Download Table 1 - Diabetes Care

Table 1. Selected incidence studies of coronary artery disease in type 1 diabetes
Reference / Study
Study population /
Results
Comments
hypothesis
Deckert et al. Prognosis of
289 patients diagnosed
Myocardial infarction was the
Clinical manifestations of late
diabetics with diabetes
before 1933 and before the
cause of death in 25% of
diabetes complications were
onset before the age of
patient was thirty-one years
deceased patients. Of the total
considerably less common in patients
thirty-one. I. Survival,
old were followed to assess
population, 21% exhibited
who were still alive after more than
causes of death, and
the incidence and cause of
objective signs of myocardial
forty years of diabetes than in patients
complications.
mortality.
infarction.
who died before their fortieth year of
Diabetologia 14:363-370,
diabetes.
1978. (1)
Dorman et al. The
1966 type 1 diabetes patients Standardized mortality ratios for Before age 20, the primary excess in
Pittsburgh Insulin-
diagnosed between 1950 and cardiovascular disease in
mortality was within 6 months after
Reference / Study
Study population /
Results
Comments
hypothesis
Dependent Diabetes
1981 were followed to
patients with type 1 diabetes
onset, and due to acute diabetic
Mellitus (IDDM) morbidity
assess survival.
compared to the general U.S.
complications. After age 20, the
and mortality study.
population were 1137 for white
annual mortality risk was
Mortality Results. Diabetes
males and 1591 for white
approximately 2%, which was more
33:271-276, 1984. (3)
females.
than 20 times greater than for the
U.S. population.
Krolewski et al. Magnitude
292 patients with juvenile-
Of the 292 patients in the study,
CAD mortality risk was similar by
and determinants of
onset, type 1 diabetes
80 died by January 1, 1981.
gender. Age at diabetes onset and eye
coronary artery disease in
mellitus were followed for
CAD accounted for 35% of all
complications did not contribute to
juvenile-onset, insulin-
20 to 40 years to assess the
deaths, far higher than in non-
CAD mortality risk.
dependent diabetes
incidence of coronary artery
diabetic men (8%) and women
mellitus. Am J Cardiol.
disease (CAD) mortality.
(4%) in the Framingham study.
59:750-755, 1987. (4)
Reference / Study
Study population /
Results
hypothesis
Diabetes Epidemiology
Mortality status was
There were a total of 147 deaths
Research International
determined for all
(1.8%). Of those, 6% were
Mortality Study Group.
individuals diagnosed with
attributed to coronary artery
International-evaluation
type 1 diabetes at the age of
disease / cerebrovascular
cause-specific mortality and <18 years between 1965 and
IDDM. Diabetes Care
1979, who were taking
14:55–60, 1991. (9)
insulin at the time of
hospital discharge in
population-based cohorts
from Japan (n=1394), Israel
(n=611), Allegheny County
(n=986), and Finland
(n=5146). Mortality was
accident.
Comments
Reference / Study
Study population /
Results
Comments
hypothesis
determined as of January 1,
1985.
Moss et al. Cause-specific
Cause-specific age-sex
Age-sex standardized mortality
Cause of death was determined from
mortality in a population-
standardized mortality ratios
ratios were significantly high
death certificates. Diabetic persons
based study of diabetes.
were assessed in a
(p<0.05) in younger onset
experienced very high mortality,
Am J Public Health
geographically defined
persons for all heart disease
especially from vascular diseases,
81:1158-1162, 1991. (5)
population of younger onset
(9.1), ischemic heart disease
compared to the general population.
(diagnosed <30 years and
(10.1), and other heart disease
taking insulin, n=1200)
(6.3).
persons followed for 8.5
years.
Tuomilehto et al. Incidence
A prospective analysis of the Of 5148 patients, 159 had a
There were virtually no cases of
Reference / Study
Study population /
Results
Comments
hypothesis
of cardiovascular disease in
incidence of cardiovascular
cardiovascular event (58 had
cardiovascular disease before 12
Type 1 (insulin-dependent)
disease was performed in all
coronary heart disease; 57
years diabetes duration. The presence
diabetic subjects with and
5148 type 1 subjects in the
stroke; 44 other heart disease).
of nephropathy in type 1 diabetes
without diabetic
Finnish Type 1 diabetes
The cumulative incidence of
subjects increased the risk of
nephropathy in Finland.
mellitus register diagnosed
cardiovascular disease by 40
coronary heart disease and that of
Diabetologia 41:784-90,
before the age of 18 years
years of age was 43% in
stroke tenfold.
1998. (31)
between 1 January 1965 and
patients with diabetic
31 December 1979
nephropathy, compared with
nationwide.
7% in patients without diabetic
nephropathy, similarly in men
and women.
Laing et al. Mortality from
23,751 patients with insulin-
Of the 1437 deaths during
Patients were defined as having type
heart disease in a cohort of
