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(Circulation. 2000;101:1506.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Hyperhomocysteinemia Increases Risk of Death, Especially in Type 2 Diabetes
5-Year Follow-Up of the Hoorn Study
From the Institute for Research in Extramural Medicine (E.K.H., J.M.D., G.N., L.M.B.) and the Department of Epidemiology and Biostatistics (P.J.K.), Vrije Universiteit, Amsterdam; and the Department of Clinical Chemistry (C.J.) and the Department of Internal Medicine (R.J.H., C.D.A.S.), University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Correspondence to Ellen K. Hoogeveen, MD, PhD, Institute for Research in Extramural Medicine, Vrije Universiteit, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail ellenhgv{at}casema.net
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Abstract |
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Background—A high serum total homocysteine (tHcy) concentration is a risk factor for death, but the strength of the relation in patients with type 2 (non–insulin-dependent) diabetes mellitus compared with nondiabetic subjects is not known. A cross-sectional study suggested that the association between tHcy and cardiovascular disease is stronger in diabetic than in nondiabetic subjects. We therefore prospectively investigated the combined effect of hyperhomocysteinemia and type 2 diabetes on mortality.
Methods and Results—Between October 1, 1989, and December 31, 1991, serum was saved from 2484 men and women, 50 to 75 years of age, who were randomly selected from the town of Hoorn, The Netherlands. Fasting serum tHcy concentration was measured in 171 subjects who died (cases; 76 of cardiovascular disease) and in a stratified random sample of 640 survivors (control subjects). Mortality risks were calculated over 5 years of follow-up by means of logistic regression. The prevalence of hyperhomocysteinemia (tHcy >14 µmol/L) was 25.8%. After adjustment for major cardiovascular risk factors, serum albumin, and HbA1c, the odds ratio (95% CI) for 5-year mortality was 1.56 (1.07 to 2.30) for hyperhomocysteinemia and 1.26 (1.02 to 1.55) per 5-µmol/L increment of tHcy. The odds ratio for 5-year mortality for hyperhomocysteinemia was 1.34 (0.87 to 2.06) in nondiabetic subjects and 2.51 (1.07 to 5.91) in diabetic subjects (P=0.08 for interaction).
Conclusions—Hyperhomocysteinemia is related to 5-year mortality independent of other major risk factors and appears to be a stronger (1.9-fold) risk factor for mortality in type 2 diabetic patients than in nondiabetic subjects.
Key Words: mortality • cardiovascular diseases • diabetes mellitus • epidemiology
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Introduction |
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Cardiovascular disease is the major cause of death in diabetic and nondiabetic subjects. The overall and cardiovascular mortality rates are 2 to 4 times higher in type 2 diabetic patients than in nondiabetic subjects.1 2 3 4 5 Type 2 diabetes is known to be associated with several other cardiovascular risk factors, including dyslipidemia and hypertension, but these do not fully explain the excess mortality rates in type 2 diabetes. Therefore, increased risk must be due, at least in part, to diabetes itself, poor metabolic control, or other factors.
Hyperhomocysteinemia is a recently recognized risk factor for
cardiovascular disease that is independent of major
risk factors such as diabetes, hypertension,
hypercholesterolemia, and
smoking.6 7 8 9 The prevalence estimates of
hyperhomocysteinemia (>14 µmol/L) vary between 5% and 30% in
the general population.10 11 12 13 Although the mechanisms by
which homocysteine promotes atherothrombosis are unknown, the
epidemiological evidence for the association of hyperhomocysteinemia
with atherothrombotic disease is strong.6 7 14 A
meta-analysis15 showed that treatment with 0.5 to
5.0 mg folic acid daily can lower serum total homocysteine (tHcy) by
15% to 40% within 
6 weeks. In addition, it has been estimated that
lowering tHcy by 5 µmol/L (1 SD) may reduce the risk of
cardiovascular death by 10%.7 Taken
together, hyperhomocysteinemia may be an important modifiable risk
factor, although this must be confirmed in randomized studies of
homocysteine-lowering treatment.
