- Email: [email protected]
Pattern and predictors of dyslipidemia in patients with type 2 diabetes mellitus
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 7 (2013) 95–100
Contents lists available at SciVerse ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx
Pattern and predictors of dyslipidemia in patients with type 2 diabetes mellitus Md N. Karim a, Kazi R. Ahmed b,*, Mohammad S. Bukht c, Jesmin Akter d, Hasina A. Chowdhury e, Sharmin Hossain b, Nazneen Anwar f, Shajada Selim g, Shahabul H. Chowdhury h, Fawzia Hossain i, Liaquat Ali j a
Directorate General of Health Services, Bangladesh Department of Health Promotion and Health Education, Bangladesh Institute of Health Sciences, Bangladesh BRAC Health Program, BRAC, Bangladesh d Department of Reproductive and Child Health, Bangladesh Institute of Health Sciences, Bangladesh e Department of Biostatistics, Bangladesh Institute of Health Sciences, Bangladesh f Research Division of Directorate General of Health Services, Bangladesh g Department Endocrinology, BIRDEM, Bangladesh h Department of Medicine, BSMMU, Bangladesh i Department of Gynae and Obs, BSMMU, Bangladesh j Department of Biochemistry and Cell Biology, Bangladesh Institute of Health Sciences, Bangladesh b c
A R T I C L E I N F O
A B S T R A C T
Keywords: T2DM Dyslipidemia Cardio vascular disease TC-HDL ratio and LDL-HDL ratio
Dyslipidemia is a major risk factor for macro-vascular complications in patients with type 2 diabetes mellitus (T2DM). Present study explored pattern and predictors of dyslipidemia in Bangladeshi T2DM patients. The cross-sectional study is conducted among 366 consecutive eligible T2DM patients aged >30 years, BIRDEM diabetic hospital, during July-to-December 2010. Physical examination, diabetic profile, lipid profile and serum createnine was performed. Adjusted odds ratio and confidence limit were generated through binary logistic regression. Most frequent form (59.3%) of dyslipidemia is low HDL. Duration of T2DM is significantly correlated with TC (P < 0.05), HDL (P < 0.05) and LDL (P < 0.05) in both male and female. Glycemic control in terms of HbA1c >7% appeared as predictor of dyslipidemia (P < 0.01). Duration T2DM is associated with increased risk of having higher TC (P < 0.05), LDL (P < 0.05) and lower HDL (P < 0.01) and does not seem to affect triglyceride (P > 0.05). T2DM with comorbid hypertension seems to predict hyper tri-glyceridemia and lower HDL. Both TC–HDL ratio and LDL–HDL ratio appeared as good predictor of all four parameters of dyslipidemia (P < 0.01). The characteristic features of diabetic dyslipidemia are low HDL, high triglyceride and LDL cholesterol level. Low HDL level is the most frequent type of abnormality. Poor glycemic control, prolonged duration, coexisting hypertension predicts dyslipidemia in T2DM. ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1. Introduction Dyslipidemia is major risk factors for macrovascular complications in patients with type 2 diabetes mellitus (T2DM) [1]. Macrovascular disease is the most common cause of morbidity and mortality in T2DM [2] and is defined as illnesses affecting the larger arteries supplying the heart, brain, and the legs, thereby causing cardiovascular disease (CVD), cerebrovascular disease, and peripheral vascular disease. There are evidence about associations between dyslipidemia and the increased risk of cardiovascular disease in patients with type 2 diabetes mellitus [3]. It predisposes the diabetic patients to the coronary heart disease in particular [4]. In patients with
* Corresponding author. E-mail address: [email protected] (K.R. Ahmed).
diabetes, alteration in distribution of lipid increased risk of atherosclerosis [5]. The majority of ischemic coronary and cerebrovascular events are precipitated by vessel occlusion caused by atherosclerotic plaque disruption, platelet aggregation, platelet adhesion and thrombosis [6]. DM believed to potentiate the effects of other common risk factors, such as smoking, hypertension and hypercholesterolemia [7]. The mortality associated with a coronary event in people with diabetes mellitus is significantly higher than that in non-diabetic individuals [8]. Patients with type 2 DM have two to four fold increase in CVD [9] and dramatically higher risk of accelerated cerebral and peripheral vascular disease [10]. Apart from dyslipidemia, platelet abnormalities also contribute significantly to increased risk of CVD in T2DM. In patients with T2DM, the platelet abnormalities are due to increased platelet agreeability and adhesiveness [6] and enhanced platelet aggregation activity may precede development of CVD [11]. Type 2
1871-4021/$ – see front matter ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dsx.2013.02.011
96
M.N. Karim et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 7 (2013) 95–100
diabetes is associated with a cluster of interrelated plasma lipid and lipoprotein abnormalities, including reduced HDL cholesterol, a predominance of small dense LDL particles, and elevated triglycerides [12]. There is evidence that each of these dyslipidemic features is associated with increased risk of CVD, the leading cause of death in patients with type 2 diabetes. Studies demonstrated association between LDL and coronary artery disease (CAD) [13]. In the past couple of decades, explosive increase in the number of people diagnosed with diabetes posing huge burden on Bangladeshi population. Dyslipidemia may further strain the already burdened health system with unleashing the risk of CVD and related diseases. The exact pathogenesis of dyslipidemia in T2DM is not yet clear. There are subgroups of T2DM patients based on differing risk and pattern of dyslipidemia, suggesting potential for involvement of extrinsic factor. The purpose of the paper is twofold. It seeks to explore the pattern of dyslipidemia in Bangladeshi T2DM patients and further to look into possible predictors for such condition. 2. Methodology The cross-sectional study is conducted in Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM) during July-to-December 2010. BIRDEM is a central tertiary hospital of the Diabetic Association of Bangladesh and diabetic patients from all over the country including referred patients from affiliated associations are destined here. Being a charity the hospital attracts patients with diverse demographic and socioeconomic background from all over the country. Thus, data generated from this hospital may be considered as a fair reflection of general diabetic population of the country. The study subjects were all DM patients seeking diabetic care at BIRDEM. A total of 366 consecutive eligible type 2 diabetic mellitus patients aged >30 years, attending the outpatient department of BIRDEM were recruited. A medical officer examined the patients for eligibility. Patients with clinical evidence of congestive heart failure (CHF), hepatic insufficiency, systemic or local infections were excluded. T2DM patients receiving any lipid lowering agent in past one month were also excluded from the study. For each eligible patient a questionnaire including epidemiologic data such as age, gender and physical activity were completed. Information about duration of diabetes, hypertension, other co-morbidities and drug history such as insulin and lipid lowering drugs were collected. All subjects then underwent physical examination, including measurements of height, weight, and blood pressure (sitting position after at least 10 min rest). Blood samples were drawn after at least 12 hours of overnight fasting. Serum glucose profile (fasting, 2-h after breakfast and HbA1c), lipid profile (total cholesterol, LDL, HDL and triglyceride) and serum createnine were measured. The classification and diagnosis of diabetes was made by the reporting physician at BIRDEM according to the World Health Organization (WHO) criteria. Physical and anthropometric measurements were taken from the patients adopting standard operating procedure. Blood pressure was measured on left arm by auscultatory method using mercury sphygmomanometer. The individuals were made comfortable and seated at least for five minutes on the chair before measurement. Hypertension was defined as blood pressure 140/90 mmhg [14]. Patients on antihypertensive drugs have also been considered as hypertensive. Body weight was measured (to the nearest 0.1 kg) with the subject standing motionless on the bathroom weighing scale. Each weighing scale was standardized every day with a weight of 50 kg. Height was measured (to the nearest 0.1 cm with the subject standing in an erect position against a vertical scale of portable
stadiometer). Overweight and obesity were defined based on BMI cutoff 25–30 kg/m2 and >30 kg/m2, respectively [15]. Poor diabetic control has been considered with HBA1c >7% [16]. Cutoff for dyslipidemia were considered with TC >200 mg/dl, TG was >150 mg/dl and LDL >100 mg/dl. For HDL cut-off for men was <40 mg/dl and for women was <50 mg/dl. Cutoff considered for serum createnine was >1.5 mg/dl [17]. Informed written consent was taken from each of the individuals prior to inclusion. The research project received ethical committees of the Diabetic association of Bangladesh. The study received approval from the ethical committee of Diabetic association of Bangladesh. For statistical analysis Stata110 I/C was used. Descriptive statistics for baseline characteristics were generated, after stratifying into sex. Relative frequency was tabulated for qualitative attributes and summary statistics (mean sd) were generated for quantitative attributes. Lipid parameters are compared across sexes through independent t-test. Quantitative values of the lipid profile were categorized to dichotomous variable based on defined criteria for determining dyslipidemia proportion. Clustering phenomenon of lipid abnormality was assessed through multiple response and cumulative frequency analysis. Person correlation coefficient to assess liner relation between lipid parameters and attributes and was presented in matrix with p value. TC–HDL ratio and LDL–HDL ratio were computed from existing lipid value through simple arithmetic division. Age sex adjusted odds ratio and confidence limit of factors were generated through binary logistic regression entering individual candidate predictor simultaneously with age and sex in separate model. Separate models were generated for all for lipid abnormality and for all alleged predictors. 3. Results 3.1. Patient’s characteristics Of the 366 T2DM patients 37.4% were male and 62.6% were female. Average age of the respondents was 48 8 years. More than two third of the patients were of age between 40 and 59 years. Around 59% had BMI < 25 kg/m2 rest were either overweight or obese. Despite being diabetic only 46.7% does sufficient physical activity and the proportion of sufficient physical activity is similar in both male and female. Co-morbid hypertension is found in 44.8% subjects, the proportion is similar in both sexes. Raised serum createnine (>1.5 mg/dl) is found in around ten percent of the subject; the proportion is more in male (12.4%) than female (8.7%) Patients were on average having diabetes for 9.3 6.7 years. More than seventy percent of the patients had diabetes for five years or longer. Only around one fourth of the DM patients were maintaining good glycemic control (HbA1c < 7%). Proportion of better glycemic control is higher in female (27.9%) than male (21.2%). Around 38% of the DM patients are on insulin (Table 1). 3.2. Pattern of dyslipidemia Mean comparison through independent t test revealed no statistically significant difference in any of the lipid parameters (P > 0.05) between men and women. Average total cholesterol among T2DM patients was 182.2 47.2 mg/dl (men 183.9 women 181.1), triglyceride was 171.4 66.9 mg/dl (men 178.6 women 167.2), LDL was 108.9 31.9 mg/dl (men 112.5 women 106.8), HDL was 41.8 8.4 mg/dl (men 41.3% women 42.1%). Most common (59.3%) form of dyslipidemia found in T2DM patients is lower HDL, the proportion is much higher in women (71.2%) than men (39.4%). Hyper-triglyceridemia is found in around 51% (men 57% women 47.2%), raised LDL is found in 51% patients (men 56.2%, women 48%). Around 21% were found to have raised total cholesterol the proportion is slightly higher in men
M.N. Karim et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 7 (2013) 95–100 Table 1 Patient characteristics (n = 366).
