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VOLUME 11 NUMBER 4 • NOVEMBER 2014
REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
cardiovascular risk of all changes in ApoB-containing lipoproteins in
diabetes, and as such has also been found to be a strong predictor
for cardiovascular risk,
78
particularly in patients with diabetes.
79
The
measurement and use of non-HDL as a therapeutic goal may
therefore be of particular clinical utility in this population.
Dyslipidaemia is also implicated in the pathogenesis of dia-
betic microvascular disease.
80
Elevated levels of total and LDL
cholesterol,
81,82,83
and high TG levels
83
may have causative roles in the
development of retinal hard exudates and diabetic maculopathy.
High TG levels have also been linked with an increased risk for prolif-
erative diabetic retinopathy.
84
The DCCT/EDIC (Diabetes Control and
Complications Trial/Epidemiology of Diabetes Interventions and Com-
plications) study found the severity of retinopathy was positively asso-
ciated with TG and negatively associated with HDL cholesterol levels
in all patients, and with ApoB and LDL levels in men.
85
Data from the
UKPDS showed that elevated TG levels are independently associated
with incident microalbuminaemia (HR: 1.13, 95% CI: 1.07–1.19) and
macroalbuminaemia (HR: 1.19, 95% CI: 1.11–1.27), both markers of
nephropathy.
86
In addition, atherogenic lipid abnormalities have been
implicated in the development of diabetic nephropathy.
87,88
Despite the presence of other lipid abnormalities in atherogenic
dyslipidaemia, there is evidence that reductions in LDL cholesterol
levels with statins are of benefit in patients with type 2 diabetes.
The HPS study investigated the effect on vascular mortality of a
substantial LDL reduction among 5 963 patients with diabetes, and
found that use of simvastatin was associated with a 22% reduction
in the relative risk of vascular events.
89
These results were reflected in
the CARDS (Collaborative Atorvastatin Diabetes Study) study, which
found a rate reduction of 37% for major cardiovascular events in
the atorvastatin group.
90
A meta-analysis of 18 686 patients across
14 statin trials (21.7% of all participants) subsequently confirmed
the benefits of statin treatment, with each 1 mmol/l reduction in LDL
levels associated with a 9% reduction in all-cause mortality, 13%
reduction in vascular mortality, 21% reduction in major vascular
events, 22% reduction in MI or coronary death, 25% reduction in
coronary revascularisation and 21% reduction in stroke.
91
It is clear from extensive large-scale clinical trials that statin
therapy is of benefit for people with diabetes, and should be
considered for all diabetic individuals who are at sufficiently high
risk of cardiovascular events
91
yet, despite reductions in event rates,
a large residual macrovascular risk remains.
89-91
The reasons behind
this excessive residual risk are unknown; however, it is postulated
to be either the result of an underestimate of the benefits of long-
term LDL-lowering strategy as survival and event curves continue
to diverge, or that it is not possible to further reduce risk through
LDL lowering and the excess risk is instead a result of other factors
such as the high TG and low HDL cholesterol levels seen in the
atherogenic dyslipidaemia common in patients with diabetes.
Pharmacological interventions to reduce
cardiovascular risk
The investigation of agents as add-on therapies to statin treatment
to reduce cardiovascular risk may help to determine the cause of
this excess risk, and several clinical trials have investigated, or are
investigating, the use of existing agents such as nicotinic acid, as
well as ongoing trials of novel molecules to treat dyslipidaemia in
high-risk patients.
One of the more significant developments in recent times has
been the undermining of the role of HDL as a suitable therapeutic
target for cardiovascular risk reduction. While the plasma HDL
concentration remains a significant risk predictor and an essential
component of patient diagnosis and risk evaluation, the central role
HDL plays as a causal mediator in atherogenesis has been called
into question.
Large-scale Mendelian randomisation studies of both common
and rare genetic variants that alter HDL concentration
92-95
show no relationship with clinical events, in marked contrast to the
strong and consistent relationship seen with similar genetic variants
affecting LDL concentrations.
54
The strengths and weaknesses of
using studies of this type to determine causal mechanisms have been
debated,
96
however it is argued that, if genetic variants determining
HDL concentrations are not themselves independently associated
with clinical outcomes, then HDL concentration in isolation is
unlikely to be a direct cause of clinical events. Instead, HDL may be
a surrogate marker of other, more fundamentally causal particles.
Recent clinical trials into therapeutic interventions to alter HDL
concentration reinforce these findings. The use of nicotinic acid
as an add-on to statin therapy was investigated in two large-scale
trials, the AIM-HIGH (Atherothrombosis Intervention in Metabolic
Syndrome with Low HDL/High Triglycerides: Impact on Global
Health Outcomes) trial97 and the recently published HPS2-THRIVE
(Heart Protection Study 2 – Treatment of High-Density Lipoprotein
to Reduce the Incidence of Vascular Events).
89,98
Both of these
studies showed that adding nicotinic acid to raise HDL levels had
no impact on clinical outcomes. While the AIM-HIGH trial could be
criticised for being insufficiently powered to detect clinical events,
the results of HPS2-THRIVE are considered more definitive and are
likely to bring to an end the use of niacin as a therapeutic agent to
reduce cardiovascular risk. On a cautionary note, however, it should
be noted that, while AIM-HIGH used an extended-release nicotinic
acid preparation (Niaspan), HPS2-THRIVE used a combination of
extended-release nicotinic acid with laropiprant, an anti-flushing
agent and prostaglandin D-inhibitor. It is assumed that both of
these agents are equivalent, yet there remains the possibility that
off-target effects of laropiprant confounded the results.
Inhibition of cholesterol ester transfer protein (CETP) has been
shown to have the potential to impact on the lipid content and
concentration of all lipoprotein factions, notably with significant
increases in HDL concentration. However the development of
two CETP inhibitors, torcetrapib and dalcetrapib, was terminated
following phase III trials showing, respectively, an increase in total
mortality rate and a lack of clinical efficacy.99,100 The problem
with interpreting these clinical data is that the HDL particle is
considered to have several independent functional characteristics
such as reverse cholesterol transport and an anti-oxidant effect,
and therefore merely measuring the HDL concentration may not be
sufficient without more sophisticated functional assays.
101
Novel molecules in development may provide additional options
for this patient group. Two further CETP inhibitors, anacetrapib and
evacetrapib, are currently in clinical development, and in addition
to their activity to raise HDL levels, also reduce LDL levels over and
above statin therapy.
102,103
The ongoing phase III REVEAL (Randomized
EValuation of the Effects of Anacetrapib Through Lipid-modification)
and ACCELERATE studies will determine whether this class of agents
is able to reduce the risk of major coronary events in patients with
established vascular disease,
104,105
and in light of recent evidence, it
appears unlikely that any additional risk reduction observed will be
able to be attributed to their effect on HDL levels.
The insulin-sensitising properties of peroxisome proliferator-
activated receptor
γ
(PPAR-
γ
) agonists in patients with diabetes are