Current Health Sciences Journal Vol. 35, No. 2, 2009 [628190]

Current Health Sciences Journal Vol. 35, No. 2, 2009
Review
Statins Therapy, C-Reactive Protein ( CRP )
Levels and Type 2 Diabetes
FLORIANA ELVIRA IONICĂ(1), MARIA MOȚA(2), CĂTĂLINA PISOSCHI(1),
FLORICA POPESCU(1), ELIZA GOFIȚĂ(1)
(1)Faculty of Farmacy, University of Medicine and Pharmacy. Craiova; (2)Faculty of Pharmacy,
University of Medicine and Pharmacy. Craiova
ABSTRACT Purpose: The effectiveness of therapy with hydroxymethylglutaryl -coenzyme A (HMG -CoA)
reductase inhibitors, or statins, for reducing elevated C -reactive protein (CRP) levels and cardiovasc ular risk at
patient with type 2 diabetes. Atherosclerotic plaque growth may be attenuated with therapy aimed at minimizing
inflammation. CRP is considered to be a major inflammatory cytokine that functions as a non-specific defense
mechanism in response t o tissue injury or infection. Synthesized mainly in the liver, CRP activity is stimulated by
other cytokines, especially interleukin (IL) -6, IL -1b, and tumor necrosis factor -a (TNF -a). CRP binds to a variety of
molecules, particularly liposomes and lipoproteins, such as LDL and VLDL cholesterol, and is a powerful activator of
the classic complement way. Accumulating evidence suggests that CRP, which is also found within macrophages of
atherosclerotic plaques, is causally or mechanistically related to atherothrombosis. Inflammation plays an important
role in the pathogenesis of type 2 diabetes. Because increased levels of CRP have been associated with arterial -wall
inflammation, statins can prevent ischemia by both inhibiting deposition of lipids and decreasi ng inflammation.
Conclusions : Inflammation underlies diabetes and may predict it. The role of lowering CRP in reducing the risk for
and improving the prognosis of diabetes is undergoing assessment. The lowering of elevated CRP levels by statins
may reduce the risk of cardiovascular events independently of the effect of statins on lipid levels. The results of
ongoing clinical trials will continue to provide data on the additive value of testing levels of CRP and other
inflammatory markers for cardiovascular risk assessment and should delineate the clinical utility of such testing in
various disease states.
KEY WORDS statins, C -reactive protein, diabetes type 2, cardiovascular risk
Introduction
Despite advances in the detection of risk
factors, cardiovascular events continues to affect
many patients worldwide. The National
Cholesterol Education Program (NCEP)
developed guidelines for the treatment of high
blood cholesterol in adult patients, known as the
Adult Treatment Panel III (ATP III) Guidelines.
The maj or emphasis of the ATP III Guidelines is
the primary prevention of CHD in at -risk patients
by lowering levels of low -density -lipoprotein
(LDL) cholesterol.[1] While it is crucial to achieve
lipid goals, it is important to realize that half of all acute myo cardial infarctions (MI) occur in
patients with normal lipid levels.
[2,3] Considering
that treatment of LDL cholesterol, high -density –
lipoprotein (HDL) cholesterol, and triglycerides to
goal levels only partially reduces CHD risk, the
risk of CHD complicat ions stemming from acute
and chronic inflammatory processes must be
quantified.