3.3. Predictors of dyslipidemia
Sex
Variables
Total n (%)
Male n (%)
Female n (%)
Age (years) 30–40 40–49 50–59 60
28 51 50 08
(20.5) (37.2) (36.5) (05.8)
30 (13.1) 76 (33.2) 102 (44.5) 21 (09.2)
58 (15.8) 127 (34.7) 152 (41.6) 29 (07.9)
BMI Not overweight Overweight Obese
81 (59.1) 42 (30.7) 14 (10.2)
135 (59.0) 65 (28.4) 29 (12.6)
216 (59.1) 107 (29.2) 43 (11.7)
Physical activity Sufficient Insufficient
64 (46.7) 73 (53.3)
107 (46.7) 122 (53.3)
171 (46.7) 195 (53.3)
Hypertension No Yes
75 (54.7) 62 (45.3)
127 (55.5) 102 (44.5)
202 (55.2) 164 (44.8)
Duration of DM <5 years 5–10 years 10 years
48 (35.1) 38 (27.7) 51 (37.2)
60 (26.2) 66 (28.8) 103 (45.0)
108 (29.5) 104 (28.4) 154 (42.1)
HbA1c <7 7
29 (21.2) 108 (78.8)
64 (27.9) 165 (72.1)
93 (25.4) 273 (74.6)
Taking insulin No Yes
90 (65.7) 47 (34.3)
138 (60.3) 91 (39.7)
228 (62.3) 138 (37.7)
S. Createnine <1.5 1.5
120 (87.6) 17 (12.4)
209 (91.3) 20 (8.7)
329 (89.9) 37 (10.1)
Results are expressed as number (percentage), S. Createnine, serum createnine; HbA1c, glycosylated hemoglobin; BMI, body mass index.
(23.4%) than women (19.2%). Around 84.4% of study subjects had at least one lipid abnormality. Around 55.7% of the patients had two or more abnormality, 33% had three or more abnormality and 9% had all four lipid parameters abnormal. The proportions are almost similar in men and women (Table 2).
Table 2 Lipid profile of the study subjects (n = 366). Variables
Sex
Total n (%)
Male n (%)
Female n (%)
TC <200 mg/dl 200 mg/dl
105 (76.6) 32 (23.4)
185 (80.8) 44 (19.2)
290 (79.2) 76 (20.8)
TG <150 mg/dl 150 mg/dl
58 (42.3) 79 (57.7)
121 (52.8) 108 (47.2)
179 (48.9) 187 (51.1)
HDL Lowa Normal
83 (60.6) 54 (39.4)
66 (28.8) 163 (71.2)
149 (40.7) 217 (59.3)
LDL <100 mg/dl 100 mg/dl
60 (43.8) 77 (56.2)
119 (52.0) 110 (48.0)
179 (48.9) 187 (51.1)
Dyslipidemia None One Two Three All four
24 38 32 32 11
33 67 51 56 22
57 (15.6) 105 (28.7) 83 (22.7) 88 (24.0) 33 (09.0)
(17.5) (27.7) (23.4) (23.4) (08.0)
97
(14.4) (29.3) (22.3) (24.5) (09.6)
a HDL < 40 mg/dl in male and <50 mg/dl in female, Results are expressed as number (percentage), TG, triglyceride; TC, total cholesterol; HDL, high density lipoprotein-cholesterol; LDL, low density lipoprotein-cholesterol.
Matrix in Table 3 illustrates correlation coefficient generated through person correlation stratified in to sex. Among male duration of diabetes was significantly correlated with TC (r 0.339), HDL (r 0.223) and LDL (r 0.388). Among female also duration of diabetes was significantly correlated with TC (r 0.145), HDL (r 0.173) and LDL (r 0.261). Correlation of BMI is only significant in male and with TC (r 0.176). Age and serum createnine seem to be unrelated with any of lipid profile parameters measured. Age and sex adjusted odds ratio was generated for developing lipid abnormality through binary logistic regression. Glycemic control in terms of HbA1c > 7% appeared as predictor of having abnormal value in all four lipid parameters (P < 0.01). Duration T2DM is associated with increased risk of having higher TC (P < 0.05), LDL (P < 0.05) and lower HDL (P < 0.01) and does not seem to affect triglyceride (P > 0.05). T2DM with co-morbid hypertension seems to predict hyper-tri-glyceridemia and lower HDL. We explored the potential of TC–HDL ratio and LDL–HDL ratio as predictor of dyslipidemia. Both the ratio appeared as significant predictor of abnormal value in all four parameters of dyslipidemia (Table 4). 4. Discussion Dyslipidemia in terms of at least one lipid abnormality found in our sample of T2DM patients is as high as 84.4%. Low HDL is the most common among the four forms of dyslipidemia and this is particularly much higher in women than men. In type 2 diabetes mellitus lipid abnormalities are well documented [18]. However the reported prevalence of diabetic dyslipidemia has varied across literature [19]. This wide variation can be attributed to the studied population and the degree of glycemic control and to the variation of the definition of the ‘‘cut-off’’ for hypercholesterolemia and hyper tri-glyceridemia. The pattern of lipid disorder, however, differs between ethnicities and populations. In our study about one in every five T2DM patients had hyper-cholesterolaemia and about half had hyper-triglyceridaemia and LDL which is higher than other study done in Africa [20] but lower than from the UK [21]. In the Framingham Heart Study [22] 13% of men and 24% of women with diabetes mellitus had increased total plasma cholesterol levels. The prevalence of high plasma triglyceride levels in individuals with T2DM was also significantly higher than in those without. In their study the prevalence of low HDL cholesterol level in those with diabetes mellitus was almost twice as high as the prevalence in non-diabetic individuals. A similar pattern of altered plasma lipid profiles was observed in the UK Prospective Diabetes Study (UKPDS) [23]. In their study, total cholesterol levels of those with diabetes mellitus and control individuals did not differ. However, women with T2DM had markedly higher LDL cholesterol levels than women who were not diabetic. The plasma triglyceride levels of patients with T2DM were substantially increased, whereas HDL cholesterol levels were markedly reduced in both men and women with diabetes mellitus compared with the nondiabetic controls. The pathophysiology of lipid abnormalities in diabetes is not yet totally explained, insulin resistance leading to altered metabolism of triglyceride rich lipoproteins believed to play a pivotal role in the development of diabetic dyslipidemia by influencing several factors [24]. The main cause of the three cardinal features of diabetic dyslipidemia is the increased free fatty-acid release from insulin-resistant fat cells [25]. Insulin resistance and low HDL levels might have a common mediator; several key enzymes that are involved in HDL cholesterol metabolism are altered in people with insulin resistance [26,27]. The fact that free fatty acid levels are elevated in individuals with
M.N. Karim et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 7 (2013) 95–100
98
Table 3 Relationship according to gender (n = 366). TG
Variables
r Male (n = 137)
Female (n = 229)
Age DM duration BMI S. creatinine Age DM duration BMI S. creatinine
TC p
0.092 0.068 0.033 0.077 0.004 0.053 0.006 0.041
HDL
r
0.285 0.430 0.705 0.374 0.958 0.421 0.923 0.537
p 0.078 0.339 0.176 0.070 0.013 0.145 0.048 0.056
0.364 *0.001 *0.040 0.420 0.847 *0.028 0.467 0.400
LDL
r
p 0.040 0.232 0.047 0.044 0.049 0.173 0.082 0.030
0.645 *0.006 0.586 0.607 0.463 *0.009 0.216 0.654
r
p 0.036 0.388 0.052 0.040 0.042 0.261 0.014 0.086
0.678 *0.001 0.542 0.639 0.523 *0.001 0.837 0.193
The level of significance at p < 0.05; r = correlation coefficient; TG, triglyceride; TC, total cholesterol; HDL, high density lipoprotein-cholesterol; LDL, low density lipoproteincholesterol; S. Creatinine, serum creatinine; BMI, body mass index.
