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R C Turner Diabetes Research Laboratories,
Nuffield Department of Medicine, University of Oxford, Radcliffe
Infirmary, Oxford OX2 6HE
Correspondence to: Professor
Turner robert.turner{at}drl.ox.ac.uk
Objective: To evaluate baseline risk factors for
coronary artery disease in patients with type 2 diabetes mellitus.
Patients with type 2 diabetes mellitus have a twofold to threefold
increased incidence of diseases related to atheroma,1 and
those who present in their 40s and 50s have a twofold increased total
mortality.2 In the United Kingdom the incidence of
macrovascular complications in patients with type 2 diabetes mellitus
is twice that of microvascular disease.3 The greater
mortality in patients with type 2 diabetes mellitus than in the general
population cannot be explained only by the presence of the three
classic risk factors for coronary artery disease Previous prospective studies of patients with type 2 diabetes mellitus
had comparatively few patients and cardiovascular end points.5-11 Many of these studies have not measured the
concentration of low density lipoprotein cholesterol, potentially the
most important lipid fraction.
12 13
We report a prospective study of white patients with recently diagnosed
type 2 diabetes mellitus. After entry to the United Kingdom prospective
diabetes study14 patients were assessed for baseline risk
factors after initial treatment by diet for 3 months. The
association of coronary artery disease with baseline risk factors
has been assessed irrespective of subsequent treatments.
Patients
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Abstract
Top
Abstract
References
Design: A stepwise selection procedure, adjusting for
age and sex, was used in 2693 subjects with complete data to determine
which risk factors for coronary artery disease should be included in a
Cox proportional hazards model.
Subjects: 3055 white patients (mean age 52) with
recently diagnosed type 2 diabetes mellitus and without evidence of disease related to atheroma. Median duration of follow up was 7.9 years. 335 patients developed coronary artery disease within 10 years.
Outcome measures: Angina with confirmatory abnormal
electrocardiogram; non-fatal and fatal myocardial infarction.
Results: Coronary artery disease was significantly
associated with increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, and increased triglyceride concentration, haemoglobin A1c, systolic blood pressure, fasting plasma glucose
concentration, and a history of smoking. The estimated hazard ratios
for the upper third relative to the lower third were 2.26 (95%
confidence interval 1.70 to 3.00) for low density lipoprotein
cholesterol, 0.55 (0.41 to 0.73) for high density lipoprotein
cholesterol, 1.52 (1.15 to 2.01) for haemoglobin A1c, and
1.82 (1.34 to 2.47) for systolic blood pressure. The estimated hazard
ratio for smokers was 1.41(1.06 to 1.88).
Conclusion: A quintet of potentially modifiable risk
factors for coronary artery disease exists in patients with type 2 diabetes mellitus. These risk factors are increased concentrations of
low density lipoprotein cholesterol, decreased concentrations of high
density lipoprotein cholesterol, raised blood pressure, hyperglycaemia,
and smoking.
Key messages
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Introduction
that is, smoking,
hypertension, and an increased plasma cholesterol
concentration.4
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Subjects and methods
Between 1977 and 1991, 5102 patients aged 25 to 65 years
with type 2 diabetes mellitus based on a fasting plasma glucose
concentration >6 mmol/l on two occasions were recruited to the
study14; 4775 (94%) had fasting plasma glucose values
>7.0 mmol/l, which is consistent with the American Diabetic
Association's definition of diabetes. Of the 7108 patients originally
referred for entry to the study, 2006 (28%) were excluded. These were
of a similar age and sex and had a similar fasting plasma glucose
concentration as those patients included in the study. The main reasons
for exclusion were myocardial infarction in the previous year, current angina or heart failure, accelerated hypertension, proliferative or
preproliferative retinopathy, renal failure with a plasma
creatinine concentration >175 µmol/l, other life threatening
disease such as cancer, an illness requiring systemic steroids, an
occupation which precluded insulin treatment, language difficulties, or
ketonuria >3 mmol/l suggestive of insulin dependent diabetes
mellitus.