treated diabetes, diagnosed
follow-up, 536 were from
1 diabetes if diagnosed under the age
Reference / Study
Study population /
Results
Comments
hypothesis
23,000 patients with
under the age of 30 years
cardiovascular disease (369
of 30 years and if on insulin
insulin-treated diabetes.
and from throughout the
from ischaemic heart disease).
treatment.
Diabetologia 46:760-765,
United Kingdom, was
Ischaemic heart disease
2003. (11)
identified during the period
mortality rates per 100,000
1972 to 1993 and followed
person-yrs in the cohort were
for mortality until December
higher than in the general
2000.
population (107 in men, 73 in
women). Standardized mortality
ratios were 44.8 (20.5-85.0) at
ages 20-29 and 41.6 (26.7-61.9)
at ages 30-39 in women and
11.8 (5.4-22.4) and 8.0 (5.111.9) respectively in men.
Reference / Study
Study population /
Results
Comments
hypothesis
Wisconsin Epidemiologic
Persons with type 1 diabetes
The 20-year age-adjusted
Study of Diabetic
who were receiving care in
cumulative incidences were
Retinopathy (Klein et al.
11 counties in Wisconsin
18.1% for angina, 14.8% for
Arch Intern Med. 164:1917- (n=996) were examined at
myocardial infarction (MI), and
1924, 2004.) (28)
5.9% for stroke.
baseline (1980-1982), and 4,
10, 14, and 20 years later.
McAlpine et al. The annual Patients (942 who had, and
Using a mid year estimate of
Patients were defined as having type
incidence of diabetic
29 who developed type 1
patients with diabetes the
1 diabetes if diagnosed at <35 years
complications in a
diabetes) alive and
annual mortality rate was 14.6 /
of age and either insulin-treated, or
population of patients with
registered with a Tayside,
1000. The incidence rates of
initially treated with oral
type 1 and type 2 diabetes.
Scotland, GP for the
complications per 1000 patients
hypoglycemic medications or diet
Diabet Med. 22:348-352,
duration of 1997 or who
were: angina 8.8 and
alone but progressed to insulin within
2004. (141)
died during this time.
myocardial infarction 8.6.
1 month.
Reference / Study
Study population /
Results
Comments
hypothesis
Soedamah-Muthu et al.
Baseline risk factors and
151 (6.5%) patients developed
Type 1 diabetes was defined as
Risk factors for coronary
coronary heart disease
CHD. The 7-year incidence
diabetes diagnosed before the age of
heart disease in type 1
(CHD) at follow-up were
rate was 8.0 (per 1,000 person-
36 years with a continuous need for
diabetic patients in Europe:
assessed in 2,329 type 1
years) in men and 10.2 in
insulin within 1 year of diagnosis.
the EURODIAB
diabetic patients without
women.
Prospective Complications
prior CHD from 31 centers
Study. Diabetes Care
in 16 European countries.
27:530-537, 2004. (7)
Lewis et al. Predicting
Baseline information was
During six to nine years of
Patients were defined as having type
vascular risk in type 1
collected for 2136 patients
follow up, 110 patients (5%)
1 diabetes if diagnosed at <35 years
diabetes: stratification in a
with type 1 diabetes using
developed macrovascular
of age.
hospital based population in the Royal College of
disease.
Reference / Study
Study population /
Results
hypothesis
Scotland. Diabet Med.
Physicians of Edinburgh
22:164-171, 2005. (142)
Diabetes Register in order to
assess their the absolute
cardiovascular risk.
Soedamah-Muthu et al.
Subjects with type 1
The cumulative incidence of
High risk of cardiovascular
diabetes (n=7479) and age
cardiovascular disease was 3%
disease in patients with type and sex-matched controls
(219/7479) in type 1 diabetes
1 diabetes mellitus in the
(n=38116) were followed for and 0.76% (289/38116) in
UK, a cohort study using
7 years to assess major
controls, for a 4.5 fold greater
the General Practice
cardiovascular events.
risk in diabetes. Women with
Research Database.
type 1 diabetes experienced
Diabetes Care 29:798-804,
greater relative risks of heart
2006. (143)
disease than men, compared to
Comments
Reference / Study
Study population /
Results
Comments
hypothesis
those without diabetes.
Pambianco et al. The 30
The cumulative incidence of
No change in cumulative
The number of CAD cases was lower
Year Natural History of
diabetes complications was
incidence was observed by 30
than for other complications reported
Type 1 Diabetes
assessed in the Pittsburgh
years of diabetes duration
(ESRD, neuropathy, mortality),
Complications. The
Epidemiology of Diabetes
(p=0.84).
which showed a decline.
Pittsburgh Epidemiology of
Complications (EDC) study
Diabetes Complications
cohort at 20, 25, and 30
Study Experience.
years of type 1 diabetes.
Diabetes 55:1463-1469,
2006. (8)
Table 2. Selected studies of coronary arteries and surrogate markers of atherosclerosis in type 1 diabetes: principal findings
Reference / Study
Study population / hypothesis
Results
Carotid intima medial wall thickness
Nathan et al. Intensive diabetes
The progression of carotid