In a cross-sectional analysis, hyperhomocysteinemia appeared to be a stronger risk factor for cardiovascular disease in type 2 diabetic subjects than in nondiabetic subjects.13 Such an interaction between hyperhomocysteinemia and type 2 diabetes with regard to cardiovascular risk may be clinically important, as it implies that homocysteine-lowering treatment may be especially effective in type 2 diabetes. In view of these considerations, we investigated the combined effect of hyperhomocysteinemia and diabetes with respect to 5-year risk of death in a population-based study.
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Methods |
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Design and Study Population
The Hoorn Study is a prospective study of glucose tolerance and other cardiovascular risk factors in a 50- to 75-year-old general white population. The baseline examination was conducted from October 1, 1989, until December 31, 1991.16 Briefly, a random sample of all men and women 50 to 75 years of age was drawn from the municipal population registry office of Hoorn, The Netherlands; 2484 subjects were enrolled in this cohort (response rate 71%). All subjects, except previously diagnosed diabetic subjects treated with oral glucose-lowering agents or insulin, underwent a 75-g oral glucose tolerance test (OGTT) and were classified according to the World Health Organization (1985) criteria.17 A second OGTT (participation rate 93%) was performed for reasons of efficiency in a random subsample (n=1122) stratified by 2-hour glucose values of the first test, age, and sex. Finally, from this subsample, an age-stratified, sex-stratified, and glucose tolerance–stratified random subsample (n=715), the "subcohort," was drawn. Glucose tolerance was divided into 3 categories on the basis of the mean of the 2 OGTTs: NGT, (n=334), IGT, (n=197), and type 2 diabetes mellitus (n=184).
A case-control study nested within the cohort was carried out. The survivors of the subcohort (as defined above) served as control subjects. Every subject who died within 5 years of follow-up of the entire cohort was ascertained and selected for the present study. Information on subjects’ vital status on January 1, 1997, was collected from the mortality registry of the municipality of Hoorn. Information on vital status of 137 subjects who moved out of town was obtained from the new local municipalities. We determined whether each subject had died during or survived the first 5 years of follow-up. Causes of death were extracted from medical records of the general practitioners and the hospital of Hoorn, verified by a physician, and classified according to the 9th revision of the International Classification of Diseases (ICD).18 Death from cardiovascular disease was defined by ICD codes 390-459.
During the 5-year follow-up, 172 participants died, 75 of whom were included in the subcohort (n=715). No serum was available for the measurement of tHcy from 1 of the subjects who died. Thus, analyses were performed on 811 subjects, and tHcy was measured in stored sera. The Hoorn Study was approved by the Ethics Review Committee of the University Hospital Vrije Universiteit Amsterdam. Informed consent was obtained from all participants.
Measurement of tHcy
Fasting blood samples were centrifuged within 1 hour
after collection. Serum was stored at -20°C for 4 to 7 years. There
is good evidence that serum tHcy concentrations are stable for 
10
years.19 Serum total (free plus protein bound)
homocysteine was measured with tri-n-butylphosphine as the
reducing agent and ammonium 7-fluorobenzo-2-oxa-1,3-diazole-4-sulfonate
as the thiol-specific fluorochromophore, followed by
high-performance liquid chromatography with
fluorescence detection.20 The intra-assay and
interassay coefficients were 2.1% and 5.1%.
Other Variables
Blood pressure was measured as the mean of 4 measurements taken
on 2 different occasions with the use of a random-zero sphygmomanometer
under standardized conditions. Fasting and 2-hour postload venous
plasma glucose concentrations were measured with a glucose
dehydrogenase method (Merck). Fasting serum total
cholesterol, HDL-cholesterol, and
triglycerides were measured by enzymatic techniques
(Boehringer-Mannheim). Serum albumin was assessed with
the bromcresol purple method. Hypoalbuminemia was defined as
albumin 
34 g/L.21 All laboratory measurements
were carried out in a blinded fashion with respect to mortality,
glucose tolerance status, and other clinical data.
Statistical Analysis
Prevalence of hyperhomocysteinemia, defined as serum tHcy level
>14 µmol/L,12 in the entire cohort was
back-calculated by means of direct standardization. Briefly, the
prevalence of hyperhomocysteinemia was determined in 24 strata [age
(50 to 59, 60 to 69, and 70 to 75 years), sex (male and female), and
glucose tolerance (NGT, IGT, and newly diagnosed and known type 2
diabetes mellitus)] of the subsample. To assess the prevalence of
hyperhomocysteinemia in the original population-based sample (standard
n=2484), the prevalence of hyperhomocysteinemia was back-calculated
from the magnitude of each age, sex, and glucose tolerance category
stratum.
