Diabetologia (1998) 41: 1397±1399
Ó Springer-Verlag 1998

Letters to the editor
Lipoprotein(a) as a coronary risk factor
in Japanese patients with Type II(non-insulin-dependent) diabetes mellitus.
Relation with apolipoprotein(a) phenotypes
Dear Sir,Lipoprotein(a), Lp(a), is a LDL-like lipoprotein particle thatcontains apo(a), a member of the plasminogen superfamily,
covalently linked to apo B100 [1]. Numerous clinical studies
have shown that Lp(a) is an independent risk factor for coronary heart disease [1, 2], with some dissent. Type II (non-insulin-dependent) diabetes mellitus is another major risk factor
for coronary heart disease [3] and is associated with various
coronary risk factors such as dyslipoproteinaemia, hypertension and obesity. Therefore, it is important to define the roleof Lp(a) in association with coronary heart disease and Type IIdiabetes. Conflicting results have been reported; several reports have shown that Lp(a) is an independent risk factor[4±9], but others failed to show an association.
Plasma Lp(a) concentrations have large inter-individualvariations and at least half of these are attributable to apolipoprotein(a), (apo(a)), size polymorphism [10]. Since apo(a) isoforms are genetically determined, demonstration of their association strongly supports the causal relation, which is difficult
to prove when only plasma Lp(a) concentrations are related
to coronary heart disease in case control studies. In thisregard, only Ruiz et al. [7] assessed the relation between plasma Lp(a) concentrations, apo(a) phenotypes and coronary
heart disease in Type II diabetes of Caucasian patients. Theyfound that raised Lp(a) concentrations were associated withcoronary heart disease and this association was partially accounted for by the increased presence of apo(a) isoforms ofsmall size.
We investigated the relation between plasma Lp(a) concentrations, apo(a) phenotypes and coronary heart disease in Japanese Type II diabetic patients. We also tested the hypothesisthat plasma Lp(a) concentrations are influenced by glycaemic
control or diabetic nephropathy or both, which had been
described, albeit controversy, in other studies.
For the study we recruited randomly 270 men with Type IIdiabetes, aged 59.7 ± 7.8 years. We compared 46 patients withcoronary heart disease (CHD+) who had had either a previous

Corresponding author: S. Ishibashi, M. D., Ph. D., Departmentof Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

myocardial infarction, or coronary artery bypass graft surgery,or ischaemic changes in the electrocardiogram with or without
exercise, or a combination of these, with 171 patients withoutcoronary heart disease (CHD). We treated 28, 101 and 88 patients respectively with insulin, sulphonylurea, and diet alone.
Hypolipidaemic drugs such as statins and fibric acid derivatives were given to 181 patients and 85 patients were treatedwith antihypertensive medication such as calcium channel
blockers and angiotensin converting enzyme inhibitors. Plasma Lp(a) concentrations were determined by enzyme-linked
immunosorbent assay. Phenotypes of Lp(a) were determinedby immunoblotting of SDS-polyacrylamide gel electrophoresisand classified according to Kraft et al. [11]. Serum triglycerides, Lp(a) concentrations, and urinary albumin excretion
rates were logarithmically transformed before inclusion because the distribution of these values was highly skewed. Student's t -test was used for continuous variables. Contingency
table chi-square test was used for qualitative traits. KruskalWallis test was used to test the association between apo(a)phenotypes and Lp(a) concentrations. Logistic regression
model was used to determine the independence of the variables which showed relevant association by univariate analyses. Pearson's correlation coefficient was calculated. JMP Version 3 (SAS Institute Inc., N. C., USA) were used for calculations.
Age, duration of diabetes, body mass index, glycated haemoglobin (HbA1c), systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, HDL-cholesterol, Lp(a),urinary albumin excretion rates, smoking habit (non-smoker,smoker, ex-smoker), treatment of diabetes (diet alone, oral hypoglycaemic agents, insulin), hypertension (anti-hypertensive
treatment or BP > 160/95 mm Hg), hypolipidaemic medication,and macro- or microalbuminuria were compared among CHD+
patients and CHD patients. Differences were observed for age(59 ± 8 vs 66 ± 7 years; p < 0.01), diabetes duration (15 ± 8 vs22 ± 9 years; p < 0.01), Lp(a) (0.17 ± 0.18 vs 0.25 ± 0.23 g/l; p <0.01), diastolic blood pressure (74 ± 9 vs 70 ± 9 mm Hg; p <0.05), hypertension (odds ratio = 4.37; p < 0.001), hypolipidaemic medication (odds ratio = 4.15; p < 0.01), macro- or microalbuminuria (odds ratio = 4.23; p < 0.01). CHD+ patients showed
noticeably lower DBP than CHD patients, probably because
anti-hypertensive medication had been introduced for secondary cardiovascular prevention. Patients with high Lp(a) concentrations (> 0.30 g/l) showed higher prevalence of coronary heartdisease than those with low Lp(a) concentrations (< 0.30 g/l)
(odds ratio = 3.43; p < 0.001). Logistic regression analysis wasdone introducing the coronary risk factors that were identified
in univariate analyses (p < 0.01). High Lp(a) (p < 0.01), old age(p < 0.05) and hypolipidaemic medication (p < 0.01) seemed tobe independent coronary risk factors in our study group.