Table 4 Age and sex adjusted odds ratio for lipid parameter. Variables
Duration of DM On insulin Overweight (BMI 25 kg/m2) Hypertension S. Creatinine (>1.5 mg/dl) Insufficient physical activity HbA1C (>7%) TC–HDL ratio LDL–HDL ratio
TG
TC
HDL
OR (CI)
OR (CI)
OR (CI)
1.03 (0.99, 1.06) 1.32 (0.86, 2.03) 0.97 (0.63, 1.47) 1.50* (1.01, 2.28) 1.00 (0.61, 1.63) 0.96 (0.63, 1.46) 1.18* (1.11, 1.25) 1.66* (1.41, 1.96) 2.11* (1.63, 2.73)
*
1.06 (1.02, 1.10) 0.66 (0.38, 1.15) 0.92 (0.55, 1.55) 1.22 (0.73, 2.02) 1.36 (0.78, 2.36) 1.19 (0.71, 2.00) 1.38* (1.28, 1.49) 3.57* (2.65, 4.82) 1.62* (1.28, 2.04)
LDL
*
1.08 (1.04, 1.12) 0.93 (0.59, 1.47) 0.73 (0.47, 1.15) 1.67* (1.06, 2.62) 1.03 (0.61, 1.73) 0.65 (0.41, 1.02) 1.09* (1.04, 1.15) 3.73* (2.74, 5.06) 4.85* (3.27, 7.20)
OR (CI) 1.05* (1.02, 1.09) 1.09 (0.71, 1.67) 0.84 (0.55, 1.28) 1.15 (0.76, 1.73) 1.03 (0.61, 1.73) 1.15 (0.76, 1.75) 1.16* (1.09, 1.24) 1.33* (1.16, 1.53) 19.8* (10.4, 37.5)
OR, age and sex were adjusted odds ratio, CI, confidence interval; TG, triglyceride; TC, total cholesterol, HDL, high density lipoprotein-cholesterol; LDL, low density lipoprotein-cholesterol; S. Creatinine, serum creatinine; HbA1c, glycosylated hemoglobin. * P = <0.05. **P = <0.01. ***P = <0.00.
impaired glucose tolerance suggests that insulin resistance associated with elevated free fatty acid levels occurs even before the onset of hyperglycemia [28]. One study conducted in patients without diabetes showed that decreased glucose utilization in muscle was associated with acute elevation of free fatty acids [29]. Epidemiologic studies have also demonstrated a relationship between plasma free fatty acid levels and insulin resistance [30]. In the presence of insulin resistance, free fatty acids in the form of triglycerides are deposited in muscle, liver, heart, and pancreas. The spectrum of dyslipidemia in diabetes mellitus can include all the various types of dyslipidemia identified in the general population [31] however, evidence from epidemiological studies are mounting regarding its link mostly to insulin resistance and insulin deficiency [32]. The characteristic features of this type are a high plasma triglyceride concentration, low HDL cholesterol concentration and increased concentration of LDL–cholesterol particles; [33] just similar to our finding. These changes are very much similar to the feature of metabolic syndrome, which underlies many cases of type 2 diabetes. There are evidence that insulin resistance has striking effects on lipoprotein size and subclass particle concentrations LDL, and HDL [34]. Each of these dyslipidemia features is associated with an increased risk of cardiovascular disease [35], the leading cause of death in T2DM patients [36]. Lipid abnormalities in patients with diabetes are potentially atherogenic. Another important determinant of atherosclerosis is the activity of phospholipid-transfer protein. This protein has been suggested to have a role in the development of obesity and diabetes mellitus; thus, it might become a therapeutic target [37]. Further evidence confirms that T2DM is associated with a cluster of interrelated plasma lipid and lipoprotein abnormalities that are well recognized predictors for coronary heart disease (CHD), including reduced plasma levels of
high density lipoprotein cholesterol particles and elevated plasma levels of TG [38]. T2DM increases the risk of CHD more markedly in women than men [39]. However, the reported magnitudes of the diabetesrelated CHD risk in men and women vary widely between different studies [40]. The cause of the greater relative risk of CHD in diabetic women still not clear, but several explanations can be offered. First, adverse changes induced by T2DM in HDL cholesterol, triglycerides, low-density lipoprotein particle size and blood pressure have been found to be more pronounced in women than in men [41,42]. In addition, T2DM in women may interfere with protective mechanisms in the vascular wall and thereby lead to enhanced atherogenesis. Our data reveals a prevalence of 49% of LDL levels higher than 100 mg/dl, which is considered to pose a risk of CHD and atherosclerosis and similar to the findings of a USA study [43]. On the other hand, more than half of the patients were found to have low HDL, which is also associated with high risk of CHD and atherosclerosis. When such lipid profiles co-exist with long duration of diabetes among DM patients, a high incidence of CHD and atherosclerosis may be inevitable in the future. Our result demonstrates clustering of two or more lipid abnormality in around 55.7% subjects and of three or more lipid abnormality in 33%. Around 9% had all four lipid abnormalities. Our data identifies poor glycemic control as predictor of dyslipidemia. Similar evidence has been reported by studies [44,45]. Prolonged T2DM in our data is linked with raised TC, and LDL and lower HDL and does not seem to affect triglyceride. DM with co-morbid hypertension predicts hyper tri-glyceridemia and lower HDL. This suggests that the duration of diabetes may relate to the severity of lipid disorder in diabetes mellitus. Many studies indicating that there is alteration in vascular functional integrity in
M.N. Karim et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 7 (2013) 95–100
diabetes mellitus, and that the alteration is dependent on the duration of the condition [46,47]. A national cross-sectional chart audit study of 2473 Canadian patients with type 2 diabetes showed 55% of patients with a diagnosis of diabetes of 2 years had dyslipidemia. This proportion rose to 66% in patients with diabetes for 15 years [48]. However, Otamere et al. ruled out association of age and duration of illness with lipid profile prediction [49]. DM with co-morbid hypertension seems to predict hyper tri-glyceridemia and lower HDL. Insufficient physical activity, overweight, co-morbid renal impairment and treatment with insulin did not appear as significant predictor of dyslipidemia in T2DM. As Low HDL was found to be the most prevalent lipid abnormality, we attempted to explore for its interaction with other lipid parameters. We explored association of TC-HDL ratio and LDL-HDL ratio as predictor of dyslipidemia. Both the ratio appeared as significant predictor of all the parameters of dyslipidemia in DM patients suggesting a potential of the indicator for diabetic dyslipidemia. These two factors warrants further in detail investigation in larger samples. One limitation in our study is our estimated proportion of dyslipidemia in T2DM may not be representative of Bangladesh and rather represents of those who attended BIRDEM and are likely to have more severe disease and a higher frequency of complication; therefore estimates reported in our study are likely to be over estimate Bangladesh population. Alternatively potential survival bias may underestimate the true prevalence. A cohort study of duration longer than maximum lead time of dyslipidemia would be needed. In summary the characteristic features of diabetic dyslipidemia are a low HDL cholesterol concentration, high triglyceride and LDLcholesterol level. Low HDL level is the most frequent type of abnormality. Poor glycemic control, prolonged duration, coexisting hypertension predicts dyslipidemia in T2DM. Both TC–HDL ratio and LDL–HDL ratio predicted dyslipidemia in T2DM. DM patients must be screened and appropriate management should be instituted to reduce the risk of CHD and atherosclerosis. Health care professionals can play a valuable role for reducing the risk factors of dyslipidemia by promoting healthy lifestyle of diabetic patients. Conflict of interest None. References [1] Mooradian AD. Cardiovascular disease in type 2 diabetes mellitus: current management guidelines. Archives of Internal Medicine 2003;163:33–40. [2] Koskinen SV, Reunanen AR, Martelin TP, Valkonen T. Mortality in a large population-based cohort of patients with drug-treated diabetes mellitus. American Journal of Public Health 1998;88(May (5)):765–70. [3] Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, et al. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation 1997;95:69–75. [4] Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241(19):2035–8. [5] Thompson DM. Cardiovascular disease and diabetes. BC Endocrine Research Foundation Newsletter 1999;1:3. [6] Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care 2003;26(7):2181–8. [7] Stamler J. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434–44. [8] Sprafka JM. Trends in prevalence of diabetes mellitus in patients with myocardial infarction and effect of diabetes on survival. The Minnesota Heart Survey. Diabetes Care 1991;14:537–43. [9] Haffner SM. Dyslipidemia management in adults with diabetes. Diabetes Care 2004;27(January (Suppl. 1)):S68–71. [10] Brown WV. Risk factors for vascular disease in patients with diabetes. Diabetes Obesity & Metabolism 2000;2(November (Suppl. 2)):S11–8.