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Follow up, identification, and classification of end points
Patients were seen every three months in the clinics, and
any events that were clinically important were noted. To ascertain whether predetermined criteria for the end points were attained two
independent doctors received full information on the patients but
without details of treatment.14 Any discrepancies between the two doctors were adjudicated by two independent senior doctors. All
end points were coded according to ICD-9 (international classification of disease, 9th revision).15
that is, fatal or non-fatal myocardial infarction or clinical angina
with an abnormal electrocardiogram at rest or after a treadmill test; fatal or non-fatal myocardial infarction; and fatal
myocardial infarction.
Baseline risk factors assessment
Height, waist, and hip circumferences were measured, and the
smoking status and amount of exercise taken were ascertained by
questionnaire.14 Retinopathy was assessed by modified
Wisconsin grading of four colour photographs of each eye taken at 30°
to the horizontal.14 Blood pressure was recorded as the
mean of measurements taken 2 and 9 months after diagnosis with
electronic sphygmomanometers. Hypertension was defined as systolic
blood pressure
160 mm Hg or diastolic blood pressure
90 mm Hg,
or both, or antihypertensive treatment. After the initial treatment diet, patients were fasted overnight and the following concentrations measured: fasting plasma glucose, haemoglobin A1c, low
density lipoprotein cholesterol, high density lipoprotein cholesterol, and insulin.
14 16
Statistical analyses
Data are reported as means (SD), geometric means (1 SD
interval), or percentages. Variables for patients included in or
excluded from the analyses were compared by t tests,
2 tests, or Fisher's exact tests.
60 years. Continuous
variables were grouped into thirds. The effect of potential risk
factors on the three aggregate end points was assessed by Cox
proportional hazards models,19 with censoring at 10 years' follow up. The relation of single risk factors with events
after adjustment for age and sex was assessed in 2693 patients with all
risk factors measured. Multivariate selection of risk factors was done
by a stepwise procedure after adjustment for age and sex. Estimated
hazard ratios are represented graphically, with 95% confidence
intervals estimated for each group by treating the relative risks as
floating absolute risks so that the appropriate variability for each
group is
shown.20
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Results |
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Table 1 shows the baseline risk factors assessed for the 2693 white patients who had no previous indication of disease related to atheroma and had complete data when studied after the initial treatment diet. The men who were entered into the United Kingdom prospective diabetes study but excluded from this analysis because of previous cardiovascular disease were older (mean age 56 (SD7) years), had higher systolic blood pressure (mean 141(20) mm Hg), were more likely to be hypertensive (46%), and were more likely to be smokers (10% had never smoked, 51% were ex-smokers, and 39% were current smokers) (P<0.01 for each). Women who were excluded from the study were also older (mean age 56 (8) years) and had higher systolic blood pressure (mean 145 (20) mm Hg) (P<0.01 for each). Baseline concentrations of total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and triglyceride did not differ in subjects according to the presence of disease related to atheroma (P>0.01).
Standardised mortality ratio
During the first five years of the study the standardised
mortality ratio was not very different from that in the general population, possibly because patients with life threatening illnesses were excluded from the study (table 2). After the first five years of
the study patients with type 2 diabetes mellitus had an increased total
mortality compared with the general population.
Relation of baseline risk factors with adjustment for age and sex
Table 3 shows the relation of potential risk factors, stratified
by thirds, to coronary artery disease in 280 patients with end points.
Important variables were low density lipoprotein cholesterol concentration, high density lipoprotein cholesterol concentration, and
also triglyceride concentration, haemoglobin A1c, systolic blood pressure, fasting plasma glucose concentration, and smoking; each
of these had a positive association except high density lipoprotein cholesterol concentration. Similar associations were seen for fatal or
non-fatal myocardial infarction (192 patients with end points) and
fatal myocardial infarction (79 patients with end points). Retinopathy
was associated with fatal myocardial infarction (P=0.005) but not with
fatal or non-fatal myocardial infarction (P=0.124) or with coronary
artery diseases (P=0.082).