A growing database[12,13] reinforces the concept
that inflammation also plays an important role in
the pathogenesis of type 2 diabetes and links diabetes with concomitant cond itions with
inflammatory components.[14] Evidence exists for
the prior linkage of euglycemic insulin resistance
as a proinflammatory state that may have existed
for years before the occurrence of type 2
diabetes.[15]
Atherosclerosis is a complex disease no t solely
dependent on the accumulation of lipids in vessel
walls. Lipid deposition, along with macrophage
infiltration and creation, promotes an
inflammatory response marked by increased levels
of C-reactive protein (CRP).[4] A nonrandomized
cohort of pati ents with CHD showed that
hydroxymethylglutaryl -coenzyme A (HMG-CoA)
reductase inhibitors (statins) decreased plasma
levels of CRP.[5] This effect is primarily observed
in patients with elevated CRP levels. Elevated
levels of CRP have been shown to be a st rong
predictor of future cardiovascular events, perhaps
even stronger than LDL cholesterol levels.[6]
Modest elevations of CRP can be found even
in apparently healthy people.[7] A progressive rise
in CRP can reflect augmented stages of vascular
Asist. univ. drd. Floriana Ionică, Dept of Toxicology , Fac. of Pharmacy, Univ . of Medicine and Pharmacy. Craiova 87

Floriana Elvira Ionică and colab: Statins therapy, C -reactive protein (CRP) levels and type 2 diabetes
inflammatio n, but the specific clinical conditions
under which this occurs are incompletely
understood.
Although LDL cholesterol remains a major risk
component for cardiovascular disease, at least one-third of coronary events occur in individuals
with LDL levels < 13 0 mg/dl,12 which is
generally considered an average level in individuals without overt coronary artery disease.
Evaluation of CRP levels under those clinical
conditions may be very helpful in risk
stratification. Reports that CRP levels are elevated
during acute cardiovascular and cerebrovascular
events suggest that CRP has value in predicting
the subsequent occurrence of such events.
[8,9]
Most of the benefit ascribed to statins derives
from the reduction of cardiovascular mortality
because of well -document ed reductions in LDL
cholesterol levels. Obtained data suggest that
statins reduce inflammation and may affect CRP
levels.[3,10] Considered a modifiable risk factor,
CRP is an inflammatory marker that can indicate the presence of active vascular inflammati on and
atherosclerosis and may be decreased with statin therapy.
[4] CRP levels have been shown to remain
constant over long periods of time and exhibit no
diurnal variation, suggesting that CRP may be a
reliable predictor of cardiovascular risk.[6] This
statin-mediated reduction of CRP levels is
independent of the drug's lipid-lowering effects.[11]
In addition, many clinical trials have explored the association of statin -induced reduction of CRP
levels and whether this reduction decreases CHD
endpoints, suc h as fatal and nonfatal MI.
The purpose of this review is to discuss clinical
trials evaluating the effectiveness of statin therapy
for reducing elevated CRP levels and associated
cardiovascular events. A literature search was
completed using MEDLINE (1999, 2007) and
EMBASE using the following search terms: C –
reactive protein, statin or HMG-CoA reductase
inhibitors, diabetes type 2, cardiovascular events.
References used in the primary literature were
reviewed to identify additional articles.
Role of statin s
Because of the high numbers of mortalities due
to cardiovascular diseases, primary prevention is
of the utmost importance.
The major aim of statin therapy has been to
decrease lipid deposition in the arterial walls.
Statins prevent the intracellular prod uction of
cholesterol in hepatocytes by blocking the rate –
limiting step in cholesterol synthesis.[16,17] HMG-
CoA reductase inhibitors upregulate receptors in
the liver, which enhances the removal of LDL cholesterol from the plasma. It has been demonstrated that statins have an effect on
markers of inflammation, including CRP,
independent of their lipid-lowering effect.