Adjusting for other risk factors, progression of the intima-
therapy and carotid intima-media
intima-media thickness was
media thickness was significantly less in the group that had
thickness in type 1 diabetes
examined in 611 persons who
received intensive therapy during the DCCT than in the group
mellitus. N Engl J Med
had been randomly assigned to
that had received conventional therapy.
348:2294-2303, 2003. (14)
receive conventional diabetes
treatment during the DCCT and
in 618 who received intensive
diabetes treatment.
Frost et al. Determinants of early
The course of carotid artery
In a multiple linear regression analysis, the changes of plaque
Reference / Study
Study population / hypothesis
Results
carotid atherosclerosis
intima-media thickness was
frequency and of the nephropathy status between baseline and
progression in young patients
determined over a period of 2.5
follow-up examinations were independent predictors of the
with type 1 diabetes mellitus.
years in 102 patients with Type 1 annual progression rate of carotid artery intima-media
Exp Clin Endocrinol Diabetes
Diabetes (age <40 years,
110:92-94, 2002. (144)
diabetes duration >2 years at
thickness.
baseline examination).
Hayaishi-Okano et al. Elevated
The mean and maximum intima-
Multivariate regression analyses for both diabetic and
C-reactive protein associates with
media thicknesses of the carotid
nondiabetic subjects as a single group showed that hs-CRP
early-stage carotid atherosclerosis
artery were assessed using
levels are independently correlated with the mean intima-
in young subjects with type 1
ultrasound B-mode imaging in
media thicknesses and maximum intima-media thicknesses
diabetes. Diabetes Care 25:1432-
55 patients with Type 1 Diabetes
levels (p=0.002 and p=0.023, respectively) as well as with
1438, 2002. (145)
(22 men, 33 women, aged
diastolic blood pressure, sex, and duration of diabetes. In
22.1+3.6 years, diabetes duration Type 1 Diabetes, hs-CRP concentration (p=0.01) and sex
14.2+5.7 years) and 75 age-
(p=0.01) interacted independently of maximum intima-media
Reference / Study
Study population / hypothesis
Results
matched healthy nondiabetic
thicknesses; HbA1c was not a significant correlate.
subjects (28 men, 47 women).
Jarvisalo et al. Carotid artery
Carotid intima-media thickness
In a multivariate model for all subjects, independent correlates
intima-media thickness in
was measured in 85 children
for intima-media thickness were the diabetic state (p<0.001),
children with type 1 diabetes.
(mean age, 11+2 years): 50 with
LDL cholesterol level (p<0.001), and systolic blood pressure
Diabetes 51:493-8, 2002. (146)
type 1 diabetes (mean duration,
(p<0.001). In children with diabetes but not in controls, LDL
4.4+3.0 years) and 35 controls
oxidizability correlated significantly with mean intima-media
matched for age, sex, and body
thickness (r=0.47, p<0.05), and this relationship remained
size.
significant after controlling for LDL cholesterol.
Yavuz et al. Ultrasonic
Intimal medial thickness was
Patients and control subjects showed no association between
evaluation of early atherosclerosis
evaluated in 52 children and
intima-media thickness and sex, systolic blood pressure,
in children and adolescents with
adolescents (aged 3-18 years)
diastolic blood pressure, serum lipid levels or left ventricular
type 1 diabetes mellitus. J
with uncomplicated Type 1
ejection fraction. However, age correlated with carotid
Reference / Study
Study population / hypothesis
Results
Pediatr Endocrinol Metab.
Diabetes and 43 age- and
arterial wall thickness in both diabetic and control groups.
15(8):1131-6, 2002. (147)
gender-matched controls.
Gunczler et al. Cardiac mass and
Intimal medial thickness was
Carotid intima-media thickness was similar between groups,
function, carotid artery intima-
evaluated in 20 children and
as were LV ejection fraction at rest and pulmonary venous
media thickness and lipoprotein
adolescents (10 males, 10
flow velocities. LDL cholesterol and Lpa levels were
(a) levels in children and
females) with Type 1 Diabetes
increased in patients compared to controls (p<0.01), while
adolescents with type 1 diabetes
before 3.4+3.3 years (mean age
total cholesterol, HDL cholesterol and serum triglyceride
mellitus of short duration. J
11.9+3.6 years, HbA1c:
levels were similar.
Pediatr Endocrinol Metab.
8.0+1.9%) and 20 controls aged
15(2):181-6, 2002. (148)
12.1+3.4 years, matched for sex,
height and weight.
Berger et al. Carotid artery
To investigate changes in carotid
Subjects with Type 1 Diabetes did not differ from controls in
structure and function in young
artery structure and function
carotid artery distensibility or compliance. Carotid artery
Reference / Study
Study population / hypothesis
Results
adults with type 1 diabetes
over a 3-yr follow-up period, 28
intimal-medial thickness was slightly, but not significantly