Stepwise selection of risk factors
Table 4 shows the selected risk factors with P values from the
stepwise multivariate Cox models. Factors that were not important were
body mass index, waist to hip ratio, exercise, triglyceride concentration, and fasting plasma glucose or insulin concentration, and
these were not included in the final model. The exclusion of
triglyceride concentration and not high density lipoprotein cholesterol
concentration was not due solely to imprecision of measurements, since
baseline triglyceride concentration correlated with the values 6 months
later in subjects randomised to, and remaining on, the diet
(rs=0.72 (95% confidence interval 0.68 to
0.76)). This correlation was greater than the correlation between repeated high density lipoprotein measurements
(rs=0.52 (0.45 to 0.58)). Baseline
triglyceride concentration correlated with high density lipoprotein
cholesterol concentration (rs=
0.27
(P<0.0001)). No significant interaction term was identified between
high density lipoprotein cholesterol concentration and low density
lipoprotein cholesterol concentration.
Estimated hazard ratios
Table 5 and the figure show the Cox model estimated hazard ratios
for age and sex and the stepwise selected variables for coronary artery
disease in 3055 patients (335 with a coronary artery disease). A
similar pattern of hazard ratios was seen for fatal or non-fatal
myocardial infarction (233 patients with an event) and fatal
myocardial infarction (103 patients with an event). Although diastolic
blood pressure had a stronger relation than systolic blood pressure
with any myocardial infarction or fatal myocardial infarction,
replacement by systolic blood pressure did not affect the
results.
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Discussion |
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This study shows that in patients with type 2 diabetes mellitus increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, hyperglycaemia, hypertension, and smoking (all measured on completion of a treatment diet after diagnosis), are risk factors for coronary artery disease, defined as fatal and non-fatal myocardial infarction or angina. Previous studies have shown inconsistent results, being dependent on univariate analyses in small studies, with few patients having clinical end points. Total cholesterol concentration was reported to be a risk factor in some 5 7 21 but not other studies, 6 8 22 and most had not measured both low density lipoprotein cholesterol and high density lipoprotein cholesterol concentrations. Hyperglycaemia was similarly reported as a risk factor in some 5 6 8 11 21 22 but not other studies,7 and hypertension similarly in some 5 22 but not other studies. 6-8 11 21 The present study shows that patients with type 2 diabetes mellitus have the same risk factors for coronary artery disease as the general population.23 This study confirms that patients with non-insulin diabetes mellitus have an increased total mortality compared with the general population, although this was not apparent in the initial 5 years, probably because diabetic patients with life threatening illness were excluded from the United Kingdom prospective diabetes study.
Major risk factors
Low density lipoprotein and total cholesterol
An
increased concentration of low density lipoprotein cholesterol or total
cholesterol at baseline was a major risk factor for coronary artery
disease. This is similar to the general
population.
13 24 25
Increased concentrations of low
density lipoprotein cholesterol may be more pathogenic in patients with
type 2 diabetes mellitus than in non-diabetic patients because of the
presence of small dense low density lipoprotein cholesterol
particles26 and oxidation of glycated low density
lipoprotein cholesterol.27 The 1.57 increased risk for an
increment of 1 mmol/l in low density lipoprotein cholesterol
concentration equates to a 36% risk reduction for a decrement of
1 mmol/l , similar to the 31% risk reduction achieved with a
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor in men with
hypercholesterolaemia.13 The subgroup analysis of the
simvastatin study28 showed that the diabetic patients had similar protection to that of non-diabetic patients.25 A
decreased concentration of high density lipoprotein cholesterol was an
independent risk factor for coronary artery disease. The 15% decrease
in the risk of coronary artery disease associated with a 0.1 mmol/l
increment in high density lipoprotein cholesterol concentration is
compatible with the 8-12% reduction reported from prospective American
studies.29 Triglyceride concentration was a risk
factor for coronary artery disease after adjustment for age and sex,
but it was not an independent risk factor when the other variables were
included in the model. This is in accord with other studies, possibly
because of the greater biological variability of triglyceride than high
density lipoprotein cholesterol measurements.30 However,
we found over 6 months that the concentration of high density
lipoprotein cholesterol was more variable than that of triglyceride,
possibly because of less precision with the assay (coefficient of
variation 6% v 2%) and because patients were receiving
dietary advice and had a more uniform dietary intake than in the
general population. As control of plasma triglyceride and high density
lipoprotein cholesterol concentrations is interlinked through
lipoprotein lipase and hepatic lipase activities, it may not be
feasible to separate the contributions of triglyceride and high density
lipoprotein cholesterol to coronary artery disease. Postprandial
triglyceride values may have an additional atherogenic role to the
fasting values that were measured.31
Haemoglobin A1c
There was an increase in risk
of coronary artery disease with haemoglobin A1c of >6.2%,
the upper range of normal values, in accord with other studies which
suggest that glycaemia above the normal range gives an increased risk
for macrovascular disease.