[17]
Atherosclerotic plaque growth may be
attenuated with therapy aimed at minimizing
inflammation.[11] Because increased levels of CRP
have been associated with arterial -wall
inflammation, the reduction in CRP levels may
reduce the extent of endothelial -cell opsonization,
macrophage recruitment, and blunting of nitric
oxide release. Prevention of vasoconstriction by
attenuating the proinflamm atory process and
preserving vasodilation may allow sufficient
perfusion to prevent myocardial ischemia. Further
research is needed to determine the extent to
which CRP contributes to the inflammatory
process. The use of statins may prevent ischemia
by bot h inhibiting deposition of lipids and
decreasing inflammation.[11] Several trials have
been aimed at developing a correlation between
statin -induced reductions in CRP and a subsequent
decline in coronary events.[3,10]
CRP and diabetes type 2
It has been suggested that low grade
inflammation may play a role in the development
of type 2 diabetes.[12] Patients with type 2 diabetes
had increased levels of hsCRP.[18,19] High hsCRP
levels were found to be a independent predictor of
risk for the development of ty pe 2 diabetes.[20,22] In
the Women's Health Study[14] and the West of
Scotland Coronary Prevention Study
(WOSCOPS),[23] patients with the highest levels
of hsCRP were at a much higher risk of
developing diabetes. Interleukin-6 was also found
to be a predictor of who would develop type 2
diabetes and increasing levels of hsCRP and IL -6
were associated with insulin resistance.[14]
Elevated levels of hsCRP and plasminogen-
activator inhibitor (PAI) have been demonstrated
to predict the incidence of type 2 diabe tes in the
IRAS.[12] Abdominal obesity and the subsequent
secretion of pro -inflammatory cytokines and acute
phase reactants may contribute to the relationship between chronic inflammation and type 2
diabetes. Adipocytes are 1 of many cells that
secrete IL -6 and the amount of IL -6 produced by
adipocytes is proportional to the amount of fat cell mass. Interleukin -6 is the main stimulus for
hepatic CRP production, and adipocytes supply approximately 33% of systemic IL -6.
[14]
Therefore, increased cytokine production by adipocytes in obese people may be the stimulus
for increased CRP production. In support of a
connection between obsesity and chronic
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Current Health Sciences Journal Vol. 35, No. 2, 2009
inflammation, IL-6 and hsCRP levels decreased in
obese, post -menopausal women after 6 months of
weight loss.[24] Increased glucose utilization and
insulin sensitivity were also apparent in these women after the 6 months.
Much evidence exists that inflammatory
mechanisms play a major role in the cascade of
events that results in rupture of atherosclerotic
plaque. Upreg ulation of receptors for advanced
glycation end products has been associated with
enhanced inflammatory reactions. Increased
expression of these receptors has been found to be
associated with impaired glycemic control and
may be a contributory factor in the complex array
of mechanisms that leads to accelerated
atherosclerosis in patients with diabetes.
[25]
In a national survey study, respondents with
hemoglobin A1c (A1C) levels ≥ 9% had a
significantly higher rate of elevated CRP than
those with A1C levels < 7%. This suggests an
association between diminished glycemic control
and systemic inflammation in people with
established diabetes.[26]
In a nested case- control study carried out as
part of the Women’s Health Study among initially
nondiabetic participant s who developed diabetes
over the course of the study, median baseline
levels of IL -6 and CRP were significantly higher
among case than among control subjects (P<0.001), and increasing levels of both markers
were associated with a higher risk of developing
diabetes.
[14] In this study, increased CRP levels
predicted the new onset of diabetes even after adjustment for obesity, coronary risk factors, and fasting insulin levels.
Clinical Trials
Evaluation of recent clinical trials, including
WOSCOPS, PRINCE, AFCAPS/ TexCAPS, MIRACL, CURVES, REVERSAL, and JUPITER,
demonstrated the correlation of statin therapy with
decreased levels of CRP. WOSCOPS found that
patients with CRP values of >4.59 mg/L at
baseline were at the highest risk of acute
cardiovascular events.
The PRINCE trial evaluated the
antiinflammatory effects of pravastatin and found
a mean 16.9% reduction in CRP levels after 24
weeks of therapy.
[27]
AFCAPS/TexCAPS researchers found that
lovastatin provided a 14.8% reduction in the
median levels of CRP ( p < 0.001).[28]
The MIRACL study showed that atorvastatin
reduced CRP levels by 83% ( p < 0.001).
Researchers in the CURVES study found a significant reduction in CRP levels with pravastatin, simvastatin, and atorvastatin compared with baseline ( p < 0.025) .
