Journal of Diabetes and Its Complications 15 (2001) 270 – 276
Serum lipoprotein(a) concentration as a cardiovascular risk factor in Kuwaiti Type 2 diabetic patients Nabila A. Abdellaa,*, Olusegun A. Mojiminiyib, Abayomi O. Akanjib, Hisham Al Mohammadia, Mohamed A. A. Moussac a
Department of Medicine, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait b Department of Pathology, Faculty of Medicine, Kuwait University, Safat, Kuwait c Department of Community Medicine, Faculty of Medicine, Kuwait University, Safat, Kuwait Received 19 October 2000; accepted 15 May 2001
Abstract Serum lipoprotein(a) [Lp(a)], a risk factor for coronary heart disease (CHD) in some nondiabetic populations, is largely under genetic control and varies among ethnic and racial groups. We evaluated serum Lp(a) concentration and its relationship with traditional CHD risk factors (age, sex, smoking, hypertension, dyslipidemia) as well as stage of diabetic nephropathy in 345 type 2 diabetic patients. Lp(a) concentration was skewed with median (2.5th, 97.5th percentiles) of 25.0 (8.1, 75.7) mg/dl. Twenty-three of 55 (41.8%) patients with CHD had increased ( > 30 mg/dl) Lp(a) compared with 102 of 290 (35.1%) patients without CHD ( P = .35). Twelve of 27 (44.4%) female patients with CHD had increased Lp(a) compared to 11 of 28 (39.3%) males ( P = .70). Lp(a) was significantly ( P < .05) higher in females than males, but the logistic regression analysis showed significant association of Lp(a), LDL-C, and duration of diabetes mellitus (DM) with CHD in male patients only. Although female patients with CHD and macroalbuminuria had significantly ( P < .05) higher Lp(a) than normoalbuminuric female patients without CHD, no such association was found in males and no significant association was found between Lp(a) and the degree of albuminuria. Partial correlation analysis controlling for age, sex, and BMI showed significant correlation of Lp(a) with total cholesterol only ( P = .03) and no correlation was found with other lipid parameters. Multiple regression analysis did not show significant associations of Lp(a) with standard CHD risk factors, HbA1c, and plasma creatinine. This study is in agreement with studies in other populations, which showed that Lp(a) may not be an independent risk factor for CHD in patients with DM. However, as Lp(a) could promote atherogenesis via several mechanisms, follow-up studies in our patients will confirm if increased Lp(a) concentration can partly account for the poorer prognosis when diabetic patients develop CHD. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Lipoprotein(a); Diabetes mellitus; Coronary heart disease; Diabetic complications; Kuwaiti Arabs
1. Introduction Lipoprotein(a) [Lp(a)] has atherogenic and thrombotic properties, and increased serum Lp(a) concentrations have been described in several studies as correlating with coronary heart disease (CHD) in nondiabetic populations (Cremer et al., 1994; Rosengren, Wilhemsen, Eriksson, Risberg, & Wedel, 1990; Schaefer et al., 1994; Valentine, Grayburn, Vega, & Grunely, 1994). The risk of cardiovas-
* Corresponding author. Tel.: +965-531-9596; fax: +965-533-8907. E-mail address:
[email protected] (N.A. Abdella).
cular disease is increased in both types 1 and 2 diabetes mellitus (DM), and Lp(a) has attracted attention as a potential risk factor. In some studies in patients with type 1 diabetes, Lp(a) concentration has been shown to be elevated, related to metabolic control and degree of microalbuminuria (Boemi, Sirolla, Fumelli, & James, 1999; Bruckert et al., 1990; Gazzaruso et al., 1998; Haffner, 1993). However, other studies in diabetic subjects failed to confirm these observations and failed to link Lp(a) to CHD risks (Durlach et al., 1996; Haffner, 1993; Pedreno et al., 2000; Westerhuis & Venekamp, 1996). These studies cast significant doubt on the hypothesis that Lp(a) is causally linked to CHD in diabetic subjects.