(abstract). Diabetes 52(Suppl.
(of 33 at baseline) subjects with
greater in Type 1 Diabetes subjects versus controls (p=0.07).
1):A45, 2003. (149)
Type 1 Diabetes were compared
to 28 age and sex-matched
controls (both groups 17 males;
DMs 18.8±1.3, controls 18.7±2.0
yr; DM duration 12.6±3.4 yr).
Singh et al. Vascular function
To evaluate endothelium-
Endothelium-dependent vasodilation was significantly lower
and carotid intimal-medial
dependent vasodilation and
in diabetic compared with healthy children (p<0.001), but
thickness in children with insulin-
carotid intimal-medial thickness,
there was no difference in endothelium-independent
dependent diabetes mellitus. J
31 diabetic (age 15.0+2.4 years;
vasodilation or mean carotid intimal-medial thickness
Am Coll Cardiol. 41:661-665,
diabetes duration 6.8+3.9 years)
between the groups.
2003. (23)
and 35 age-matched healthy
children (age 15.7+2.7 years)
Reference / Study
Study population / hypothesis
Results
were studied.
Coronary artery calcification
Colhoun et al. The effect of type
Coronary artery calcification and
Among control subjects, men were more likely to have
1 diabetes mellitus on the gender
coronary risk factors were
coronary artery calcification compared to women (OR 4.5,
difference in coronary artery
compared in 199 type 1 diabetes
p<0.0001, adjusted OR 2.2). However, among individuals
calcification. J Am Coll Cardiol.
patients and 201 controls of
with type 1 diabetes, women were 3 times more likely to
36:2160-2167, 2000. (16)
similar age (30-55 years) and
present with coronary artery calcification compared to men
gender (50% male) distribution.
(p=0.02).
Olson et al. Coronary calcium in
The relationship of coronary
Coronary artery calcification had 84 and 71% sensitivity for
adults with type 1 diabetes: a
artery calcification with
total CAD in men and women, respectively, and 100%
stronger correlate of clinical
prevalent clinical coronary artery sensitivity for MI or obstructive CAD. In subjects with
coronary artery disease in men
disease and established
angina only, calcification sensitivity was 83% in men and
Reference / Study
Study population / hypothesis
Results
than in women. Diabetes
cardiovascular disease (CVD)
46% in women. Calcification was an independent correlate of
49:1571-1578, 2000. (17)
risk factors was studied in 302
CAD in men and overall, and of MI or obstructive CAD in
type 1 diabetes subjects from the
both sexes. However, coronary artery calcification was not
Pittsburgh Epidemiology of
independently associated with angina and ischemic ECG in
Diabetes complications study.
either sex.
Dabelea et al. Effect of type 1
To examine whether estimated
Insulin resistance was associated with coronary artery
diabetes on the gender difference
insulin resistance and insulin
calcification in both type 1 diabetes and control subjects (OR
in coronary artery calcification: a
resistance-related factors are
1.6 and 1.4, respectively, p<0.001), independent of CAD risk
role for insulin resistance? The
associated with coronary artery
factors. There was a male excess of calcification in controls
Coronary Artery Calcification in
calcification (CAC), a total of
(OR 2.7, adjusted for age, smoking, LDL and HDL
Type 1 Diabetes (CACTI) Study.
656 patients with type 1 diabetes
cholesterol) and in type 1 diabetic patients (OR 2.2, adjusted
Diabetes 52:2833-2839, 2003.
and 764 control subjects aged
for the same factors and diabetes duration). Gender
(15)
20-55 years was selected from
differences in insulin resistance associated fat distribution
the CACTI study.
seemed to explain the increased coronary calcification in
Reference / Study
Study population / hypothesis
Results
women compared to men.
Angiographic / intravascular ultrasound
Crall et Roberts. The extramural
Clinical and morphologic
The patients with diabetes had significantly more extramural
and intramural coronary arteries
observations of the coronary
coronary luminal narrowing by atherosclerotic plaques than
in juvenile diabetes mellitus:
arteries in 9 patients with type 1
the controls. The lumens of one or more of the 4 major
analysis of nine necropsy patients
diabetes (average age at onset, 9
epicardial coronary arteries were narrowed more than 75% in
aged 19 to 38 years with onset of
years) were compared to those of cross-sectioned area in 6 of the diabetic patients and in none
diabetes before age 15 years. Am
9 controls (mean age, 29 years).
of the control subjects.
Valsania et al. Severity of
Clinical and angiographic
Compared to non-diabetic individuals, persons with diabetes
coronary artery disease in young
findings were examined in 32
were more likely to have severe narrowings, to have
patients with insulin-dependent
patients with type 1 diabetes and
narrowings in all three major coronary arteries, and to have
J Med. 64:221-30, 1978. (18)
Reference / Study
Study population / hypothesis
Results