99
[11] Halushka PV, Rogers RC, Loadholt CB, Colwell JA. Increased platelet thromboxane synthesis in diabetes mellitus. Journal of Laboratory and Clinical Medicine 1981;97(January (1)):87–96. [12] American Diabetes Association. Management of dyslipidemia in adults with diabetes (position statement). Diabetes Care 2003;26(Suppl. 1):S83–6. [13] Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease risk. Circulation 1990;82:495–506. [14] World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complication. Report of a WHO Consultation. Part 1. Diagnosis and Classification of Diabetes Mellitus. Geneva: World Health Organization, Department of Noncommunicable Disease Surveillance; 1999. [15] World Health Organization. Obesity and overweight. World Health Report; 2002. [16] Dowse GK, Humphrey ARG, Collins VR, Plehwe W, Gareeboo H, Fareed D, et al. Prevalence and risk factors for diabetic retinopathy in the multiethnic population of Mauritius. American Journal of Epidemiology 1998;147:448–57. [17] American Diabetes Association. Clinical practice recommendation. American Diabetes Association (ADA); 2009. [18] American Diabetes Association (ADA). Standards of medical care in diabetes. Diabetes Care 2007;30:4–41. [19] Barrett-Connor E, Grundy SM, Holdbrook MJ. Plasma lipids and diabetes mellitus in an adult community. American Journal of Epidemiology 1982;115: 657–63. [20] Seyoum B, Abdulkadir J, Berhanu P, Feleke Y, Mengistu Z, Worku Y, et al. Analysis of serum lipids and lipoproteins in Ethiopian diabetic patients. Ethiopian Medical Journal 2003;41(1):1–8. [21] Lawrence JM, Bennett P, Young A, Robinson AM. Primary care screening for diabetes in general practice: cross sectional population study. BMJ 2001;323: 548–51. [22] Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. American Heart Journal 1985;110:1100–7. [23] [No authors listed] UKPDS U.K. Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care 1997;20:1683–7. [24] Joshua A, Becham B, Libby P. Diabetes and atherosclerosis. JAMA 2002;287: 2570–81. [25] Haffner SM, Lehto S, Ro¨nnemaa T, Pyo¨ra¨la¨ K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior history of myocardial infarction. The New England Journal of Medicine 1998;339:229–34. [26] Dullaart RP. Type 2 diabetes mellitus is associated with differential effects on plasma cholesteryl ester transfer protein and phospholipid transfer protein activities and concentrations. Scandinavian Journal of Clinical and Laboratory Investigation 2004;64:205–15. [27] Borggreve SE. Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins. European Journal of Clinical Investigation 2003;33: 1051–69. [28] Bluher M, Kratzsch J, Paschke R. Plasmalevels of tumor necrosis factor, angiotensin II, growth hormone, and IGF-I are not elevated in insulin-resistant obese individuals with impaired glucose tolerance. Diabetes Care 2001;24: 328–34. [29] Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. The Journal of Clinical Investigation 1999;103: 253–9. [30] Reaven GM, Chen YD. Role of abnormal free fatty acid metabolism in the development of non-insulin-dependent diabetes mellitus. The American Journal of Medicine 1988;85:106–12. [31] Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a populationbased study of 13,000 men and women with 20 years of follow-up. Archives of Internal Medicine 2004;164:1422–6. [32] Hachem SB, Mooradian AD. Familial dyslipidaemias: an overview of genetics, pathophysiology and management. Drugs 2006;66:1949–69. [33] American Diabetes Association (ADA). Management of dyslipidemia in adults with diabetes. Diabetes Care 2002 Jan;25(suppl 1):S74–7. [34] Garvey WT, Kwon S, Zheng D, Shaughnessy S, Wallace P, Hutto A, et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes 2003;52:453–62. [35] Mooradian AD. Dsylipidemia in type 2 diabetes mellitus. Nature Clinical Practice Endocrinology and Metabolism 2008;5:3150–9. [36] Barrett-Connor E, Giardian EG, Gitt AK, Gudat U, Steinberg HO, Tscheope D. Women and heart disease: the role of diabetes and hyperglycemia. Archives of Internal Medicine 2004;164(9):9344–942. [37] Vergeer M. Evaluation of phospholipid transfer protein as a therapeutic target. Future Lipidology 2008;3:327–35. [38] Craig WY, Neveux LM, Palomaki GE, Cleveland MM, Hadow JE. Lipoprotein (a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies. Clinical Chemistry 1998;44(11):2301–6. [39] Juutilainen A, Kortelainen S, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Gender difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes Care 2004;27(December (12)):2898–904.
100
M.N. Karim et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 7 (2013) 95–100
[40] Kanaya AM, Grady D, Barrett-Connor E. Explaining the sex difference in coronary heart disease mortality among patients with type 2 diabetes mellitus: a meta analysis. Archives of Internal Medicine 2002;162(August (15)):1737–45. [41] Howard BV, Cowan LD, Go O, Welty TK, Robbins DC, Lee ET. Adverse effects of diabetes on multiple cardiovascular disease risk factors in women. The Strong Heart Study. Diabetes Care 1998;21(August (8)):1258–65. [42] Siegel RD, Cupples A, Schaefer EJ, Wilson PW. Lipoproteins, apolipoproteins, and low-density lipoprotein size among diabetics in the Framingham offspring study. Metabolism Clinical and Experimental 1996;45(October (10)):1267–72. [43] Saaddine JB, Engelgau MM, Beckles GL, Gregg EW, Thompson TJ, Narayan KM. A diabetes report card for the United States: quality of care in the 1990s. Annals of Internal Medicine 2002;136:565–74. [44] Abdel-Aal NM, Ahmet AT, Froelicher ES, Batieha AMS, Hamza MM, Ajloni KM. Prevalance of dyslipidemia in patients with type 2 diabetes mellitus in Jordan. Saudi Medical Journal 2008;29(10):1423–8.
[45] Gonen B, White N, Schonfeld G. Plasma levels of appoprotein B in patients with diabetes mellitus; the effect of glycimec control. Metabolism 1985;34:675–9. [46] Schwart CJ, Valente AJ, Spargue EA, Kelly JL, Cayatte AJ, Rozels M. Pathogenesis of the atherosclerotic lesion: implication for diabetes mellitus. Diabetes Care 1992;15:1156–67. [47] Talat N, Amir K, Gulsena M, Bilal B. Dyslipidemias in type 2 diabetes mellitus patients in a teaching hospital of Lahore, Pakistan. Pakistan Journal of Medical Sciences 2003;19:283–6. [48] Harris SB, Ekoe´ JM, Zdanowicz Y, Webster-Bogaert S. Glycemic control and morbidity in the Canadian primary care setting (results of the diabetes in Canada evaluation study). Diabetes Research and Clinical Practice 2005;70: 90–7. [49] Otamere HO, Aloamaka CP, Okokhere PO, Adisa WA. Lipid profile in diabetes mellitus; What impact has age and duration. British Journal of Pharmacology and Toxicology 2011;2(3):135–7.
