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Do Statins Have Effects Beyond Lipid-Lowering?
The debate continues as to whether or not statins have effects other than those that lower lipids that may provide additional cardiovascular benefits. An array of proposed pleiotropic effects have been suggested, including anti-inflammatory, antithrombotic, and vascular effects (Slide 1). What do the data suggest at this time in regards to statin therapy and the pleiotropic effects of such therapy?
The Data
Aggressive statin therapy can slow or even halt the progression of atherosclerotic plaques. In the recent REVERSAL trial, for example, high-dose atorvastatin appeared to halt disease progression compared to more moderate lipid lowering (<a href="http://www.cardiosource.com/rapidnewssummaries/index.asp?
EID=22&DoW=Sun&SumID=161#" target="_blank">Slide 2</a>).1 Moreover,
a new study, presented at ACC '06, suggests that high-dose rosuvastatin actually produces plaque regression (Slide 3).2
The plaque stabilization effects of high-dose statin therapy are consistent with the biological effects of statins on inflammation, endothelial function, and coagulation.3 But are the effects explainable by alterations in lipid levels alone or are there other mechanisms contributing to the benefits seen?
In late 2005, an analysis of data from PROVE IT-TIMI 22 showed that intensive therapy using atorvastatin 80 mg was associated with a significant reduction in the composite clinical endpoint of death, myocardial infarction (MI), or rehospitalization for recurrent acute coronary syndrome (ACS) as early as 30 days after the acute event compared with standard-dose pravastatin (40 mg).4 A trend
in favor of intensive therapy was evident at 15 days after randomization (Slide 4). Similar results were reported at about the same time for patients in the ASCOT-LLA study, where there was a trend for benefit from atorvastatin as early as 30 days following randomization, with significant benefits observed at 90 days, 180 days, one year, two years, and then maintained through the termination of the trial (3.3 years).5
These very early benefits of intensive statin therapy are in sharp contrast with the Program on the Surgical Control of Hyperlipidemias (POSCH) trial, in which ileal bypass was associated with a dramatic early reduction in low-density lipoprotein (LDL) cholesterol but no early reduction in clinical events.6 Plus, a number of trials suggest that the apparent benefit from statin therapy is often delayed a year or more.7
What potential mechanisms might explain the
early effects of statin therapy? Statins inhibit HMG-CoA reductase, which is responsible for the reduction in circulating LDL ch
olesterol beginning one to two weeks after therapy initiation. Statins also inhibit HMG-CoA reductase within endothelial cells, vascular smooth muscle cells, and inflammatory cells (the monocyte/macrophage system), which affects important signaling pathways. In cell culture, animal, and clinical studies, these effects appear within hours after statin administration and may be dose dependent.3,8
The PROVE IT-TIMI 22 authors cited median C-reactive protein (CRP) level at 30-days (1.6 mg/l in the atorvastatin group compared with 2.3 mg/l in the standard therapy arm; p<0.001) as supporting greater early anti-inflammatory pleiotropic effects with intensive statin therapy.9,10
Another marker of inflammation was evaluated in the MIRACL trial, which evaluated intensive atorvastatin therapy given early after ACS. Patients in the placebo group with initial levels of
soluble CD40 ligand (sCD40-L) above the 90th percentile had a higher risk of recurrent events compared with patients with sCD40-L concentrations
at or below the 90th percentile. However, the increased risk associated with high initial sCD40-L was completely abrogated by treatment with atorvastatin.
Recent studies have shown that the severity of endothelial dysfunction also relates to cardiovascular risk. A number of interventions, including statins, have been shown to improve endothelial function,11,12 but is this effect just a response to LDL lowering or is it more? Consistent evidence suggests that reduction of plasma LDL improves endothelial function, which has been observed when LDL is lowered by nonpharmacologic means such as diet in animals, and with bile acid resins, plasma apheresis, and statins. Yet there is evidence, too, that pleiotropic effects of statins may be relevant based on reduced cellular concentrations of important and biologically active intermediates that influence endothel
ial phenotype. Statins directly enhance expression, phosphorylation state, and activity of the endothelial isoform of nitric oxide (NO) synthase, and CR
P reduces NO synthase expression, suggesting a mechanism by which statins may specifically protect against the adverse effects of inflammation on the vasculature.