1056-8727/01/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 1 0 5 6 - 8 7 2 7 ( 0 1 ) 0 0 1 6 2 - 3
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Progressive vascular disease of the large and small vessels is characteristic of the diabetic state. Although the pathogenesis is complex and multifactorial, the accelerated atherosclerosis, which occurs in patients with DM, results from a complex interaction of factors such as hyperglycemia (Ceriello, Russo, Amstad, & Cerutti, 1996; Lorenzi, Cagliero, & Toledo, 1985), oxidative stress (Baynes, 1991; Giugliano, Ceriello, & Paolisso, 1996), advanced glycation end products (Armstrong et al., 1992; Wautier et al., 1996), and hyperlipidemia (Mulec, Johnsen, Wiklund, & Bjorek, 1996; Taranov et al., 1996). Other risk factors, such as hypertension and cigarette smoking, magnify the extent and rate of progression of the vascular lesions. Although serum Lp(a) concentration is largely under genetic control, Lp(a) synthesis and catabolism could be influenced by insulin or by diabetes and its metabolic complications as shown by studies in patients with type 1 DM (Boemi et al., 1999; Bruckert et al., 1990; Gazzaruso et al., 1998; Haffner, 1993). Furthermore, the atherogenic and thrombogenic potential of Lp(a) could be increased in diabetic patients. The Kuwaiti population is at high risk of CHD, estimated now to be the most common underlying cause of adult death. Mortality from the disease increased by about 50% in the decade from 1972 to 1981 (Kurtz, 1984; Radovanovic, 1994) and correlates with high prevalence rates of type 2 DM among the adult population reaching a figure of 14.8% (Abdella, Al Arouj, Al Nakhi, Al Assoussi, & Moussa, 1998). The aim of this study was to evaluate serum Lp(a) concentration in Kuwaiti type 2 diabetic patients and correlate the values with various cardiovascular risk factors and diabetes-related complications.
2. Materials and methods 2.1. Subjects The study included 345 (men and women) consecutive Kuwaiti type 2 diabetic subjects referred from primary care clinics to the specialised diabetic unit in Mubarak Al Kabeer University Teaching Hospital for evaluation. All participating subjects attended in the morning after 12 –14 h of overnight fast. The subjects were interviewed by an Arabic-speaking trained nurse and all patients gave informed voluntary consent to participate in the study according to the protocol approved by the local ethics committee and in accordance with the ethical standards laid down in the Helsinki declaration. The nurse also completed a questionnaire, which included age, smoking, duration of diabetes, and history of hypertension and/or anti-hypertensive medication. Symptoms of cardiovascular disease, previous myocardial infarction, and angina were determined by the Rose questionnaire (Rose, Blackburn, Gillum, & Prineas, 1982). Blood pressure was measured after the patient was rested for at least 5 min. Hypertension was defined as systolic
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blood pressure (SBP) 160 mm Hg, diastolic blood pressure (DBP) 95 mm Hg, according to the WHO criteria (World Health Organization Expert Committee, 1978), and/ or current history of anti-hypertensive medication. Retinopathy was assessed by fundoscopy through dilated pupils and findings were confirmed by fundus photography using a nonmydriatic fundus camera (Canon CR-4). Retinopathy was classified as nonproliferative, proliferative, and/ or advanced eye disease. Peripheral sensory neuropathy was assessed on clinical grounds by formal sensorimotor examination of the lower extremities. Electrocardiographic abnormalities compatible with CHD were coded