[29]
Results of the REVERSAL study linked
atorvastatin with a 36.4% decrease in CRP levels,
while pravastatin was associated with a 5.2%
decrease ( p < 0.0001).[31]
JUPITER is ongoing and will determine
whether long -term use of rosuvastatin can reduce
the rate of coronary events. In addition, JUPITER
investigators will evaluate the safety of long -term
rosuvastatin use in terms of total mortality, mortality unrelated to cardiovascular events, and adverse events from therapy and to determine
whether rosuvastatin reduces the frequency of
type 2 diabetes mellitus.
At the end of the study, researchers hope to
answer critical questions regarding treatment for
patients without overt hyperlipidemia but with
elevated risk for cardiovascular events, indicated
by inc reased CRP levels. A strong positive finding
from JUPITER would advocate the broader use of
statins for cardiovascular and antiinflammatory
benefits independent of lipid-lowering effects, risk reduction, even in patients who do not require the
lipid-loweri ng effects of statins.
[10]
Discussion
Strategies that target obesity and insulin
resistance, when found to be effective, may
ameliorate both endothelial dys function and low –
grade inflammation and have the theoretical
potential to decelerate or prevent the occurrence of
type 2 diabetes and card iovascular disease.[30]
Pharmacological and lifestyle interventions may
reduce both the risk for CHD and levels of CRP, if
elevated. Results of recent studies also suggest a
potential association between lower CRP levels and improved clinical outcomes with statin
therapy.
[31,32]
Approximately half of all coronary events
occur in patients without overt hyperlipidemia.[3]
Large proportions of first cardiovascular events have occurred in patients whose LDL cholesterol
levels were below the current NCEP guidelines for
intervention and treatment.
[1,6] According to NCEP
guidelines, patients without multiple risk factors
should be treated if their LDL cholesterol
concentration is over 160 mg/dL, while patients
with multiple risk factors should receive treatment
if their LDL cholesterol concentration is more
than 130 mg/dL.[1] In patients who do not qualify
for statin therapy based on these guidelines, other
methods should be used to assess their
cardiovascular risk. It is clear that the interactions
of novel biological markers, such as CRP, and
other known risk factors may contribute to the
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Floriana Elvira Ionică and colab: Statins therapy, C -reactive protein (CRP) levels and type 2 diabetes
occurrence of cardiovascular events. Screening for
CRP levels in patients without traditional risk
factors may identify a cohort of patients who
would benefit from the antiinflammatory effects
of statins.[6] Due to the high rate of cardiovascular
disorders, many patients are prescribed statins to manage their lipid abnormalities. In addition to
their lipid -lowering effects, statins reduce plas ma
levels of CRP, a soluble marker of inflammation.
The screening of patients with elevated CRP
levels may identify patients who have an increased
risk for cardiovascular events but would not
ordinarily qualify for treatment with a statin under current gui delines. Statin treatment in patients
with elevated CRP levels but normal to mildly
elevated LDL cholesterol values is currently under
investigation. The study population in JUPITER is unique because these patients are not otherwise
indicated for lipid -lowering therapy because their
LDL cholesterol levels are within normal limits.
[1]
In addition, the use of CRP levels as a predictor of cardiovascular events is not well defined for
patients who already qualify for statin treatment
because of elevated cholest erol levels. Further
investigation is warranted to clarify the utility of
routine CRP measurements and statin therapy in
these patient populations.
Conclusions
Inflammation underlies diabetes and may
predict it. The role of lowering CRP in reducing
the ri sk for and improving the prognosis of
diabetes is undergoing assessment.
The lowering of elevated CRP levels by statins
may reduce the risk of cardiovascular events
independently of the effect of statins on lipid
levels.
The results of ongoing clinical tri als will
continue to provide data on the additive value of testing levels of CRP and other inflammatory
markers for cardiovascular risk assessment and should delineate the clinical utility of such testing
in various disease states.
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Corresponding Adres s: Asist. univ. drd. Floriana Ionică, Dept of Toxicology Faculty of Farmacy, University
of Medicine and Pharmacy. Craiova, E -mail: floriana_umf@yahoo.com
91