We assessed the relation between tHcy and 5-year overall mortality in
the nested case-control study with logistic regression
analyses. We calculated odds ratios plus 95% CI for serum tHcy
both as a continuous variable, expressed per 5-µmol/L (1 SD)
increment of serum tHcy, and as a categorical variable [divided in
2 (>14 µmol/L vs 14 µmol/L) and in 4 categories
(9.0 µmol/L, 9.1 to 14.0 µmol/L, 14.1 to 19.0
µmol/L and >19.0 µmol/L)]. Odds ratios of mortality were
adjusted for the stratifying variables (ie, age, sex, and glucose
tolerance) and potentially confounding major
cardiovascular risk factors (ie, hypertension,
hypercholesterolemia, and current
smoking11 22 ). Possible interactions between tHcy and
cardiovascular risk factors were assessed in stratified
analyses and with interaction terms by means of logistic
regression.
To assess whether the observations were distorted by underlying disease that might cause both high values of serum tHcy and increased mortality rates,23 we did 2 additional analyses. First, we adjusted for serum albumin, an acute-phase protein and a putative marker of health and nutrition status.24 Second, we adjusted for the presence of cardiovascular disease at baseline, as defined elsewhere,13 although the latter analysis might obscure a true effect because cardiovascular disease may well be an intermediate factor in the causal pathway linking tHcy to mortality.25
Finally, we assessed the relation between tHcy and cardiovascular death over the first 5-years of follow-up. This analysis was restricted to the subcohort because it required the Cox proportional hazards model. All analyses were performed with SPSS for Windows 95 version 7.5.2.
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Results |
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The baseline characteristics of the patients who died and the control subjects are presented in Table 1
. The back-calculated prevalence
of hyperhomocysteinemia (>14 µmol/L) in the cohort was 25.8%.
Of all type 2 diabetic subjects, 115 (62.5%) were newly diagnosed and
69 (37.5%) were known to have diabetes and were treated with
glucose-lowering agents: 16 (8.7%) with insulin, 52 (28.3%) with
sulfonylureas, and 3 (1.6%) with metformin (of whom 2 also used
sulfonylureas). The median known duration of diabetes of subjects in
whom type 2 diabetes had previously been diagnosed was 6.4 years
(interquartile range 2.7 to 12.0). Serum tHcy concentrations did not
correlate with fasting glucose (r=0.001; P=1.0),
HbA1c (r=-0.03; P=0.4), or
serum albumin (r=-0.03; P=1.0). The mean
serum tHcy concentration in diabetic subjects treated with insulin or
glucose-lowering agents was 12.3 µmol/L (SD 8.6 µmol/L)
versus 12.5 µmol/L (SD 4.6 µmol/L) in those not so
treated (P=0.1); it was 12.3 µmol/L (SD 4.2
µmol/L) in subjects treated with insulin and 12.3 µmol/L (SD
9.6 µmol/L) in those treated with glucose-lowering agents
(P=0.4).
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Overall Mortality
The cause of death could be found in 93.6% (160 of 171); 47.5%
(76 of 160) died of cardiovascular disease, of whom 34
belonged to the subcohort. The 84 (52.5%)
noncardiovascular deaths were due to malignant
neoplasms (60), septicemia (3), respiratory tract infection (3),
respiratory disease (1), external causes (3), and other causes
(14).
In the entire cohort, the 5-year risk of death was 5.7% in
subjects with normal glucose tolerance (NGT), 7.1% in subjects with
impaired glucose tolerance (IGT), and 18.5% in subjects with diabetes;
it was 5.5% in subjects with serum tHcy 14 µmol/L and 10.8%
in subjects with serum tHcy >14 µmol/L.
The risk of 5-year overall mortality increased considerably above a
serum tHcy concentration of 14 µmol/L (Figure 1). Table 2
shows the odds ratios of overall mortality in the presence versus the
absence of other major cardiovascular risk factors.