in accordance with the Minnesota electrocardiogram (ECG) codes 1 – 3, 5 –2, 5 – 3 (possible ischemia), or 1 – 1, 1 – 2, 7 – 1 (probable ischemia or both) (Blackburn, Keys, Simonson, Rautaharju, & Punsar, 1960). Patients were classified by urinary albumin:creatinine excretion ratio. Based on the median excretion ratio of three consecutive early morning urine collections, patients were classified as normoalbuminuric (urinary albumin:creatinine ratio < 30 mg/g), microalbuminuric (urinary albumin:creatinine ratio 30 –300 mg/g), or macroalbuminuric (urinary albumin:creatinine ratio >300 mg/g). 2.2. Anthropometric and waist/hip ratio measurements Standing height and weight were measured with the subjects in light clothing and without shoes. Height was recorded to the nearest centimeters and weight to the nearest 0.1 kg. The weighing scales (Detecto-Medic, New York, USA) were standardized daily using standard weights of 20 and 70 kg. Body mass index (BMI), defined as weight in kilograms per height (in meters) squared was calculated, and used as an index for obesity. Waist:hip ratio was calculated from measurements of the waist circumference, taken at the mid point between umbilicus and xiphoid, and hip circumference, at the widest point around the hips. 2.3. Biochemical analyses Venous blood samples, collected without the use of a tourniquet from each of the patients, were analysed for serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-c), apolipoprotein A1 (apo-A1), apolipoprotein B (Apo-B), fasting plasma glucose (FPG), uric acid, creatinine, and albumin on an automated analyser (Hitachi 911 analyser; Roche, Basle, Switzerland) with dedicated reagents supplied by Roche. The respective intra- and interassay coefficients of variation (CVs) for each of the assays were: FPG 1.5% and 2.0%, TC 1.1% and 2.1%, TG 1.6% and 3.7%, LDL-C 0.9% and 2.0%, HDL-C 2.9% and 3.6%, uric acid 0.8% and 1.1%, creatinine 5.0% and 6.0%, albumin 1.0% and 1.0%, apo-A1 2.5% and 3.5%, and ApoB 2.8% and 3.2%.
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Table 1 Changes in variables with quartiles of Lp(a) in 345 Kuwaiti adults
2.3% at 400 mg/l. The corresponding between-assay CVs are 7.7% and 2.7%.
Lp(a) (mg/dl) First quartile Quartile Males Females Total
Second quartile
Third quartile
Fourth quartile
2.5. Statistical methods Total
range 0.00 – 13.00 13.00 – 20.59 20.59 – 32.75 32.75 – 98.46 0.00 – 15.31 15.31 – 25.45 25.45 – 39.61 39.61 – 91.76 0.00 – 14.63 14.63 – 22.63 22.63 – 35.24 35.24 – 98.46
Age (years) Males 52.14 Females 50.57 Total 51.24
55.75 51.10 53.05
54.76 50.24 52.16
54.44 48.96 51.28
54.26 50.22 51.94
BMI (kg/m2) Males 28.78 Females 32.01 Total 30.64
28.99 33.30 31.49
27.76 32.75 30.63
28.02 34.64 31.84
28.38 33.18 31.15
0.99 1.00 0.99
0.99 0.99 0.99
0.98 0.99 0.99
0.99 0.99 0.99
WHR Males Females Total DBP (mm Males Females Total
0.99 0.99 0.99 Hg) 81.11 84.76 83.19
SBP (mm Hg) Males 130.19 Females 136.63 Total 133.86
Data were analysed using the Statistical Package for Social Sciences (SPSS) (SPSS-X, 1998) and P < .05 value was taken as the cut-off level for significance. Skewed variables were log-transformed to make them normally distributed, and the Student’s t test was used to compare between means of two groups. One-way analysis of variance (ANOVA) test was used for comparison between more than two groups. The chi-square test was used to assess the association between two categorical variables. Logistic regression analysis was used to determine the association of CHD with different risk factors after fixing the confounding between these variables. Multiple linear regression analysis was used to ascertain the association between
