Vol. 44, No. 2 (2006)
Table 2. Prevalence of different types of dyslipidemia in males and females
P value Male Female All Patients
Lipid type*
52.0% 42.4% 45.1% Normal 0.065
48.0% 57.6% 54.9% low
HDL

40.0% 27.2% 30.9% Normal 0.014
60.0% 72.8% 69.1% high
LDL

43.0% 74.0% 65.1% Normal 0.000
57.0% 26.0% 34.9% High
T-Chol

45.0% 33.2% 36.6% Normal 0.026
55.0% 66.8% 63.4% High
TG

64% 51.2% 54.9% Normal 0.02
36% 48.8% 45.1% High
Lp(a)
60%
40%
41.2%
58.8%
46.6%
53.4%
Normal
High
0.001 Apo-B
Abbreviations: HDL, high density lipoprotein; LDL, low density lipoprotein; TG, triglycerides.
*Normal HDL value indicates HDL level more than 40 mg/dl in males and HDL value more than 50 mg/ml in females. LDL less than 100mg/dl, TG
less than 150mg/dl and total cholesterol less than 200, Lp(a) less than 40 mg/dl, and apo-B less than 110 mg/dl were regarded as normal.



DISCUSSION

Our study provided the evidence for the presence
of high prevalence of dyslipidemia in type 2 diabetic
patients. Although our patients received oral
hypoglycemic agents for hyperglycemia and in some
cases were treated with lipid lowering agents, a
significant proportion of them had abnormal lipid
profile. The most frequent was hypertriglyceridemia
(63.4%) and the least frequent was elevated total


cholesterol (35%).
Each of the dyslipidemic features is associated
with increased risk of cardiovascular disease, the
leading cause of death in patients with type 2 DM.
Fontbonne et al. in a prospective cohort study
showed that elevated plasma levels of TG in diabetic
patients was positively and significantly correlated
with CAD events and CAD mortality (18).
Hypertriglyceridemia may be the best lipid predictor
of CVD in type 2 diabetic patients (18).
0
50
100
150
200
250
chol TGNon-hdl LDL-Capo-B Lp(a) HDL-C
FemaleMale


Fig. 2. Lipid profile in females compared to males in type 2 diabetic patients.

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M. Nakhjavani et al.
Acta Medica Iranica, Vol. 44, No. 2 (2006) 115
Recent studies have demonstrated that in diabetic
patients TG levels is a risk factor for CVD
independent of HDL-C level and despite glycemic
control (19, 20). Mean levels of total cholesterol and
LDL-C in those with type 2 diabetes may not differ
significantly from those in non-diabetic subjects
(14). Type 2 diabetic patients have an abnormally
high number of small, dense LDL-C particles (21-
23).
Moreover, patients with small, dense LDL-C will
also typically have lower HDL-C and elevated TG
blood levels, which may further increase risk of
atherosclerosis (21). Although, the inaccessibility to
differentiate the LDL-C
limitation to our study, this study showed a high
prevalence of hypercholesterolemia
and high plasma level of LDL-C (about 70%) in
diabetic patients which
consideration. Additionally, the predominance of
small and dense LDL-C may clinically show itself as
an increased level of non-HDL cholesterol plasma
level (24) which shows a stronger association with
CVD and mortality than LDL-C (25). Non-HDL-C
includes all lipoprotein particles that contain apo-B
and are potentially atherogenic, including LDL-C,
Lp(a), Intermediate density lipoprotein (IDL-C), and
very low density lipoprotein (VLDL-C) (26). Sixty
one percent of patients had non-HDL plasma level
more than 160 mg/dl. This may to some extent be
due to predominance of small, dense LDL-C
particles and in some part due to elevated plasma
level of TG, Lp(a) and apo-B. Fifty six percent of
patients had apo-B plasma levels more than 110
mg/dl and 49% had Lp(a) higher than 40 mg/dl that
may contribute in high plasma level of non-HDL
cholesterol.
Type 2 DM is also associated with low plasma
levels of HDL-C (5). It is well documented that
reduced HDL-C levels are associated with an
increased risk of coronary heart disease (27). It may
be due to a number of HDL-C particles functions
that possibly will
cardioprotective effects, including promotion of
cellular cholesterol efflux and anti-oxidative and
anti-inflammatory properties (15). Moreover, low
HDL-C levels are often accompanied by elevated
TG levels (28), and the combination has been
subclasses was a
(64.2%)
requires special
contribute to direct
strongly associated with an increase in risk of CHD
(29-31). HDL-C levels below 50 mg/dl were present
in 58% of females and below 40 mg/dl in 48% of
males. Although this abnormality was more frequent
in females it was not statistically significant. In this
study, there was no significant correlation between
TG and HDL-C levels. This may be in part due to
the fact that consumption of lipid-lowering agents
was not considered as exclusion criterion of the
patients. Furthermore, in this study the increase in
atherogenic lipoproteins including LDL-C, Lp(a) and
apo-B were correlated with each other. This may
expose patients to an accelerated risk for
atherosclerosis.
It has been reported that type 2 DM increase the
risk of CHD more markedly in women than in men
(2-6). Adverse changes induced by type 2 DM in
some cardiovascular risk factors, such as HDL-C,
total cholesterol, TG, LDL-C particle size and blood
pressure have been found to be more pronounced in
women than in men (7-9). Juutilainen et al. in their
study of 1059 type 2 diabetic subjects aged 45-64
years found a considerably higher diabetes related
relative risk for a major CHD event in diabetic
women than in men (1). They found that the burden
of obesity, elevated blood pressure, and atherogenic
dyslipidemia (low HDL cholesterol and high TG)
was, in the presence of diabetes, greater in women
than men. In a meta-analysis of prospective studies
of coronary death among women with DM by
Warren et al. they found that the relative risk of
coronary death from diabetes was greater for women
than men (32).
In this study, clustering of CAD risk factors such
as high systolic and diastolic blood pressure and
higher plasma level of total cholesterol, non-HDL
cholesterol, TG, LDL-C, Lp(a) and apo-B, and
abnormal HDL-C levels were more pronounced in
women compared to men (Fig. 2). What is the reason
for this difference between women and men? One
popular theory to explain the sex difference relates to
HDL cholesterol. Walden et al. suggested that HDL
cholesterol levels are lower in diabetic women than
men (33). In fact it has also been postulated that the
inverse association between CHD and HDL levels is
stronger in women than men. Gorden et al. showed
that for each milligram-per-deciliter increase in

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Dyslipidemia in type 2 diabetes
116 Acta Medica Iranica, Vol. 44, No. 2 (2006)
HDL, there was ~2% decrease in CHD risk in men,
but a 3% decrease in women (21).
There are many other theories proposed to
account for the excess risk from diabetes in women.
These include differences in coagulation (34), the
pattern of obesity between men and women (35), and
possible role for hyperinsulinemia (36). Diabetes
may also alter estrogen
mechanisms (37). Furthermore,
inflammation may have a greater role in perturbing
insulin action in women, or inflammatory factors
may interact with female sex hormones, resulting in
a decrease of protective effects of estrogens on body
fat distribution and insulin action (38). The
discussion of these theories is beyond the scope of
our study; suffice it to say that the underlying basis
for the sex difference in risk from diabetes remains,
for the most part, speculative.

Conflict of Interests
The authors declare that they have no competing
interests.

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