Additional adjustment for dyslipidemia, body mass index, or
pack-years of smoking did not attenuate the strength of the association
between serum tHcy and death, nor did additional adjustment for serum
albumin (Table 2). There was a graded inverse relation
between serum albumin and death that was not altered by
adjustment for potential confounders (Table 2). Subjects with
hypoalbuminemia had a 2.2-fold (95% CI 1.2 to 3.9) greater
risk of death compared with subjects with serum albumin levels
>34 g/L.
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We evaluated possible interaction and did not observe substantial
differences among the strata of the following risk factors: male sex,
hypertension, hypercholesterolemia, and current
smoking (data not shown). After stratification by diabetes and
adjustment for age, sex, hypertension, current smoking,
hypercholesterolemia, and serum albumin
in the logistic regression model, the odds ratio of 5-year mortality
associated with hyperhomocysteinemia was, however, 1.34 (0.87 to 2.06)
in nondiabetic subjects and 2.51 (1.07 to 5.91) in diabetic subjects
(P=0.08 for interaction; Figures 2 and 3).
This indicates that hyperhomocysteinemia is a stronger (1.9-fold, 95%
CI 0.7 to 4.9) risk factor for death in diabetic than in nondiabetic
subjects. For each 5-µmol/L increment of serum tHcy, the odds ratio
was 1.17 (0.92 to 1.50) in nondiabetic subjects and 1.60 (1.02 to 2.51)
in diabetic subjects. (Subjects with NGT and IGT were pooled because
the odds ratio of 5-year mortality associated with hyperhomocysteinemia
did not differ substantially between these categories and the odds
ratio remained similar if NGT and IGT were pooled; data not shown.) An
additional analysis revealed that among diabetic subjects with
hyperhomocysteinemia, those with known diabetes had the highest
relative risk of mortality. After adjustment for age and sex,
the odds ratio of 5-year mortality associated with hyperhomocysteinemia
was 2.58 (0.90 to 7.40) for subjects with newly diagnosed diabetes and
3.18 (0.74 to 13.74) for subjects with known diabetes. This interaction
showed a significant trend (P=0.04): The odds ratio
increased gradually over the 3 subgroups: nondiabetic, newly diagnosed
diabetic, and known diabetic subjects. Finally, in a stratified
analysis, after adjustment for cardiovascular
risk factors and the presence of cardiovascular disease
at baseline, we again found interaction: The odds ratio of 5-year
mortality associated with hyperhomocysteinemia was 1.27 (0.82 to 1.96)
in nondiabetic subjects and 2.55 (1.08 to 6.02) in diabetic subjects
(P=0.07 for interaction).
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Cardiovascular Death
The mean serum tHcy concentration did not differ between subjects
who died of cardiovascular and
noncardiovascular causes (13.9 µmol/L, SD
6.5 µmol/L, and 13.5 µmol/L, SD 5.0 µmol/L;
P=0.6) but was higher in subjects who died of
cardiovascular disease compared with those who survived
the first 5 years of follow-up (13.9 µmol/L, SD 6.5
µmol/L, and 12.6, SD 5.9 µmol/L; P=0.006).
After adjustment for the stratifying variables, the hazard ratio (95% CI) of cardiovascular death was 1.65 (0.81 to 3.31) for hyperhomocysteinemia, 1.58 (1.04 to 2.42) for each category increment of serum tHcy, and 1.55 (1.08 to 2.23) for each 5-µmol/L increment of serum tHcy. After additional adjustment for hypertension, hypercholesterolemia, and current smoking, these hazard ratios were 1.60 (0.65 to 3.01), 1.51 (0.98 to 2.32), and 1.45 (1.01 to 2.08), respectively. Because of the limited number of cases in the subcohort, we could not investigate the issue of interaction of hyperhomocysteinemia and diabetes with regard to cardiovascular death.
