16-05-2013, 04:19 PM
Niacin and Statin Combination Therapy for Atherosclerosis Regression and Prevention of Cardiovascular Disease Events
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ABSTRACT
Despite substantial risk reductions targeting low-density lipoprotein cholesterol with statins, there remains significant
residual risk as evidenced by incident and recurrent cardiovascular disease (CVD) events among statintreated
patients. Observational studies have shown that low levels of high-density lipoprotein cholesterol (HDL-C)
are associated with increased CVD risk. It remains unclear whether strategies aimed at increasing HDL-C in addition
to background statin therapy will further reduce risk. The AIM-HIGH (Atherothrombosis Intervention in Metabolic
Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial, which compared
combined niacin/simvastatin with simvastatin alone, failed to demonstrate an incremental benefit of niacin
among patients with atherosclerotic CVD and on-treatment low-density lipoprotein cholesterol values 70 mg/dl,
but this study had some limitations. Previously, small randomized, clinical trials of niacin plus statins showed
that modest regression of carotid atherosclerosis is possible in individuals with CVD, CVD risk equivalents, or
atherosclerosis. This viewpoint summarizes these imaging trials studying niacin and places them in the context
of the failure of AIM-HIGH to support the HDL-C–increasing hypothesis.
INTRODUCTION
3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors
(statins) are the standard of care for the management of
dyslipidemia. Although statins provide 25% to 40% reductions
in cardiovascular disease (CVD) risk, there is considerable
residual risk in persons who receive this therapy. Two
mechanistically distinct adjunctive treatment options include
efforts to further reduce low-density lipoprotein cholesterol
(LDL-C) or attempts to increase high-density
lipoprotein cholesterol (HDL-C). Triglyceride lowering
(and, thus, further apolipoprotein B lowering) is also important,
and non–HDL-C is a secondary target goal in the
Adult Treatment Panel III guidelines.
Review of the Niacin RCTs
With Surrogate Endpoints
The ARBITER-2 and -3. ARBITER-2 tested 1,000 mg
extended-release niacin (ERN) versus placebo on top of
background statin therapy on the change in mean common
carotid intima-media thickness (cIMT) measured by
B-mode ultrasound (7). Niacin-treated patients without
insulin resistance experienced reduced cIMT progression
compared with those treated with placebo. Extended out to
24 months in ARBITER-3, combined niacin/statin therapy
conferred cIMT regression (8). Clinical endpoints were few
in ARBITER-2 and not significantly different between
groups.
The HALTS trial. The HALTS trial (9) compared the
effects of 2 adjunctive lipid-lowering medications, ezetimibe
and ERN, added to background statin therapy. At 14
months, assignment to niacin conferred a significant average
reduction of cIMT, whereas the cIMT measurements in the
ezetimibe group were unchanged.
Reconciling Differences
Between the Surrogate Studies
Although the HALTS trial (9) and the Oxford Niaspan
Study (10) suggested niacin conferred more regression of
carotid disease (cIMT or wall area) compared with
ezetimibe or placebo, preliminary data from NIA Plaque
study (11) showed that in an older, generally well-treated
group, the addition of niacin failed to offer incremental
benefit over statin therapy. Differences between the study
results may be due: 1) the site imaged; 2) differences in the
primary outcome; 3) differences in baseline HDL-C values;
or 4) differences in LDL-C achieved on therapy.
Concluding Thoughts
HDL-targeted therapeutics in a post-ILLUMINATE,
post-AIM-HIGH era. ILLUMINATE (14) and AIMHIGH
(12) demonstrated that increasing HDL-C levels
through pharmacotherapy is neither adequate nor necessary
for predicting cardiovascular benefit. Low HDL-C levels
may be simply a marker of risk, given its association with
metabolic syndrome and insulin resistance, and not a causal
factor. If this is the case, a strategy to increase HDL-C
levels via pharmacotherapy may not translate to additional
clinical benefit.
There are other therapeutic agents under investigation
targeting HDL-C (2). Other oral medications include the
CETP inhibitors, niacin receptor (GPR109A) agonists,
liver X receptor agonists, peroxisome proliferator–activated
receptor agonists, and oral apolipoprotein A-I mimetic
peptides. Parenteral approaches include apolipoprotein A-I
(Milano or wild type) phospholipid complexes, apolipoprotein
A-I mimetic peptides, or delipidated autologous HDL.