Evidence of the effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors (statins) within continuum of atherothrombotic conditions and particularly in the treatment
and prevention of coronary heart disease (CHD) is well established. Large-scale, randomized,
prospective trials involving patients with CHD have shown that statins reduce the clinical
consequences of atherosclerosis, including cardiovascular deaths, nonfatal myocardial infarction
and stroke, hospitalization for acute coronary syndrome and heart failure, as well as the need for
coronary revascularization. Direct testing of varying degrees of low-density lipoprotein (LDL)-
cholesterol lowering has now been carried out in 4 large outcomes trials: PROVE IT-TIMI 22, A
to Z, TNT and IDEAL. However, the question whether more aggressive LDL-cholesterol lowering
by high-dose statins monotherapy is an appropriate strategy is still open: higher doses of
statins are more effective mainly for the prevention of the nonfatal cardiovascular events but
such doses are associated with an increase in hepatotoxicity, myopathy and concerns regarding
noncardiovascular death. Moreover, despite the increasing use of statins, a significant number of
coronary events still occur and many such events take place in patients presenting with type 2
diabetes and metabolic syndrome. More and more attention is now being paid to combined
atherogenic dyslipidemia which typically presented in patients with type 2 diabetes and metabolic
syndrome. This mixed dyslipidemia (or ‘lipid quartet’) - hypertriglyceridemia, low highdensity
lipoprotein (HDL)-cholesterol levels, a preponderance of small, dense LDL particles and
an accumulation of cholesterol-rich remnant particles - emerged as the greatest ‘competitor’ of
LDL-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of
the fibrates trials (BIP, HHS, VAHIT and FIELD) give further support to the hypothesis that
patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be
the ones to derive the most benefit from therapy with fibrates. However, different fibrates may
have a somewhat different spectrum of effects. Other lipid-modifying strategies included using
of niacin, ezetimibe, bile acid sequestrants, CETP inhibitors and omega-3 fatty acids.
Particularly, ezetimibe/statins combinations provide superior lipid-modifying benefits compared
with any statins monotherapy in patients with atherogenic dyslipidemia. Atherogenic dyslipidemia
is associated with increased levels of chylomicrons and their remnants containing 3 main
components: apolipoprotein B-48, triglycerides and cholesterol ester of intestinal origin.
Reduction in accessibility for one of them (specifically cholesteryl ester lessening due to ezetimibe
administration) could lead to a decrease of the entire production of chylomicrons and
result in a decrease of the hepatic body triglycerides pool as confirmed in number of clinical
studies. However, the ENHANCE study showed no difference in the progression of carotid
atherosclerosis between ezetimibe/simvastatin vs. simvastatin alone over a 2-year period.
Conclusions regarding ezetimibe/statins combinations should not be made until the three large
clinical outcome trials will be completed within the next 2-3 years. In addition, bezafibrate as a
pan-PPAR activator has clearly demonstrated beneficial pleiotropic effects related to glucose
metabolism, insulin sensitivity and pancreatic beta cell protection. Because fibrates, niacin,
ezetimibe, omega-3 fatty acids and statins each regulate serum lipids by different mechanisms,
combination therapy - selected on the basis of their safety and effectiveness, could be more helpful
in achieving a comprehensive lipid control as compared with statins monotherapy.
Copyright / Drug Dosage
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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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