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Letters to the editor

Table 1. Frequencies of apo(a) phenotypes and plasma Lp(a)concentrations in Type II diabetic patients with coronary heartdisease, CHD+, or without, CHD
CHD±

CHD+

pn

Lp(a)
n
concentrations

Lp(a)concentrations

BS1
F
FS3
FS4
S1
S1S2
S1S3
S1S4
S2
S2S3
S2S4
S3
S3S4S4O112
1424974456
26
47
30.58
0.230.54 ± 00.51
0.13 ± 0.10
0.40 ± 0.02
0.93 ± 0.06
0.31 ± 0.20
0.28 ± 0.29
0.19 ± 0.17
0.36 ± 0.06
0.11 ± 0.08
0.17 ± 0.08
0.07 ± 0.05
0.02 ± 0.01

00022211027164
90±±±0.42 ± 0.04
0.15 ± 0.13
1.00 ± 0.16
0.290.66±0.31 ± 0.30
0.35 ± 0.07
0.16 ± 0.14
0.21 ± 0.11
0.12 ± 0.12±±±±±NS
p < 0.05±±±NSNSNSNSNS±Total

1710.17 ± 0.18460.25 ± 0.23

p < 0.01

Mean ± SD (g/l). The mean values of Lp(a) were compared by
student's t -test after log10 transformation. NS; non-significant.

Table 1 shows the frequency distribution of apo(a) isoforms
and Lp(a) concentrations in each apo(a) phenotype subgroup.
In both CHD+ patients and CHD patients, large isoforms (designated S3, S3/S4 and S4) predominated. The overall distribution of apo(a) isoforms was displaced towards low molecularmass isoforms in CHD+ patients (p = 0.033). The frequency ofsmall apo(a) alleles (subjects having either F, B, S1 or S2) was
higher in CHD+ patients than in CHD patients (odds ratio = 1.98; p = 0.052). In both groups the differences in Lp(a)concentrations among apo(a) phenotypes were highly significant (Kruskal-Wallis test: c 2 = 77.4; p < 0.0001 for CHD patients and c 2 = 22.6; p < 0.01 for CHD+ patients). There is aninverse association of apo(a) size with Lp(a) concentrations.
In each phenotype subgroup, CHD+ patients tended to havehigher Lp(a) concentrations than CHD patients, but the difference was not statistically significant.
Neither HbA1c (r = 0.02; p = 0.82) nor urinary albumin excretion rates (r = 0.02; p = 0.84) were correlated significantlywith plasma Lp(a) concentrations.
In conclusion, we have confirmed that increased plasma
Lp(a) concentrations are a strong independent coronary risk
factor in our Japanese study group of Type II diabetic patients.
Furthermore, the association between the high Lp(a) concentrations and coronary heart disease is partly accounted for bythe increased presence of small apo(a) isoforms. To prevent future coronary heart disease in Type II diabetic patients efforts
should be directed at screening diabetic patients for highLp(a) concentrations and a vigorous management of coronary
establishing risk factors in these patients.
Yours sincerely,
K. Murakami, S. Ishibashi, Y. Yoshida, N. Yamada, Y. Akanuma

References
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Diabetologia (1998) 41: 1397±1398