Contents lists available at SciVerse ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx
Pattern and predictors of dyslipidemia in patients with type 2 diabetes mellitus Md N. Karim a, Kazi R. Ahmed b,*, Mohammad S. Bukht c, Jesmin Akter d, Hasina A. Chowdhury e, Sharmin Hossain b, Nazneen Anwar f, Shajada Selim g, Shahabul H. Chowdhury h, Fawzia Hossain i, Liaquat Ali j a
Directorate General of Health Services, Bangladesh Department of Health Promotion and Health Education, Bangladesh Institute of Health Sciences, Bangladesh BRAC Health Program, BRAC, Bangladesh d Department of Reproductive and Child Health, Bangladesh Institute of Health Sciences, Bangladesh e Department of Biostatistics, Bangladesh Institute of Health Sciences, Bangladesh f Research Division of Directorate General of Health Services, Bangladesh g Department Endocrinology, BIRDEM, Bangladesh h Department of Medicine, BSMMU, Bangladesh i Department of Gynae and Obs, BSMMU, Bangladesh j Department of Biochemistry and Cell Biology, Bangladesh Institute of Health Sciences, Bangladesh b c
A R T I C L E I N F O
A B S T R A C T
Keywords: T2DM Dyslipidemia Cardio vascular disease TC-HDL ratio and LDL-HDL ratio
Dyslipidemia is a major risk factor for macro-vascular complications in patients with type 2 diabetes mellitus (T2DM). Present study explored pattern and predictors of dyslipidemia in Bangladeshi T2DM patients. The cross-sectional study is conducted among 366 consecutive eligible T2DM patients aged >30 years, BIRDEM diabetic hospital, during July-to-December 2010. Physical examination, diabetic profile, lipid profile and serum createnine was performed. Adjusted odds ratio and confidence limit were generated through binary logistic regression. Most frequent form (59.3%) of dyslipidemia is low HDL. Duration of T2DM is significantly correlated with TC (P < 0.05), HDL (P < 0.05) and LDL (P < 0.05) in both male and female. Glycemic control in terms of HbA1c >7% appeared as predictor of dyslipidemia (P < 0.01). Duration T2DM is associated with increased risk of having higher TC (P < 0.05), LDL (P < 0.05) and lower HDL (P < 0.01) and does not seem to affect triglyceride (P > 0.05). T2DM with comorbid hypertension seems to predict hyper tri-glyceridemia and lower HDL. Both TC–HDL ratio and LDL–HDL ratio appeared as good predictor of all four parameters of dyslipidemia (P < 0.01). The characteristic features of diabetic dyslipidemia are low HDL, high triglyceride and LDL cholesterol level. Low HDL level is the most frequent type of abnormality. Poor glycemic control, prolonged duration, coexisting hypertension predicts dyslipidemia in T2DM. ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1. Introduction Dyslipidemia is major risk factors for macrovascular complications in patients with type 2 diabetes mellitus (T2DM) [1]. Macrovascular disease is the most common cause of morbidity and mortality in T2DM [2] and is defined as illnesses affecting the larger arteries supplying the heart, brain, and the legs, thereby causing cardiovascular disease (CVD), cerebrovascular disease, and peripheral vascular disease. There are evidence about associations between dyslipidemia and the increased risk of cardiovascular disease in patients with type 2 diabetes mellitus [3]. It predisposes the diabetic patients to the coronary heart disease in particular [4]. In patients with
* Corresponding author. E-mail address: [email protected] (K.R. Ahmed).
diabetes, alteration in distribution of lipid increased risk of atherosclerosis [5]. The majority of ischemic coronary and cerebrovascular events are precipitated by vessel occlusion caused by atherosclerotic plaque disruption, platelet aggregation, platelet adhesion and thrombosis [6]. DM believed to potentiate the effects of other common risk factors, such as smoking, hypertension and hypercholesterolemia [7]. The mortality associated with a coronary event in people with diabetes mellitus is significantly higher than that in non-diabetic individuals [8]. Patients with type 2 DM have two to four fold increase in CVD [9] and dramatically higher risk of accelerated cerebral and peripheral vascular disease [10]. Apart from dyslipidemia, platelet abnormalities also contribute significantly to increased risk of CVD in T2DM. In patients with T2DM, the platelet abnormalities are due to increased platelet agreeability and adhesiveness [6] and enhanced platelet aggregation activity may precede development of CVD [11]. Type 2
1871-4021/$ – see front matter ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dsx.2013.02.011
96
M.N. Karim et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 7 (2013) 95–100
diabetes is associated with a cluster of interrelated plasma lipid and lipoprotein abnormalities, including reduced HDL cholesterol, a predominance of small dense LDL particles, and elevated triglycerides [12]. There is evidence that each of these dyslipidemic features is associated with increased risk of CVD, the leading cause of death in patients with type 2 diabetes. Studies demonstrated association between LDL and coronary artery disease (CAD) [13]. In the past couple of decades, explosive increase in the number of people diagnosed with diabetes posing huge burden on Bangladeshi population. Dyslipidemia may further strain the already burdened health system with unleashing the risk of CVD and related diseases. The exact pathogenesis of dyslipidemia in T2DM is not yet clear. There are subgroups of T2DM patients based on differing risk and pattern of dyslipidemia, suggesting potential for involvement of extrinsic factor. The purpose of the paper is twofold. It seeks to explore the pattern of dyslipidemia in Bangladeshi T2DM patients and further to look into possible predictors for such condition. 2. Methodology The cross-sectional study is conducted in Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM) during July-to-December 2010. BIRDEM is a central tertiary hospital of the Diabetic Association of Bangladesh and diabetic patients from all over the country including referred patients from affiliated associations are destined here. Being a charity the hospital attracts patients with diverse demographic and socioeconomic background from all over the country. Thus, data generated from this hospital may be considered as a fair reflection of general diabetic population of the country. The study subjects were all DM patients seeking diabetic care at BIRDEM. A total of 366 consecutive eligible type 2 diabetic mellitus patients aged >30 years, attending the outpatient department of BIRDEM were recruited. A medical officer examined the patients for eligibility. Patients with clinical evidence of congestive heart failure (CHF), hepatic insufficiency, systemic or local infections were excluded. T2DM patients receiving any lipid lowering agent in past one month were also excluded from the study. For each eligible patient a questionnaire including epidemiologic data such as age, gender and physical activity were completed. Information about duration of diabetes, hypertension, other co-morbidities and drug history such as insulin and lipid lowering drugs were collected. All subjects then underwent physical examination, including measurements of height, weight, and blood pressure (sitting position after at least 10 min rest). Blood samples were drawn after at least 12 hours of overnight fasting. Serum glucose profile (fasting, 2-h after breakfast and HbA1c), lipid profile (total cholesterol, LDL, HDL and triglyceride) and serum createnine were measured. The classification and diagnosis of diabetes was made by the reporting physician at BIRDEM according to the World Health Organization (WHO) criteria. Physical and anthropometric measurements were taken from the patients adopting standard operating procedure. Blood pressure was measured on left arm by auscultatory method using mercury sphygmomanometer. The individuals were made comfortable and seated at least for five minutes on the chair before measurement. Hypertension was defined as blood pressure 140/90 mmhg [14]. Patients on antihypertensive drugs have also been considered as hypertensive. Body weight was measured (to the nearest 0.1 kg) with the subject standing motionless on the bathroom weighing scale. Each weighing scale was standardized every day with a weight of 50 kg. Height was measured (to the nearest 0.1 cm with the subject standing in an erect position against a vertical scale of portable
stadiometer). Overweight and obesity were defined based on BMI cutoff 25–30 kg/m2 and >30 kg/m2, respectively [15]. Poor diabetic control has been considered with HBA1c >7% [16]. Cutoff for dyslipidemia were considered with TC >200 mg/dl, TG was >150 mg/dl and LDL >100 mg/dl. For HDL cut-off for men was <40 mg/dl and for women was <50 mg/dl. Cutoff considered for serum createnine was >1.5 mg/dl [17]. Informed written consent was taken from each of the individuals prior to inclusion. The research project received ethical committees of the Diabetic association of Bangladesh. The study received approval from the ethical committee of Diabetic association of Bangladesh. For statistical analysis Stata110 I/C was used. Descriptive statistics for baseline characteristics were generated, after stratifying into sex. Relative frequency was tabulated for qualitative attributes and summary statistics (mean sd) were generated for quantitative attributes. Lipid parameters are compared across sexes through independent t-test. Quantitative values of the lipid profile were categorized to dichotomous variable based on defined criteria for determining dyslipidemia proportion. Clustering phenomenon of lipid abnormality was assessed through multiple response and cumulative frequency analysis. Person correlation coefficient to assess liner relation between lipid parameters and attributes and was presented in matrix with p value. TC–HDL ratio and LDL–HDL ratio were computed from existing lipid value through simple arithmetic division. Age sex adjusted odds ratio and confidence limit of factors were generated through binary logistic regression entering individual candidate predictor simultaneously with age and sex in separate model. Separate models were generated for all for lipid abnormality and for all alleged predictors. 3. Results 3.1. Patient’s characteristics Of the 366 T2DM patients 37.4% were male and 62.6% were female. Average age of the respondents was 48 8 years. More than two third of the patients were of age between 40 and 59 years. Around 59% had BMI < 25 kg/m2 rest were either overweight or obese. Despite being diabetic only 46.7% does sufficient physical activity and the proportion of sufficient physical activity is similar in both male and female. Co-morbid hypertension is found in 44.8% subjects, the proportion is similar in both sexes. Raised serum createnine (>1.5 mg/dl) is found in around ten percent of the subject; the proportion is more in male (12.4%) than female (8.7%) Patients were on average having diabetes for 9.3 6.7 years. More than seventy percent of the patients had diabetes for five years or longer. Only around one fourth of the DM patients were maintaining good glycemic control (HbA1c < 7%). Proportion of better glycemic control is higher in female (27.9%) than male (21.2%). Around 38% of the DM patients are on insulin (Table 1). 3.2. Pattern of dyslipidemia Mean comparison through independent t test revealed no statistically significant difference in any of the lipid parameters (P > 0.05) between men and women. Average total cholesterol among T2DM patients was 182.2 47.2 mg/dl (men 183.9 women 181.1), triglyceride was 171.4 66.9 mg/dl (men 178.6 women 167.2), LDL was 108.9 31.9 mg/dl (men 112.5 women 106.8), HDL was 41.8 8.4 mg/dl (men 41.3% women 42.1%). Most common (59.3%) form of dyslipidemia found in T2DM patients is lower HDL, the proportion is much higher in women (71.2%) than men (39.4%). Hyper-triglyceridemia is found in around 51% (men 57% women 47.2%), raised LDL is found in 51% patients (men 56.2%, women 48%). Around 21% were found to have raised total cholesterol the proportion is slightly higher in men
M.N. Karim et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 7 (2013) 95–100 Table 1 Patient characteristics (n = 366).