Table 2 Biochemical variables according to CHD status in 345 Kuwaiti adults 79.89 81.04 80.56
81.70 81.24 81.44
80.03 84.49 82.60
80.69 82.86 81.94
131.11 128.90 129.83
128.05 130.92 129.70
129.14 133.08 131.41
129.62 132.36 131.19
Duration of DM (years) Males 9.59 10.86 Females 10.41 10.52 Total 10.06 10.66
10.08 9.14 9.54
9.83 10.06 9.96
10.09 10.03 10.06
Blood glycated hemoglobin (HbA1c) was measured on a DCA 2000 analyser with dedicated reagent cartridges supplied by Bayer Corporation (Elkhart, IN, USA). Fresh morning samples for measurement of urinary albumin and creatinine were obtained on three occasions from each subject and measured in a DCA 2000 analyzer with dedicated reagent cartridges supplied by Bayer. The respective intra- and interassay CVs for urine albumin were 3.0% and 4.0% and for urinary creatinine 2.2% and 3.5%. 2.4. Lp(a) Lp(a) was quantitatively estimated in plasma by an enzymatic immunoassay (ELISA) Tint Elize Lp(a) provided by Biopool (Biopool, Umea˚, Sweder). This is an Lp(a) mass measurement assay with an anti-Lp(a) polyclonal antibody that traps Lp(a) and a peroxidase-conjugated antilipoprotein a polyclonal antibody in a ‘‘sandwich’’ assay. The withinassay CV is 6.6% at Lp(a) concentration of 100 mg/l and
CHD No
Yes
Male (n) Female (n)
119 171
28 27
P value
Lp(a) Males Females Total
23.97 ± 15.83 28.45 ± 17.81 26.61 ± 17.14
28.27 ± 21.25 29.71 ± 19.96 28.98 ± 20.45
.149 .629 .226
9.36 ± 1.87 9.49 ± 1.88 9.44 ± 1.87
9.81 ± 1.85 9.50 ± 1.74 9.66 ± 1.79
.241 .972 .384
Total cholesterol (mmol/l) Males 5.72 ± 1.45 Females 5.86 ± 1.14 Total 5.80 ± 1.28
5.63 ± 1.27 5.94 ± 1.18 5.78 ± 1.23
.833 .751 .934
HDL-C (mmol/l) Males Females Total
0.90 ± 0.24 1.05 ± 0.28 0.99 ± 0.27
0.90 ± 0.20 1.00 ± 0.29 0.95 ± 0.25
.979 .451 .364
LDL-C (mmol/l) Males Females Total
4.44 ± 1.59 4.31 ± 1.24 4.36 ± 1.39
4.45 ± 1.16 4.43 ± 1.38 4.44 ± 1.26
.732 .673 .564
TG (mmol/l) Males Females Total
2.57 ± 1.69 2.15 ± 1.30 2.33 ± 1.49
2.90 ± 1.79 3.00 ± 2.43 2.95 ± 2.10
.249 .025 .012
Serum creatinine (mmol/l) Males 93.6 ± 20.3 Females 72.8 ± 14.7 Total 81.5 ± 20.1
115.3 ± 82.2 78.8 ± 20.8 97.7 ± 63.1
.086 .082 .013
HbA1c (%) Males Females Total
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Lp(a) and a number of associated factors (retinopathy, neuropathy, FPG, HbAlc, TC, TG, creatinine, urinary albumin:creatinine ratio) after correcting for age and sex.
3. Results 3.1. Results in relation to Lp(a) Lp(a) concentration in the patients was skewed, with a skewness of 2.62 and a kurtosis of 12.79. Therefore, the
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data were log-transformed to normalise the distribution. Table 1 shows the demographic and clinical characteristics of the Kuwaiti diabetic patients classified by gender and quartiles of Lp(a) concentration. Table 2 depicts the biochemical variables of the patients according to gender and presence or absence of CHD. Twenty-three of 55 (41.8%) patients with CHD had increased (>30 mg/dl) Lp(a) compared with 102 of 290 (35.1%) patients without CHD ( P = .35). Twelve of 27 (44.4%) female patients with CHD had increased Lp(a) compared to 11 of 28 (39.3%) males ( P = .70). Partial
Table 3 Biochemical profile of 345 Kuwaiti diabetic patients, according to urinary albumin:creatinine ratio Urinary albumin:creatinine ratio Variable a
Male (n) Female (n) HbA1c(%) Male Female FPG (mmol/l) Male Female
< 30 mg/g 75 85
30 to < 300 mg/g 50 88
300 mg/g 20 23
P value
9.1 (6.0, 13.5) 9.0 (6.2, 12.7)
9.8 (5.6, 14.0) 9.8 (6.3, 13.8)
10.1 (6.9, 13.0) 9.8 (6.1, 13.1)
< .01 < .01
11.0 (5.8, 18.2) 11.0 (5.6, 21.6)
13.6 (5.7, 24.4) 12.7 (5.7, 21.1)
13.7 (6.7, 18.5) 12.7 (5.5, 24.1)
< .01 N.S.