diabetes mellitus. Am Heart J.
in 31 non-diabetic subjects
narrowings in distal segments. Severe narrowing of multiple
122:695-700, 1991. (19)
(matched for age and symptoms)
vessels was more prevalent in men compared to women and in
undergoing elective cardiac
individuals with hypercholesterolemia.
catheterization for evaluation of
coronary artery disease.
Pajunen et al. Angiographic
This retrospective angiography
Persons with type 1 diabetes had greater global severity
severity and extent of coronary
study comprised 64 (24 women
(p<0.001), global extent (p<0.001), and global atheroma
artery disease in patients with
and 40 men) type 1 diabetic
burden (p<0.001) indexes than control subjects. Quantitative
type 1 diabetes mellitus. Am J
patients and nondiabetic control
coronary angiographic-derived indexes of CAD were, on
Cardiol. 86:1080-1085, 2000.
subjects. To estimate the
average, 1.4- to 4.3-fold higher in persons with diabetes
(20)
severity, extent, and overall
compared to controls, and particularly affected women.
"atheroma burden" of CAD.
Angiographic indices did not relate to HbA1c in the Type 1
Diabetes subjects, but did to HDL cholesterol.
Reference / Study
Study population / hypothesis
Results
Larsen et al. Silent coronary
Coronary atheromatosis was
Fifteen percent of patients had abnormal exercise ECGs, and
atheromatosis in type 1 diabetic
evaluated in patients with type 1
34% had angiographic diameter stenosis >50% in one or more
patients and its relation to long-
diabetes in the Oslo study with
of the main coronary arteries. All patients examined with
term glycemic control. Diabetes
no symptoms of CAD by
intracoronary ultrasound had developed atherosclerotic
51:2637-2641, 2002. (21)
exercise electrocardiogram
plaques with an increased intimal thickness (>0.5 mm) in one
(ECG) in 39 patients and
or more of the coronary arteries. Coronary artery plaque
quantitative coronary
formation (by ultrasound) was significantly related to mean
angiography and by
HbA1c during 18 years after adjustment for total cholesterol
intravascular ultrasound (IVUS)
and age (p<0.05).
examinations in 29 patients.
Kowalewski et al. Late
To assess the influence of
The nonlinear regression model showed that duration of
potentials: are they related to
cardiovascular complications on
diabetes, cardiac autonomic neuropathy, and left ventricular
cardiovascular complications in
the occurrence of late ventricular
posterior wall were the strongest independent parameters of
children with Type 1 Diabetes? J
potentials, 72 children (36 boys,
late ventricular potentials occurrence (p<.001, 0.01 and 0.005,
Reference / Study
Study population / hypothesis
Results
Diabetes Complications 16:263-
36 girls) with Type 1 Diabetes
respectively).
270, 2002. (150)
(6.5+2.8 years duration) and 55
sex- and age-matched healthy
children were studied.
Giunti et al. Electrocardiographic
The prevalence of ECG left
In multivariate logistic regression analysis variables
left ventricular hypertrophy in
ventricular hypertrophy and its
independently related to ECG left ventricular hypertrophy
type 1 diabetes: prevalence and
association with coronary heart
after adjustment for age, sex, and diabetes duration were
relation to coronary heart disease
disease (CHD), microvascular
CHD, QTc, SBP, triglycerides, and waist to hip ratio.
and cardiovascular risk factors:
complications, QTc, and QTd
the Eurodiab IDDM
was assessed in 3,250 type 1
Complications Study. Diabetes
European diabetic subjects.
Care 28:2255-2257, 2005. (27)
Senior et al. Coronary artery
CAD prevalence was determined
CAD was associated with age, diabetes duration,
Reference / Study
Study population / hypothesis
Results
disease is common in nonuremic,
by ECG stress testing and
hypertension, and smoking. Although specific, ECG stress
asymptomatic Type1 Diabetic
myocardial perfusion imaging in
testing and myocardial perfusion imaging were not sensitive
islet transplant candidates.
60 consecutive type 1 diabetic
as correlates of CAD on angiography (specificity 0.97 and
Diabetes Care 28:866-872, 2005.
islet transplant candidates
0.93, sensitivity 0.17 and 0.04, respectively) but helped
(62)
(average age 46 years, 23 men,
identify 2/3 subjects requiring revascularization.
and 47% ever smokers).
Other studies
Haller et al. Radial artery
Radial artery tonometry was
Heart rate corrected augmentation index was increased in type
tonometry demonstrates arterial
performed in 98 children with
1 diabetes suggesting arterial stiffness.
stiffness in children with type 1
type 1 diabetes and 57 controls.
diabetes. Diabetes Care 27:29112917, 2004. (151)
Reference / Study
Study population / hypothesis
Results
Sundell et al. Lifetime glycaemic
The effect of lifetime glycemic
Hyperemic myocardial blood flow was inversely associated
exposure predicts reduced
exposure on coronary
with log HbA1c months both in the fasting state (r = -0.70,