3.3. Predictors of dyslipidemia
Sex
Variables
Total n (%)
Male n (%)
Female n (%)
Age (years) 30–40 40–49 50–59 60
28 51 50 08
(20.5) (37.2) (36.5) (05.8)
30 (13.1) 76 (33.2) 102 (44.5) 21 (09.2)
58 (15.8) 127 (34.7) 152 (41.6) 29 (07.9)
BMI Not overweight Overweight Obese
81 (59.1) 42 (30.7) 14 (10.2)
135 (59.0) 65 (28.4) 29 (12.6)
216 (59.1) 107 (29.2) 43 (11.7)
Physical activity Sufficient Insufficient
64 (46.7) 73 (53.3)
107 (46.7) 122 (53.3)
171 (46.7) 195 (53.3)
Hypertension No Yes
75 (54.7) 62 (45.3)
127 (55.5) 102 (44.5)
202 (55.2) 164 (44.8)
Duration of DM <5 years 5–10 years 10 years
48 (35.1) 38 (27.7) 51 (37.2)
60 (26.2) 66 (28.8) 103 (45.0)
108 (29.5) 104 (28.4) 154 (42.1)
HbA1c <7 7
29 (21.2) 108 (78.8)
64 (27.9) 165 (72.1)
93 (25.4) 273 (74.6)
Taking insulin No Yes
90 (65.7) 47 (34.3)
138 (60.3) 91 (39.7)
228 (62.3) 138 (37.7)
S. Createnine <1.5 1.5
120 (87.6) 17 (12.4)
209 (91.3) 20 (8.7)
329 (89.9) 37 (10.1)
Results are expressed as number (percentage), S. Createnine, serum createnine; HbA1c, glycosylated hemoglobin; BMI, body mass index.
(23.4%) than women (19.2%). Around 84.4% of study subjects had at least one lipid abnormality. Around 55.7% of the patients had two or more abnormality, 33% had three or more abnormality and 9% had all four lipid parameters abnormal. The proportions are almost similar in men and women (Table 2).
Table 2 Lipid profile of the study subjects (n = 366). Variables
Sex
Total n (%)
Male n (%)
Female n (%)
TC <200 mg/dl 200 mg/dl
105 (76.6) 32 (23.4)
185 (80.8) 44 (19.2)
290 (79.2) 76 (20.8)
TG <150 mg/dl 150 mg/dl
58 (42.3) 79 (57.7)
121 (52.8) 108 (47.2)
179 (48.9) 187 (51.1)
HDL Lowa Normal
83 (60.6) 54 (39.4)
66 (28.8) 163 (71.2)
149 (40.7) 217 (59.3)
LDL <100 mg/dl 100 mg/dl
60 (43.8) 77 (56.2)
119 (52.0) 110 (48.0)
179 (48.9) 187 (51.1)
Dyslipidemia None One Two Three All four
24 38 32 32 11
33 67 51 56 22
57 (15.6) 105 (28.7) 83 (22.7) 88 (24.0) 33 (09.0)
(17.5) (27.7) (23.4) (23.4) (08.0)
97
(14.4) (29.3) (22.3) (24.5) (09.6)
a HDL < 40 mg/dl in male and <50 mg/dl in female, Results are expressed as number (percentage), TG, triglyceride; TC, total cholesterol; HDL, high density lipoprotein-cholesterol; LDL, low density lipoprotein-cholesterol.
Matrix in Table 3 illustrates correlation coefficient generated through person correlation stratified in to sex. Among male duration of diabetes was significantly correlated with TC (r 0.339), HDL (r 0.223) and LDL (r 0.388). Among female also duration of diabetes was significantly correlated with TC (r 0.145), HDL (r 0.173) and LDL (r 0.261). Correlation of BMI is only significant in male and with TC (r 0.176). Age and serum createnine seem to be unrelated with any of lipid profile parameters measured. Age and sex adjusted odds ratio was generated for developing lipid abnormality through binary logistic regression. Glycemic control in terms of HbA1c > 7% appeared as predictor of having abnormal value in all four lipid parameters (P < 0.01). Duration T2DM is associated with increased risk of having higher TC (P < 0.05), LDL (P < 0.05) and lower HDL (P < 0.01) and does not seem to affect triglyceride (P > 0.05). T2DM with co-morbid hypertension seems to predict hyper-tri-glyceridemia and lower HDL. We explored the potential of TC–HDL ratio and LDL–HDL ratio as predictor of dyslipidemia. Both the ratio appeared as significant predictor of abnormal value in all four parameters of dyslipidemia (Table 4). 4. Discussion Dyslipidemia in terms of at least one lipid abnormality found in our sample of T2DM patients is as high as 84.4%. Low HDL is the most common among the four forms of dyslipidemia and this is particularly much higher in women than men. In type 2 diabetes mellitus lipid abnormalities are well documented [18]. However the reported prevalence of diabetic dyslipidemia has varied across literature [19]. This wide variation can be attributed to the studied population and the degree of glycemic control and to the variation of the definition of the ‘‘cut-off’’ for hypercholesterolemia and hyper tri-glyceridemia. The pattern of lipid disorder, however, differs between ethnicities and populations. In our study about one in every five T2DM patients had hyper-cholesterolaemia and about half had hyper-triglyceridaemia and LDL which is higher than other study done in Africa [20] but lower than from the UK [21]. In the Framingham Heart Study [22] 13% of men and 24% of women with diabetes mellitus had increased total plasma cholesterol levels. The prevalence of high plasma triglyceride levels in individuals with T2DM was also significantly higher than in those without. In their study the prevalence of low HDL cholesterol level in those with diabetes mellitus was almost twice as high as the prevalence in non-diabetic individuals. A similar pattern of altered plasma lipid profiles was observed in the UK Prospective Diabetes Study (UKPDS) [23]. In their study, total cholesterol levels of those with diabetes mellitus and control individuals did not differ. However, women with T2DM had markedly higher LDL cholesterol levels than women who were not diabetic. The plasma triglyceride levels of patients with T2DM were substantially increased, whereas HDL cholesterol levels were markedly reduced in both men and women with diabetes mellitus compared with the nondiabetic controls. The pathophysiology of lipid abnormalities in diabetes is not yet totally explained, insulin resistance leading to altered metabolism of triglyceride rich lipoproteins believed to play a pivotal role in the development of diabetic dyslipidemia by influencing several factors [24]. The main cause of the three cardinal features of diabetic dyslipidemia is the increased free fatty-acid release from insulin-resistant fat cells [25]. Insulin resistance and low HDL levels might have a common mediator; several key enzymes that are involved in HDL cholesterol metabolism are altered in people with insulin resistance [26,27]. The fact that free fatty acid levels are elevated in individuals with
M.N. Karim et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 7 (2013) 95–100
98
Table 3 Relationship according to gender (n = 366). TG
Variables
r Male (n = 137)
Female (n = 229)
Age DM duration BMI S. creatinine Age DM duration BMI S. creatinine
TC p
0.092 0.068 0.033 0.077 0.004 0.053 0.006 0.041
HDL
r
0.285 0.430 0.705 0.374 0.958 0.421 0.923 0.537
p 0.078 0.339 0.176 0.070 0.013 0.145 0.048 0.056
0.364 *0.001 *0.040 0.420 0.847 *0.028 0.467 0.400
LDL
r
p 0.040 0.232 0.047 0.044 0.049 0.173 0.082 0.030
0.645 *0.006 0.586 0.607 0.463 *0.009 0.216 0.654
r
p 0.036 0.388 0.052 0.040 0.042 0.261 0.014 0.086
0.678 *0.001 0.542 0.639 0.523 *0.001 0.837 0.193
The level of significance at p < 0.05; r = correlation coefficient; TG, triglyceride; TC, total cholesterol; HDL, high density lipoprotein-cholesterol; LDL, low density lipoproteincholesterol; S. Creatinine, serum creatinine; BMI, body mass index.