Apo-A1 (g/l) Male Female
1.30 (0.92, 1.79) 1.48 (1.08, 1.94)
1.37 (0.94, 1.87) 1.56 (1.18, 2.00)
1.44 (1.01, 1.66) 1.57 (1.07, 2.06)
N.S. N.S.
Apo-B (g/l) Male Female
1.23 (0.83, 1.75) 1.26 (0.81, 1.77)
1.23 (0.70, 1.97) 1.32 (0.89, 2.03)
1.44 (0.96, 2.57) 1.34 (1.02, 1.92)
< .01 N.S.
Total cholesterol (mmol/l) Male Female
5.49 (3.50, 7.80) 5.60 (3.71, 8.53)
5.50 (3.72, 9.28) 6.03 (3.57, 9.26)
6.70 (3.70, 13.60) 5.65 (4.13, 8.10)
< .05 N.S.
HDL-C (mmol/l) Male Female
0.90 (0.55, 1.51) 1.00 (0.48, 1.65)
0.90 (0.42, 1.52) 1.02 (0.48, 1.69)
0.94 (0.49, 1.24) 1.10 (0.64, 1.71)
N.S. N.S.
LDL-C (mmol/l) Male Female
3.97 (2.30, 7.64) 4.00 (2.43, 8.08)
4.15 (2.40, 7.51) 4.20 (2.61, 8.26)
5.20 (2.80, 11.70) 4.35 (2.90, 7.30)
< .01 N.S.
Triglycerides (mmol/l) Male Female
1.90 (0.80, 7.92) 1.80 (0.74, 5.14)
2.25 (0.74, 7.84) 2.00 (0.98, 8.58)
3.10 (0.72, 12.70) 2.40 (0.90, 5.70)
< .01 < .05
Uric acid (mmol/l) Male Female
288.0 (194.9, 562.4) 254.0 (114.5, 467.9)
289.5 (163.3, 681.7) 317.5 (214.0, 567.0)
328.0 (204.0, 477.0) 317.5 (214.0, 567.0)
< .01 < .01
Creatinine (mmol/l) Male Female
90.0 (67.9, 140.5) 68.0 (54.6, 105.8)
87.0 (69.3, 434.0) 69.0 (54.2, 125.0)
102.0 (75.0, 141.0) 79.5 (52.0, 142.0)
N.S. < .05
Data are median (2.5th, 97.5th percentiles). One-way ANOVA test. All abbreviations as in the text. a Numbers do not add to total frequency because patients with incomplete data are excluded.
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correlation analysis controlling for age, sex, and BMI showed significant correlation of Lp(a) with total cholesterol only ( P = .03) and no correlation was found with other lipid parameters. Kruskal –Wallis ANOVA on the association between Lp(a) and other traditional risk factors showed significant association with HDL-C ( P = .02) in male patients and TG ( P = .01) in all patients. In male patients, logistic regression analysis showed significant association of Lp(a), LDL-C, and duration of DM with CHD. Although female patients with CHD and macroalbuminuria had significantly ( P < .05) higher Lp(a) than normoalbuminuric female patients without CHD, no such association was found in males and no significant association was found between Lp(a) and the degree of albuminuria (Table 3).