coronary vasoreactivity in Type 1
vasoreactivity was examined in
p<0.05) and during clamp (r = -0.35, p<0.05) adjusting for
diabetic subjects. Diabet Med.
43 otherwise healthy type 1
lipids, blood pressures, sex, smoking, body mass index and
22:45-51, 2005. (152)
diabetic subjects.
age. However, no significant correlation was detected
between hyperemic flow and HbA1c or plasma glucose values
measured immediately preceding the PET study.
Table 3. Coronary artery calcification in type 1 diabetes – the C3T1 pooled dataset
Males
Diabetes
Control
Females
Overall
Diabetes
Control
Diabetes
Control
Mean (SD) CAC score (Agatston) in those with any calcification
Age (yrs)
20-29
5.1 (7.9)
4.5 (8.3)
27.7 (97.4)
4.1 (2.2)
15.0 (64.7)
4.4 (6.9)
30-39
68.4 (165.6)
24.5 (83.1)
62.8 (103.6)
6.0 (11.8)
66.0 (142.2)
19.9 (72.7)
>40
285.1 (548.1)
94.5 (249.8)
306.6 (446.6)
20.3 (45.5)
294.9 (503.8)
75.3 (218.5)
21.1% (19)
16.7 (9)
12.5% (15)
4.7 (4)
16.2% (34)
9.3 (13)
Prevalence of any CAC (>0)
Age (yrs)
20-29
Males
Females
Overall
Diabetes
Control
Diabetes
Control
Diabetes
Control
30-39
39.2% (96)
31.5 (64)
26.9% (71)
10.7 (21)
32.8% (167)
21.3 (85)
>40
72.0% (154)
57.5 (126)
57.7% (128)
21.4 (44)
64.7% (282)
40.0 (170)
<20
32.5% (55)
Not applicable
16.4% (32)
Not applicable
23.9% (87)
Not applicable
20-29
42.5% (94)
32.2% (76)
37.2% (170)
30-39
72.2% (91)
55.0% (77)
63.2% (168)
>40
87.9% (29)
82.9% (29)
85.3% (58)
Diabetes duration (yrs)
Age and diabetes duration (yrs)
Age 20-34 yrs
Diabetes duration <20 yrs
24.0% (25)
Diabetes duration >20 yrs
30.0% (30)
Age >35 yrs
Not applicable
11.6% (17)
23.4% (29)
Not applicable
16.8% (42)
26.3% (59)
Not applicable
Males
Females
Overall
Diabetes
Control
Diabetes
Control
Diabetes
Control
Diabetes duration <20 yrs
46.2% (30)
Not applicable
30.6% (15)
Not applicable
39.5% (45)
Not applicable
Diabetes duration >20 yrs
65.7% (184)
53.3% (153)
59.4% (337)
Table 4. Predictors of coronary artery disease (CAD) in type 1 diabetes (prospective cohort studies)
Study
Population
Multivariable predictors
Comments
Lehto et al. Arterioscler
177 patients with type 1
By follow-up, 20 (11.3%) patients died of
Thromb Vasc Biol. 19:1014-
diabetes (87 men and 90
CHD and 28 (15.8%) had a serious CHD
1019, 1999. (42)
women) without
event. A previous history of MI (HR 8.0,
nephropathy, age 45 to 64
p<0.001), high HbA1 (>10.4%, the highest
years at baseline and >30
tertile, HR 5.4, p=0.01), and diabetes
years at the time of diabetes
duration (>16 years, the highest tertile, HR
diagnosis were followed for
4.2, p=0.01) were associated with CHD
7 years.
death and incidence of all CHD events.
The Pittsburgh
A cohort of 603 individuals
Blood pressure, lipid levels, inflammatory
Subjects were diagnosed
Epidemiology of Diabetes
with childhood onset (<17
markers, renal disease, and peripheral
with type 1 diabetes (or
Complications (EDC) study
years of age) type 1 diabetes
vascular disease showed a positive gradient
seen within 1 year of
Study
Population
Multivariable predictors
Comments
(Orchard et al. Diabetes
diagnosed between 1950 and
across the groups of no CAD, angina, and
diagnosis) at the
Care 26:1374-1379, 2003.)
1980 were followed from
hard CAD, whereas estimated glucose
Children’s Hospital of
(6)
1986 to 1998. At study
disposal rate (eGDR) and physical activity
Pittsburgh.
entry, mean age was 28 years showed inverse associations (all p-values
and mean diabetes duration
for trend <0.01). Moreover, depressive
was 19 years. A total of 108
symptomatology predicted angina (p=0.02),
CAD events occurred during
whereas HbA1 showed no association with
follow-up.
subsequent CAD.
The EURODIAB
A clinic-based cohort of
Independent predictors of CHD included
Type 1 diabetes was
Prospective Complications
2329 type 1 diabetes patients
age (hazard ratio 1.5), albumin excretion
defined as diabetes
Study (Soedamah-Muthu et
aged between 15-60 years
rate (1.3 in men and 1.6 in women), waist to
diagnosed prior to 36
al. Diabetes Care 27:530-
were recruited from 27
hip ratio (1.3 in men), smoking (1.5 in
years of age with a
537, 2004) (7)
centers in 16 European
men), triglycerides (1.3 in women) or HDL
continuous need for
countries and were followed
cholesterol (0.74 in women), and systolic
insulin within the first
Study
Population
Multivariable predictors
Comments
for 7 years. At study entry,
blood pressure (1.3 in women). HbA1
year of diagnosis.
mean age was 33 and mean
univariately predicted CHD in men (but not
diabetes duration 15 years.
multivariably) and did not predict CHD in
During follow-up, 151
women at all.
patients developed coronary
heart disease (CHD).
Wisconsin Epidemiologic
Persons with type 1 diabetes
The 20-year age-adjusted cumulative
Study of Diabetic
who were receiving care in
incidences were 18.1% for angina, 14.8%
Retinopathy (Klein et al.
11 counties in Wisconsin
for myocardial infarction (MI), and 5.9%
