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VOLUME 11 NUMBER 4 • NOVEMBER 2014
155
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
this approach may give individuals a false sense of security that
they are at low risk for CHD when in fact their lifetime risk is high.
52
Indeed, studies from the USA have shown that around 50% of the
population are classified as having a low 10-year risk but a high
lifetime risk of CVD.
53,54
Those with a low 10-year but high lifetime
risk have greater subclinical disease burden and greater incidence
of atherosclerotic plaque progression (measured by techniques such
as carotid intima–media thickness) compared with individuals with
a low 10-year and low lifetime risk, even at younger ages.
53
However, despite these advantages there are limitations
associated with moving to a lifetime risk metric. In contrast to
data from Lloyd-Jones and colleagues (Fig. 3), a pooled analysis
of over 900 000 person years showed high (> 30%) lifetime risk
estimates for total CVD for all individuals, even those who are
middle-aged with optimal risk factors and without diabetes.
55
In
addition, a comparison of lifetime risk for individuals with diabetes
and stratified by obesity status from the Framingham Heart Study
also showed a lifetime risk of CVD among normal-weight men and
women with diabetes of 78.6 and 54.8%, respectively, increasing
to 86.9 and 78.8% among those who were obese.
56
These data
must be considered when attempting to define the level at which a
patient is considered to be at a high lifetime risk of CVD, particularly
in those with type 2 diabetes, given its increasing prevalence in
young adults. There will also be a significant cost impact associated
with developing CVD management strategies based on lifetime
risk due to both earlier intervention and the potential for a large
increase in the number of patients considered at risk.
In patients with type 2 diabetes, chronic hyperglycaemia
often precedes diagnosis by several years, causing extensive
vascular damage and leading to the early development of clinical
complications. Up to 50% of patients have diabetic complications
at diagnosis,
57,58
for example nephropathy and retinopathy are
present in approximately 20% of patients.
58,59
These facts provide
an imperative to intervene at an earlier stage in type 2 diabetes.
This is not limited to improving glycaemic control but to address
all modifiable cardiovascular risk factors. Data from patients in
the Systolic Hypertension in Europe Trial showed that immediate
antihypertensive treatment reduced the occurrence of stroke by
28% (
p
= 0.01) and major cardiovascular events by 15% (
p
= 0.03)
compared with delayed treatment.
60
The principle here is that it is
not simply the degree of elevation of a risk factor that is important
but also the duration of time to which the vascular endothelium is
exposed to this insult.
Glycaemic control
There is good evidence that tight glycaemic control improves the
risk of microvascular complications in the patients with diabetes,
but there is no such consensus in relation to macrovascular disease.
Three trials, ACCORD (Action to Control Cardiovascular Risk in
Diabetes),
61
ADVANCE (Action in Diabetes and Vascular Disease:
Preterax
®
and Diamicron
®
Modified-Release Controlled Evaluation)
62
and VADT (Veterans Affairs Diabetes Trial)
63
investigated the effects
of pursuing a more intensive treatment strategy to an HbA
1c
level of
either < 6.5% (ADVANCE) or < 6% (ACCORD and VADT). None of
these trials demonstrated a statistically significant reduction in the
primary combined cardiovascular end points. In the ACCORD study,
there was a 22% increase in total mortality in the intensive therapy
group largely driven by increases in cardiovascular mortality. While
there remains the possibility that this increase in mortality may be
related to hypoglycaemic events, it has been noted that most of
the deaths were among patients with poor glycaemic control who
were not reaching target, there has been no consensus reached as
to the precise cause.
However, a meta-analysis of five studies and over 30 000 patients
included data from all three of these studies and found that a more
intensive treatment strategy was associated with a significant
reduction of incident cardiovascular events and MI [OR 0.89 (0.83–
0.95) and 0.86 (0.78–0.93) respectively]. Similar reductions were
not, however, found for either stroke or cardiovascular mortality
[OR 0.93 (0.81–1.07) and 0.98 (0.77–1.23) respectively].
64
Longer
term macrovascular benefits also became evident in the 10-year
follow up of the UKPDS as more events occurred, with reductions
in the risk of MI and death from any cause in both the sulfonylurea-
insulin [RR 0.85 (0.74–0.97) and 0.87 (0.79–0.96) respectively]
and metformin groups [RR 0.67 (0.51–0.89) and 0.73 (0.59–0.89)
respectively].
65
Nevertheless, it is clear that not all patients will benefit
from pursuing an aggressive strategy for glycaemic control.
36
Consequently, the European Association for the Study of Diabetes
(EASD) and American Diabetes Association (ADA) have recently
released a joint position statement emphasising the importance
of individualising glycaemic targets in managing patients with
diabetes.
36
Diabetic dyslipidaemia and cardiovascular risk
Managing dyslipidaemia is an important part of a multifactorial
treatment approach in patients with diabetes, as it is a significant
independent predictor of CHD and mortality.
66
Patients with type
2 diabetes may have a relatively normal total cholesterol level.
However these patients may have an atherogenic dyslipidaemia
characterised by elevated triglycerides (TG), low HDL cholesterol
concentrations and small dense LDL particles.
43,41,67
The formation
of small dense LDL is of particular significance in this population as
these particles have been shown to be the major determinant of
the serum concentration of glycated ApoB.
68
Both small-dense LDL
and glycation of LDL are associated with an increase in susceptibility
to oxidative modification,
69-71
promoting its rapid uptake by
macrophages to create foam cells central to the atherosclerotic
process. In addition, patients often show elevated ApoB (reference
range 55–140 mg/dl in men and 55–125 mg/dl in women) and
non-HDL cholesterol concentrations. The risk associated with
atherogenic dyslipidaemia is uncorrelated with, and additive to,
that of the LDL cholesterol concentration alone.
67
Extensive evidence shows that in diabetic patients, elevated TG,
low HDL cholesterol and ApoB are predictors for macrovascular
complications such as CVD; and this relationship is independent of
LDL cholesterol.
67,72-75
Non-fasting TG levels, measured two to four
hours post-prandially, may be of even greater relevance to CVD
risk since atherogenic lipoprotein remains, secreted by the liver
and intestine after food, circulates in higher concentrations than
when fasting.
76,77
Although LDL cholesterol levels in persons with
diabetes tend not to be higher than those of persons matched for
age, gender and body weight, the LDL particles are more numerous
as they are smaller and more dense (depleted of cholesterol) than
in the general population.
43
As each atherogenic particle such as
LDL carries one molecule of ApoB, the ApoB concentration is often
increased and has been shown as a better predictor for CHD risk
than LDL cholesterol.
67
Non-HDL cholesterol reflects the combined