Table 4 Age and sex adjusted odds ratio for lipid parameter. Variables
Duration of DM On insulin Overweight (BMI 25 kg/m2) Hypertension S. Creatinine (>1.5 mg/dl) Insufficient physical activity HbA1C (>7%) TC–HDL ratio LDL–HDL ratio
TG
TC
HDL
OR (CI)
OR (CI)
OR (CI)
1.03 (0.99, 1.06) 1.32 (0.86, 2.03) 0.97 (0.63, 1.47) 1.50* (1.01, 2.28) 1.00 (0.61, 1.63) 0.96 (0.63, 1.46) 1.18* (1.11, 1.25) 1.66* (1.41, 1.96) 2.11* (1.63, 2.73)
*
1.06 (1.02, 1.10) 0.66 (0.38, 1.15) 0.92 (0.55, 1.55) 1.22 (0.73, 2.02) 1.36 (0.78, 2.36) 1.19 (0.71, 2.00) 1.38* (1.28, 1.49) 3.57* (2.65, 4.82) 1.62* (1.28, 2.04)
LDL
*
1.08 (1.04, 1.12) 0.93 (0.59, 1.47) 0.73 (0.47, 1.15) 1.67* (1.06, 2.62) 1.03 (0.61, 1.73) 0.65 (0.41, 1.02) 1.09* (1.04, 1.15) 3.73* (2.74, 5.06) 4.85* (3.27, 7.20)
OR (CI) 1.05* (1.02, 1.09) 1.09 (0.71, 1.67) 0.84 (0.55, 1.28) 1.15 (0.76, 1.73) 1.03 (0.61, 1.73) 1.15 (0.76, 1.75) 1.16* (1.09, 1.24) 1.33* (1.16, 1.53) 19.8* (10.4, 37.5)
OR, age and sex were adjusted odds ratio, CI, confidence interval; TG, triglyceride; TC, total cholesterol, HDL, high density lipoprotein-cholesterol; LDL, low density lipoprotein-cholesterol; S. Creatinine, serum creatinine; HbA1c, glycosylated hemoglobin. * P = <0.05. **P = <0.01. ***P = <0.00.
impaired glucose tolerance suggests that insulin resistance associated with elevated free fatty acid levels occurs even before the onset of hyperglycemia [28]. One study conducted in patients without diabetes showed that decreased glucose utilization in muscle was associated with acute elevation of free fatty acids [29]. Epidemiologic studies have also demonstrated a relationship between plasma free fatty acid levels and insulin resistance [30]. In the presence of insulin resistance, free fatty acids in the form of triglycerides are deposited in muscle, liver, heart, and pancreas. The spectrum of dyslipidemia in diabetes mellitus can include all the various types of dyslipidemia identified in the general population [31] however, evidence from epidemiological studies are mounting regarding its link mostly to insulin resistance and insulin deficiency [32]. The characteristic features of this type are a high plasma triglyceride concentration, low HDL cholesterol concentration and increased concentration of LDL–cholesterol particles; [33] just similar to our finding. These changes are very much similar to the feature of metabolic syndrome, which underlies many cases of type 2 diabetes. There are evidence that insulin resistance has striking effects on lipoprotein size and subclass particle concentrations LDL, and HDL [34]. Each of these dyslipidemia features is associated with an increased risk of cardiovascular disease [35], the leading cause of death in T2DM patients [36]. Lipid abnormalities in patients with diabetes are potentially atherogenic. Another important determinant of atherosclerosis is the activity of phospholipid-transfer protein. This protein has been suggested to have a role in the development of obesity and diabetes mellitus; thus, it might become a therapeutic target [37]. Further evidence confirms that T2DM is associated with a cluster of interrelated plasma lipid and lipoprotein abnormalities that are well recognized predictors for coronary heart disease (CHD), including reduced plasma levels of
high density lipoprotein cholesterol particles and elevated plasma levels of TG [38]. T2DM increases the risk of CHD more markedly in women than men [39]. However, the reported magnitudes of the diabetesrelated CHD risk in men and women vary widely between different studies [40]. The cause of the greater relative risk of CHD in diabetic women still not clear, but several explanations can be offered. First, adverse changes induced by T2DM in HDL cholesterol, triglycerides, low-density lipoprotein particle size and blood pressure have been found to be more pronounced in women than in men [41,42]. In addition, T2DM in women may interfere with protective mechanisms in the vascular wall and thereby lead to enhanced atherogenesis. Our data reveals a prevalence of 49% of LDL levels higher than 100 mg/dl, which is considered to pose a risk of CHD and atherosclerosis and similar to the findings of a USA study [43]. On the other hand, more than half of the patients were found to have low HDL, which is also associated with high risk of CHD and atherosclerosis. When such lipid profiles co-exist with long duration of diabetes among DM patients, a high incidence of CHD and atherosclerosis may be inevitable in the future. Our result demonstrates clustering of two or more lipid abnormality in around 55.7% subjects and of three or more lipid abnormality in 33%. Around 9% had all four lipid abnormalities. Our data identifies poor glycemic control as predictor of dyslipidemia. Similar evidence has been reported by studies [44,45]. Prolonged T2DM in our data is linked with raised TC, and LDL and lower HDL and does not seem to affect triglyceride. DM with co-morbid hypertension predicts hyper tri-glyceridemia and lower HDL. This suggests that the duration of diabetes may relate to the severity of lipid disorder in diabetes mellitus. Many studies indicating that there is alteration in vascular functional integrity in
M.N. Karim et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 7 (2013) 95–100
diabetes mellitus, and that the alteration is dependent on the duration of the condition [46,47]. A national cross-sectional chart audit study of 2473 Canadian patients with type 2 diabetes showed 55% of patients with a diagnosis of diabetes of 2 years had dyslipidemia. This proportion rose to 66% in patients with diabetes for 15 years [48]. However, Otamere et al. ruled out association of age and duration of illness with lipid profile prediction [49]. DM with co-morbid hypertension seems to predict hyper tri-glyceridemia and lower HDL. Insufficient physical activity, overweight, co-morbid renal impairment and treatment with insulin did not appear as significant predictor of dyslipidemia in T2DM. As Low HDL was found to be the most prevalent lipid abnormality, we attempted to explore for its interaction with other lipid parameters. We explored association of TC-HDL ratio and LDL-HDL ratio as predictor of dyslipidemia. Both the ratio appeared as significant predictor of all the parameters of dyslipidemia in DM patients suggesting a potential of the indicator for diabetic dyslipidemia. These two factors warrants further in detail investigation in larger samples. One limitation in our study is our estimated proportion of dyslipidemia in T2DM may not be representative of Bangladesh and rather represents of those who attended BIRDEM and are likely to have more severe disease and a higher frequency of complication; therefore estimates reported in our study are likely to be over estimate Bangladesh population. Alternatively potential survival bias may underestimate the true prevalence. A cohort study of duration longer than maximum lead time of dyslipidemia would be needed. In summary the characteristic features of diabetic dyslipidemia are a low HDL cholesterol concentration, high triglyceride and LDLcholesterol level. Low HDL level is the most frequent type of abnormality. Poor glycemic control, prolonged duration, coexisting hypertension predicts dyslipidemia in T2DM. Both TC–HDL ratio and LDL–HDL ratio predicted dyslipidemia in T2DM. DM patients must be screened and appropriate management should be instituted to reduce the risk of CHD and atherosclerosis. Health care professionals can play a valuable role for reducing the risk factors of dyslipidemia by promoting healthy lifestyle of diabetic patients. Conflict of interest None. References [1] Mooradian AD. Cardiovascular disease in type 2 diabetes mellitus: current management guidelines. Archives of Internal Medicine 2003;163:33–40. [2] Koskinen SV, Reunanen AR, Martelin TP, Valkonen T. Mortality in a large population-based cohort of patients with drug-treated diabetes mellitus. American Journal of Public Health 1998;88(May (5)):765–70. [3] Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, et al. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation 1997;95:69–75. [4] Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241(19):2035–8. [5] Thompson DM. Cardiovascular disease and diabetes. BC Endocrine Research Foundation Newsletter 1999;1:3. [6] Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care 2003;26(7):2181–8. [7] Stamler J. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434–44. [8] Sprafka JM. Trends in prevalence of diabetes mellitus in patients with myocardial infarction and effect of diabetes on survival. The Minnesota Heart Survey. Diabetes Care 1991;14:537–43. [9] Haffner SM. Dyslipidemia management in adults with diabetes. Diabetes Care 2004;27(January (Suppl. 1)):S68–71. [10] Brown WV. Risk factors for vascular disease in patients with diabetes. Diabetes Obesity & Metabolism 2000;2(November (Suppl. 2)):S11–8.