Arch Intern Med. 164:1917-
(n=996) were examined at
for stroke. Severity of diabetic retinopathy
1924, 2004) (28)
baseline (1980-1982), and 4,
was associated with angina and stroke.
10, 14, and 20 years later.
Arteriovenous ratio was associated with MI.
Of 273 deaths, 176 involved heart disease.
The severity of retinopathy and
Study
Population
Multivariable predictors
arteriovenous ratio was associated with
heart disease mortality. Nephropathy was
more informative about the cardiovascular
end points than were the blood vessel
characteristics. HbA1 was a significant
predictor for stroke incidence only.
Comments
Table 5. Morphological studies of Coronary Artery Disease in Diabetes
Reference
Number of
Population
Findings
Subjects with carotid artery
Risk for carotid plaques
Circulation
plaques not diagnosed with
increases continuously with
110:466-470, 2004
diabetes
increasing HbA1c. HbA1c
subjects
(total /
diabetic)
Jorgensen et al.
5960/0
(153)
is positively related to risk
of hard but not soft plaques.
Burke et al.
122/66
Sudden coronary deaths
Diabetic atherosclerotic
Arterioscler
with acute thrombic or
plaques have higher
Thromb Vasc Biol.
severe atherosclerosis
inflammatory cell infiltrate.
24:1266-1271,
postmortem study.
2004 (54)
Moreno et al.
95/47
Diabetic patients who had
Number of vessels with
Circulation
directional coronary
>50% lesion and the
102:2180-2184,
atherectomy for acute
percentage of total area with
2000 (52)
ischemic event compared to
lipid-rich plaque was
Reference
Number of
Population
Findings
matched controls without
greater for those with
diabetes.
diabetes. Diabetes is
subjects
(total /
diabetic)
associated with more
macrophage content in
plaques (did not differ
among diabetics receiving
different treatment: insulin,
sulphonylureas, diet).
Gyongyosi et al.
Patients with new onset of
Diabetes associated with
Coron Artery Dis.
severe/accelerated angina,
significantly greater target
10:211-219, 1999
angina at rest or angina
plaque and EEM CSA.
(154)
within 2 weeks of acute MI
Differences in constrictive
undergoing angiography
remodeling; though higher
and IVUS.
in diabetes - NS.
Patients with chronic
Those with insulin treated
Am J Cardiol.
anginal syndrome and de
diabetes had less reference
81:1298-1304,
novo native coronary
and stenosis plaque, and
Kornowski et al.
60/13
827/120
Reference
Number of
Population
Findings
stenosis, undergoing
smaller reference and
angiography and IVUS.
stenosis arterial areas than
subjects
(total /
diabetic)
1998 (47)
those with diabetes not
treated with insulin.
Impaired remodeling of
arterial shrinkage.
Henry et al. Am
820/115
Patients with and without
Diabetes is an independent
Heart J. 134:1037-
diabetes who underwent
risk factor for moderate (but
1043, 1997 (155)
coronary angiography.
not severe) stenosis, and
also for , more distal and
triple vessel disease
Cipollone et al.
Circulation
60/30
Patients undergoing carotid
RAGE overexpression,
atherectomy
enhanced inflammatory
108:1070-1077,
reaction and COX-
2003 (53)
2/mPGES-1 expression in
Type 2 diabetes samples
Reference
Number of
Population
Findings
Patients undergoing
Hypercholesterolemia has
Circ J. 61:390-395,
coronary angiography with
greater influence on
1997 (48)
only one of the following
severity of coronary artery
risk factors: Diabetes,
lesions than hypertension
Hypertension,
and diabetes. Diabetes
Hypercholesterolemia.
associated with fewer short
subjects
(total /
diabetic)
Kasaoka et al. Jpn
204/24
eccentric lesions but more
'tubular regular' lesions.
Burke et al. N Eng
113/???
J Med. 336:1276-
Men with coronary disease
Glycosylated hemoglobin
who died suddenly.
not significantly associated
1282, 1997 (140)
with acute thrombosis nor
plaque rupture.
Calton et al. Indian 75/75
Type 2 & non-diabetic
Those with type 2 diabetes
Heart J. 47:343-
patients with CAD
had more severe coronary
348, 1995 (46)
artery disease than did nondiabetics, and more
concentric stenosis.
Reference
Number of
Population
Findings
subjects
(total /
diabetic)
Females with type 2
diabetes had more severe
and more diffuse disease
than did males, but type 2
diabetes did not overall
have greater diffuse disease.
Spagnoli et al.
Patients affected by
Fibrous plaque, increased
Atherosclerosis
transient ischemic attacks
connective tissue, few foam
108:39-60, 1994
(TIA) or by stroke, with
cells and rare thrombosis
(156)
angiographic stenosis >50%
correlated with diabetes.
Deceased people who had
Plaques in those with type 1
type 1 diabetes
are comprised mostly (91%)
Mautner et al. Am
J Cardiol. 70:12641268, 1992 (157)
180/56
8/8
of fibrous tissue
(significantly more so than
older patients and young
females with fatal CAD).
Table 6. Why are the cardiovascular results of DCCT / EDIC so different from the
Epidemiologic studies?
Reasons for discrepancy between the results of DCCT / EDIC and Epidemiologic findings