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Discussion |
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This prospective, population-based study, with a 5-year follow-up, indicates that hyperhomocysteinemia is a risk factor for overall mortality in type 2 diabetic patients, independent of major cardiovascular risk factors and serum albumin, a putative general marker of health. Moreover, hyperhomocysteinemia appeared to be a stronger (
2-fold) risk factor for death in diabetic
than in nondiabetic subjects. For each 5-µmol/L (1 SD) increment
of serum tHcy, the risk of 5-year mortality rose by 17% in the
nondiabetic and by 60% in the diabetic subjects. There are several prospective studies that have investigated the relation between tHcy and risk of cardiovascular disease. Many9 26 27 28 29 30 31 32 33 34 35 36 but not all23 37 38 found a positive relation. None of the previous studies, however, investigated the possibility of interaction between hyperhomocysteinemia and diabetes with regard to risk of death. The design of the present study, with a high prevalence and an accurate diagnosis of type 2 diabetes, provided an opportunity to do so. The strength of the relation between hyperhomocysteinemia and death appeared to be stronger among those with diabetes than among those without diabetes. An interaction of hyperhomocysteinemia with diabetes is biologically plausible. High homocysteine concentrations may exert an atherothrombotic effect through increasing oxidative stress, which may induce endothelial dysfunction.14 39 40 41 Homocysteine can also affect the properties of the extracellular matrix and increase smooth muscle cell proliferation.14 Oxidative stress is thought to be increased in type 2 diabetes,42 and matrix alterations are a prominent feature of diabetes in general, both of which might make diabetes patients more susceptible to the adverse affect of hyperhomocysteinemia. The interaction with hyperhomocysteinemia observed in the present study, if confirmed, may have important implications with regard to risk management in type 2 diabetes.
Little is known about the impact of diabetes per se or its treatment on
tHcy metabolism.13 43 In the present
study, we found no relation between tHcy and fasting glucose or
HbA1c. However, 40% of the diabetic subjects
had previously been diagnosed, and we therefore cannot rule out that
changes of dietary habits may have resulted in an increase of vitamin B
intake.
The present study has several limitations. (1) We lacked data on intake and serum levels of folate, vitamin B12, and vitamin B6. We therefore were unable to explore the extent to which the relation between B vitamins and serum tHcy levels differs for diabetic and nondiabetic subjects. It has been suggested that hyperglycemia may cause an increased loss of water-soluble B vitamins.44 On the other hand, relative renal hyperfiltration among diabetic subjects may result in lower tHcy levels.45 (2) As in any study, our data were subject to classification errors. Errors in coding cause of death would not affect our analyses of overall mortality, but they would affect the count of deaths from specific causes such as cardiovascular deaths. Such errors are not likely to be related to tHcy assessment, however, and therefore will result in nondifferential misclassification, tending to underestimate the strength of the relation between hyperhomocysteinemia and cardiovascular death.25 In addition, owing to small numbers, we could not assess the effect of hyperhomocysteinemia for cardiovascular death as precisely as for overall mortality. (3) Because the follow-up period was relatively short (5 years), we cannot exclude the possibility that tHcy levels are elevated because of the presence of (sub)clinical atherosclerosis.23 46 However, adjustment for cardiovascular disease at baseline or serum albumin did not attenuate the relation between hyperhomocysteinemia and mortality. (4) Finally, we cannot rule out the possibility that incomplete adjustment for some cardiovascular risk factors may have resulted in residual confounding.
In conclusion, this study indicates that hyperhomocysteinemia is a risk factor for overall mortality and for cardiovascular death during a 5-year follow-up. The effect does not appear to be explained by other major cardiovascular risk factors. It is likely to be a stronger risk factor for overall mortality in diabetic patients than among nondiabetic subjects. Nevertheless, although strong evidence from this and other studies has accumulated linking hyperhomocysteinemia to cardiovascular disease, persuasive inferences about a causal role will likely emerge only from large randomized trials in which subjects are allocated to either homocysteine-lowering therapy or standard preventive approaches.
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Acknowledgments |
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We are indebted to Wendy Guérand for her excellent laboratory assistance, Henricus Ruhé for expediting the processing of death certificates, Eric Melse for creating graphs, and Prof Kenneth J. Rothman, DrPH (Department of Epidemiology, Boston University) for his valuable comments. Dr Coen Stehouwer was supported by a Clinical Research Fellowship from the Diabetes Fonds Nederland and the Netherlands Organization for Scientific Research (NWO).
Received August 13, 1999; revision received October 21, 1999; accepted November 2, 1999.
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