The SA Journal Diabetes & Vascular Disease Vol 11 No 4 (November 2014)

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VOLUME 11 NUMBER 4 • NOVEMBER 2014 157
SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW
well established following the development of the thiazolidinediones
pioglitazone and rosiglitazone, and the PPAR-α agonists such
as fibrates have been shown to decrease TG levels, increase
HDL levels and reduce LDL levels.43,106 Efforts have been made to
combine these effects in a dual PPAR-α/γ agonist to effectively
manage both glycaemic control and dyslipidaemia. However,
several attempts to develop a dual PPAR agonist for diabetes have
as yet been unsuccessful due to various safety concerns, including
renal dysfunction,107 bladder cancer, 108 and an increase in mortality
and cardiovascular events.109 The latest dual PPAR-α/γ agonist in
development was aleglitazar, which had been shown to decrease
TG and LDL levels, and raise HDL levels alongside insulin-sensitising
properties.110 However following an interim routine safety review the
phase III ALECARDIO study was terminated due to safety concerns
and a lack of efficacy.111 It is expected that this will spell the end
of development of this class of molecules, however a selective
PPAR-α modulator (SPPARM-α) known as K-877 remains under
development and has been shown to have a more potent effect on
triglycerides and HDL cholesterol levels than fibrates with a reduced
risk of adverse events. K-877 is currently in the early stage of clinical
development, but if successful has the potential to supersede
fibrates in the treatment of atherogenic dyslipidaemia.112
Conclusions
Despite impressive advances in its treatment, CVD remains a sig-
nificant healthcare burden in the UK and worldwide. The clustering of
cardiovascular risk factors often seen in patients with type 2 diabetes
underlines the necessity of our current multifactorial treatment
approach, yet even when receiving optimal therapy according to
best standards of care, there remains a substantial residual risk
of CVD and microvascular disease in this population. The move from
10-year to lifetime cardiovascular risk calculators should encourage
intervention to reduce cardiovascular risk at a much earlier stage, and
its proposal alongside aggressive and broad control of modifiable
risk factors aims to ease the burden of atherosclerosis prior to
the manifestations of CVD. This approach will be of particular
benefit to patients with type 2 diabetes, who have been exposed
to hyperglycaemia and other risk factors for several years prior to
diagnosis and consequently have developed complications pre
diagnosis. The atherogenic dyslipidaemia common in this patient
group also ensures they will benefit most from existing or novel
treatment strategies currently under investigation to potentially
further reduce residual cardiovascular and microvascular risk.
Conflict of interest None
Funding sources None
Acknowledgements Editorial and writing assistance was pro-
vided by Robert Kingston of Virgo HEALTH Education, with financial
support provided by F Hoffman-La Roche. AR retains full editorial
control over the content of the article, with the sponsor reviewing
it for scientific accuracy only.
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