Epidemiologic studies are simply wrong
o Positive studies; Finnish older onset without nephropathy, carotid IMT, IVUS,
LV and endothelial function

Population differences
o Duration (shorter in DCCT / EDIC)
o CVD risk status (lower in DCCT / EDIC)

Level of glycemic control achieved (better in DCCT / EDIC)

DCCT / EDIC effect due partly to other risk factors (? LDLc and triglycerides)

Two types of CAD in Type 1 Diabetes (renal / insulin resistance and glycemia
susceptibility)
Table 7. The association studies of CAD candidate genes in type 1 diabetes
Reference
Gene name/ polymorphism
Gene locus
Genetic
Phenotype
variant
Pettersson-Fernholm et al. (96)
RAGE
6p21.3
-374AA
Lower frequency of CAD, MI
17q23
II ACE
Lower frequency of CHD
T(-374)A
van Ittersum et al. (104)
ACE
Insertion/Deletion
Hokanson et al. (111)
Hepatic lipase
Genotype
15q21
T allele
11q23
360His allele
Higher proportion of CAC
LIPC-480C/T
Kretowski et al. (120)
ApolipoproteinA-IV
Gln360His
Pettersson-Fernholm et al. (107)
NPY
Higher risk of CAC
progression
7p15.1
Pro7
12p12-pter
789A1a
High frequency of CAD
Leu7Pro
Lacquemant et al. (122)
VonWillebrand factor
Thr789Ala
Higher risk of CHD
Table 8. Coronary Artery Disease Prevention and Screening Guidelines in Type 1 Diabetes Mellitus
ADA 2006 (129)

AHA 2002/3
Prevention Conference VI: Diabetes and
Limited clear direction for type 1 diabetes
adults, e.g. for Lipids “Although the data are
not definitive, consideration should be given
Cardiovascular Disease (130)

for similar lipid lowering therapy in type 1
diabetic patients as in type 2, particularly if


Endorse <100 mg/dl LDL goal for children
and adolescents with type 1 diabetes.

Though generally those with diabetes are
they have other cardiovascular risk factors or
considered at maximum risk, “...there may
features of the metabolic syndrome”.
be special considerations, such as patients
Advocate ACE use if any degree of
with type 1 diabetes…, in whom
albuminuria irrespective of BP in type 1
noninvasive testing would be useful for
diabetes.
making management decisions.”
Aspirin therapy >40 years. Consider aspirin
therapy in those 30-40 years if other risk
factors. No aspirin <21 years (Reye’s
syndrome).

AHA Scientific Statement: Guidelines for Primary
Prevention of Atherosclerotic Cardiovascular
Disease Beginning in Childhood (131)
For children and adolescents screen for lipids
at 12 years or earlier if family history of

3 baseline measures
hypercholesterolemia or early CVD (<55

MNT including soluble fiber (5-10 gm +
years); drug therapy if MNT fails to lower
LDL <160 mg/dl, or <130 mg/dl if adverse
age up to age 15 years)

Though goal is LDLc < 100 mg/dl (as
CVD risk profile. Goal LDL<100 mg/dl.
opposed to 160 mg/dl in general), drug
BP treated with drugs if >95 pc (or 130/80
initiation level is still 160 mg/dl.
which ever is lower).

Routine screening for CAD in diabetes is not
clearly recommended as “…there are no
evidence-based guidelines for screening the
asymptomatic diabetic patient for CAD”.