32 33
If glycation of
proteins was a major pathogenic factor for coronary artery disease the
increased risk would be expected to be proportional to the degree of
hyperglycaemia.34 The study showed an increased risk of
11% for each increment of 1% in haemoglobin A1c,
similar to the 10% increase in mortality from ischaemic heart
disease for an increment of 1% in haemoglobin A1c reported
in Wisconsin.35
Blood pressure
Increased blood pressure was also a
major risk factor for coronary artery disease, with a 15% increased
risk for an increase in systolic blood pressure of 10 mm Hg, which was
similar to that reported in the general population.36
Increased blood pressure was a major risk factor for fatal myocardial
infarction. This could be because hypertension is a major additional
burden to the heart when myocardial infarction ensues. The hypertension in diabetes study in 1148 patients in a factorial design is evaluating whether strict blood pressure control will prevent
complications.37
Retinopathy
Retinopathy at diagnosis was not a risk factor
for cardiovascular disease in a multivariate analysis, although
retinopathy was a risk factor for fatal myocardial infarction when only
age and sex were adjusted for. Since both retinopathy38
and microalbuminuria39 are associated with hyperglycaemia
and hypertension, which are also risk factors for coronary artery
disease, the previously described association of retinopathy and
microalbuminuria with subsequent cardiovascular mortality might reflect
the longstanding hypertension and hyperglycaemia that induced both
macrovascular and microvascular disease.
Risk factors in type 2 diabetes mellitus
Risk factors for development of coronary artery disease in
the general population may not apply once diabetes has developed. Obesity and central obesity,40 decreased physical
activity,41 and raised insulin
concentrations42 provide an increased risk for
cardiovascular disease, but in patients with type 2 diabetes mellitus
we found that none of these were major risk factors. These variables
are also risk factors for diabetes,43-45 but this study
indicates that once diabetes has developed, hypertension, increased
concentrations of low density lipoprotein or decreased concentrations
of high density lipoprotein cholesterol and hyperglycaemia measured at
baseline are greater risk factors for coronary artery disease than
these precipitating factors.
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Acknowledgments |
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The cooperation of the patients and many NHS and non-NHS staff at the centres is much appreciated. We thank Professor Eva Kohner, Mr Steve Aldington, Ms Ivy Samuel, and Mrs Caroline Wood for help with the manuscript.
Contributors: RCT and RRH coordinated the study, HM and IMS carried out the statistical analyses, HAWN provided epidemiological advice, DRM coordinated the assessment of clinical end points, and SEM provided biochemical advice. All authors wrote the paper. RCT will act as guarantor of the study.
Funding: This study received grants from the Medical Research Council; British Diabetic Association; the Department of Health; the National Eye Institute and the National Institute of Digestive, Diabetes and Kidney Disease in the National Institutes of Health, United States; the British Heart Foundation; the Health Promotion Research Trust; Charles Wolfson Charitable Trust; the Alan and Babette Sainsbury Trust; the Clothworkers' Foundation; Oxford University Medical Research Fund Committee; and pharmaceutical companies, including Novo-Nordisk, Bayer, Bristol Myers Squibb, Hoechst, Lilly, Lipha, and Farmitalia Carlo Erba. Additional funding came from Boehringer Mannheim, Becton Dickinson, Owen Mumford, Securicor, Kodak, and Cortecs Diagnostics.
Conflict of interest: None.
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References |
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(Accepted 24 October 1997)
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