99
[11] Halushka PV, Rogers RC, Loadholt CB, Colwell JA. Increased platelet thromboxane synthesis in diabetes mellitus. Journal of Laboratory and Clinical Medicine 1981;97(January (1)):87–96. [12] American Diabetes Association. Management of dyslipidemia in adults with diabetes (position statement). Diabetes Care 2003;26(Suppl. 1):S83–6. [13] Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease risk. Circulation 1990;82:495–506. [14] World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complication. Report of a WHO Consultation. Part 1. Diagnosis and Classification of Diabetes Mellitus. Geneva: World Health Organization, Department of Noncommunicable Disease Surveillance; 1999. [15] World Health Organization. Obesity and overweight. World Health Report; 2002. [16] Dowse GK, Humphrey ARG, Collins VR, Plehwe W, Gareeboo H, Fareed D, et al. Prevalence and risk factors for diabetic retinopathy in the multiethnic population of Mauritius. American Journal of Epidemiology 1998;147:448–57. [17] American Diabetes Association. Clinical practice recommendation. American Diabetes Association (ADA); 2009. [18] American Diabetes Association (ADA). Standards of medical care in diabetes. Diabetes Care 2007;30:4–41. [19] Barrett-Connor E, Grundy SM, Holdbrook MJ. Plasma lipids and diabetes mellitus in an adult community. American Journal of Epidemiology 1982;115: 657–63. [20] Seyoum B, Abdulkadir J, Berhanu P, Feleke Y, Mengistu Z, Worku Y, et al. Analysis of serum lipids and lipoproteins in Ethiopian diabetic patients. Ethiopian Medical Journal 2003;41(1):1–8. [21] Lawrence JM, Bennett P, Young A, Robinson AM. Primary care screening for diabetes in general practice: cross sectional population study. BMJ 2001;323: 548–51. [22] Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. American Heart Journal 1985;110:1100–7. [23] [No authors listed] UKPDS U.K. Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care 1997;20:1683–7. [24] Joshua A, Becham B, Libby P. Diabetes and atherosclerosis. JAMA 2002;287: 2570–81. [25] Haffner SM, Lehto S, Ro¨nnemaa T, Pyo¨ra¨la¨ K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior history of myocardial infarction. The New England Journal of Medicine 1998;339:229–34. [26] Dullaart RP. Type 2 diabetes mellitus is associated with differential effects on plasma cholesteryl ester transfer protein and phospholipid transfer protein activities and concentrations. Scandinavian Journal of Clinical and Laboratory Investigation 2004;64:205–15. [27] Borggreve SE. Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins. European Journal of Clinical Investigation 2003;33: 1051–69. [28] Bluher M, Kratzsch J, Paschke R. Plasmalevels of tumor necrosis factor, angiotensin II, growth hormone, and IGF-I are not elevated in insulin-resistant obese individuals with impaired glucose tolerance. Diabetes Care 2001;24: 328–34. [29] Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. The Journal of Clinical Investigation 1999;103: 253–9. [30] Reaven GM, Chen YD. Role of abnormal free fatty acid metabolism in the development of non-insulin-dependent diabetes mellitus. The American Journal of Medicine 1988;85:106–12. [31] Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a populationbased study of 13,000 men and women with 20 years of follow-up. Archives of Internal Medicine 2004;164:1422–6. [32] Hachem SB, Mooradian AD. Familial dyslipidaemias: an overview of genetics, pathophysiology and management. Drugs 2006;66:1949–69. [33] American Diabetes Association (ADA). Management of dyslipidemia in adults with diabetes. Diabetes Care 2002 Jan;25(suppl 1):S74–7. [34] Garvey WT, Kwon S, Zheng D, Shaughnessy S, Wallace P, Hutto A, et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes 2003;52:453–62. [35] Mooradian AD. Dsylipidemia in type 2 diabetes mellitus. Nature Clinical Practice Endocrinology and Metabolism 2008;5:3150–9. [36] Barrett-Connor E, Giardian EG, Gitt AK, Gudat U, Steinberg HO, Tscheope D. Women and heart disease: the role of diabetes and hyperglycemia. Archives of Internal Medicine 2004;164(9):9344–942. [37] Vergeer M. Evaluation of phospholipid transfer protein as a therapeutic target. Future Lipidology 2008;3:327–35. [38] Craig WY, Neveux LM, Palomaki GE, Cleveland MM, Hadow JE. Lipoprotein (a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies. Clinical Chemistry 1998;44(11):2301–6. [39] Juutilainen A, Kortelainen S, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Gender difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes Care 2004;27(December (12)):2898–904.
100
M.N. Karim et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 7 (2013) 95–100
[40] Kanaya AM, Grady D, Barrett-Connor E. Explaining the sex difference in coronary heart disease mortality among patients with type 2 diabetes mellitus: a meta analysis. Archives of Internal Medicine 2002;162(August (15)):1737–45. [41] Howard BV, Cowan LD, Go O, Welty TK, Robbins DC, Lee ET. Adverse effects of diabetes on multiple cardiovascular disease risk factors in women. The Strong Heart Study. Diabetes Care 1998;21(August (8)):1258–65. [42] Siegel RD, Cupples A, Schaefer EJ, Wilson PW. Lipoproteins, apolipoproteins, and low-density lipoprotein size among diabetics in the Framingham offspring study. Metabolism Clinical and Experimental 1996;45(October (10)):1267–72. [43] Saaddine JB, Engelgau MM, Beckles GL, Gregg EW, Thompson TJ, Narayan KM. A diabetes report card for the United States: quality of care in the 1990s. Annals of Internal Medicine 2002;136:565–74. [44] Abdel-Aal NM, Ahmet AT, Froelicher ES, Batieha AMS, Hamza MM, Ajloni KM. Prevalance of dyslipidemia in patients with type 2 diabetes mellitus in Jordan. Saudi Medical Journal 2008;29(10):1423–8.
[45] Gonen B, White N, Schonfeld G. Plasma levels of appoprotein B in patients with diabetes mellitus; the effect of glycimec control. Metabolism 1985;34:675–9. [46] Schwart CJ, Valente AJ, Spargue EA, Kelly JL, Cayatte AJ, Rozels M. Pathogenesis of the atherosclerotic lesion: implication for diabetes mellitus. Diabetes Care 1992;15:1156–67. [47] Talat N, Amir K, Gulsena M, Bilal B. Dyslipidemias in type 2 diabetes mellitus patients in a teaching hospital of Lahore, Pakistan. Pakistan Journal of Medical Sciences 2003;19:283–6. [48] Harris SB, Ekoe´ JM, Zdanowicz Y, Webster-Bogaert S. Glycemic control and morbidity in the Canadian primary care setting (results of the diabetes in Canada evaluation study). Diabetes Research and Clinical Practice 2005;70: 90–7. [49] Otamere HO, Aloamaka CP, Okokhere PO, Adisa WA. Lipid profile in diabetes mellitus; What impact has age and duration. British Journal of Pharmacology and Toxicology 2011;2(3):135–7.