4. Discussion In this study, we have assessed the Lp(a) concentration among Kuwaiti type 2 diabetic subjects and its relationship to CHD status and diabetes-related risk factors. The incidence of cardiovascular disease is increased in type 2 diabetic patients compared with nondiabetic subjects partly because of the patients’ increased levels of standard risk factors. Since increased Lp(a) concentrations have been described in some case – control (Rosengren et al., 1990; Valentine et al., 1994) and prospective studies (Cremer et al., 1994; Schaefer et al., 1994) as correlating with CHD, Lp(a) has attracted several studies in diabetic subjects as a potential risk factor for CHD. Our finding of a significant association of Lp(a) with CHD, LDL-C, and duration of diabetes in men is in agreement with these studies. However, as reported by other researchers (Durlach et al., 1996; Haffner, 1993; Pedreno et al., 2000; Westerhuis & Venekamp, 1996), we found no association of Lp(a) concentration with CHD in female Kuwaiti type 2 diabetic subjects and there is no statistically significant difference in Lp(a) concentration between patients with CHD and those without CHD (Table 2). The conflicting array of data on the association between Lp(a) and the risk of CHD has been blamed mostly on factors such as variations in sample size, methods of laboratory determination of Lp(a), type of therapy administered to achieve metabolic control, and since Lp(a) concentration is genetically determined, differences in the population studied. Several assays for Lp(a) have been shown to be affected by the variations in Lp(a) isoforms, which is determined by the number of apolipoprotein(a) kringle four domains (Marcovina, Albers, Gamble, Koschinsky, & Gaur, 1995; TaddeiPeters et al., 1993). For this reason, immunoassays may not provide an accurate measure of Lp(a) concentration if the antibodies in the assay do not bind to epitopes in apo(a) isoforms present in the Kuwaiti population. There-
fore, it is possible that our assay did not detect the particular isoforms that are responsible for relationships with arteriosclerotic disease in patients with type 2 diabetes and the results of this study should be taken in this context. However, it is also possible that the atherogenic isoforms of Lp(a) (especially those of smaller size) are not prevalent in the Kuwaiti population. Recent publications on the Kuwaiti population suggest that the higher molecular weight isoforms, which are associated with lower concentrations of Lp(a), are present in 67% of the population (Akanji, 2000; Akanji, Al-Shayji, & Kumar, 1999). It has been proposed that quantification of Lp(a) in terms of cholesterol correlates better with CHD risk (Seman et al., 1999), but whether this will identify subjects at an increased risk for CHD better than Lp(a) mass determination requires further studies. Earlier studies have suggested that the atherogenicity of Lp(a) may depend on interaction of Lp(a) with environmental or other genetic factors such as LDL-C concentration (Armstrong et al., 1986). Therefore, the lack of significant association between Lp(a) and CHD in this study may also be due to the modestly increased LDL-C in the patients studied. It has been suggested that since overt and incipient renal diseases are common in patients with diabetes, levels of Lp(a) may reflect underlying renal disease (Boemi et al., 1999). In this study, female patients with CHD and macroalbuminuria had significantly ( P < .05) higher Lp(a) than normoalbuminuric female patients without CHD. However, no significant association was found among Lp(a), CHD, and degree of microalbuminuria in men and in all the patients on multiple regression analysis. There is also conflicting evidence on changes of Lp(a) with diabetic control. While some authors have found reduced Lp(a) concentration with improved metabolic control (Boemi et al., 1999; Bruckert et al., 1990; Gazzaruso et al., 1998; Haffner, 1993), others either found no change or showed that well-controlled patients with DM had higher concentration of Lp(a) compared with control subjects (Chang, Lu, Kao, Tai, & Wu, 1995; Haffner, 1993; Joven & Viella, 1991). This study shows that glycemic control and duration of DM have no effect on Lp(a) concentration (Tables 1 and 2). In conclusion, this study has shown a significant association of Lp(a) with CHD in male diabetic subjects. Although some female diabetic subjects with CHD had increased Lp(a) concentration, no association with CHD was found. There is also no association among Lp(a), diabetic control, and microvascular complications. It is clear that if Lp(a) concentrations were linked to the macrovascular complications of diabetes, then this relationship is complex and is influenced by laboratory methodology, genetic control of isoforms, as well as the ethnic and racial mix of the population under study. Lp(a) may not be an independent risk factor for CHD in patients with
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DM, but because it could promote atherogenesis via several mechanisms, it may partly account for the higher incidence of CHD and poorer prognosis in diabetic subjects in some populations.
Acknowledgments This project was funded by a Kuwait University research grant no. MPM036. We thank Dr. Sunila George, Cynthia Pinto, and Mr. J.E. Gomez for technical and statistical help.
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