In the most recent study, published March 2006 in JACC, investigators reported that peripheral arterial disease (PAD) patients on statins have less annual decline in lower-extremity performance than PAD patients who were not taking statins. In this prospective study, the benefits in performance were evident during three years of follow-up and remained after adjusting for a number of known and potential confounders.13
Are the pleiotropic effects of statin therapy proved? In late 2005, a meta-regression analysis was published in JACC suggesting that the regression lines for non-statin and statin trials were similar and consistent with a one-to-one relationship betw
een LDL-cholesterol lowering and cardiovascular disease (CVD) and stroke reduction over five years of treatment.14 The authors concluded that the pleiotropic effects
of statins do not seem to contribute an additional cardiovascular risk reduction benefit beyond that expected from the degree of LDL-cholesterol lowering observed in other trials that primarily lowered LDL.
Interpretation
Regarding the PROVE IT-TIMI 22 data, Dr. Halcox said, What was interesting is that subjects with lower cholesterol but higher CRP appeared to do exactly as well as those with higher cholesterol and lower CRP, suggesting that CRP was as important a predictor of outcome as LDL cholesterol (Slide 5).
Also, he emphasized, subjects with the greatest number of uncontrolled risk factors (e.g., smoking, hypertension, high triglycerides, body mass index greater than 25) had high levels of
CRP even if they were receiving intensive atorvastatin therapy. According to Dr. Halcox, this underscores the need to target global risk and not assume that aggressive cholesterol-lowering will ma
ke up for uncontrolled risk factors.
How should the pleiotropic effects of statins be used in clinical practice? Dr. Halcox recommends:
The debate continues as to whether or not statins have effects other than those that lower lipids that may provide additional cardiovascular benefits. An array of proposed pleiotropic effects have been suggested, including anti-inflammatory, antithrombotic, and vascular effects (Slide 1). What do the data suggest at this time in regards to statin therapy and the pleiotropic effects of such therapy?
The Data
Aggressive statin therapy can slow or even halt the progression of atherosclerotic plaques. In the recent REVERSAL trial, for example, high-dose atorvastatin appeared to halt disease progression compared to more moderate lipid lowering (<a href="http://www.cardiosource.com/rapidnewssummaries/index.asp?
EID=22&DoW=Sun&SumID=161#" target="_blank">Slide 2</a>).1 Moreover,
a new study, presented at ACC '06, suggests that high-dose rosuvastatin actually produces plaque regression (Slide 3).2
The plaque stabilization effects of high-dose statin therapy are consistent with the biological effects of statins on inflammation, endothelial function, and coagulation.3 But are the effects explainable by alterations in lipid levels alone or are there other mechanisms contributing to the benefits seen?
In late 2005, an analysis of data from PROVE IT-TIMI 22 showed that intensive therapy using atorvastatin 80 mg was associated with a significant reduction in the composite clinical endpoint of death, myocardial infarction (MI), or rehospitalization for recurrent acute coronary syndrome (ACS) as early as 30 days after the acute event compared with standard-dose pravastatin (40 mg).4 A trend
in favor of intensive therapy was evident at 15 days after randomization (Slide 4). Similar results were reported at about the same time for patients in the ASCOT-LLA study, where there was a trend for benefit from atorvastatin as early as 30 days following randomization, with significant benefits observed at 90 days, 180 days, one year, two years, and then maintained through the termination of the trial (3.3 years).5
These very early benefits of intensive statin therapy are in sharp contrast with the Program on the Surgical Control of Hyperlipidemias (POSCH) trial, in which ileal bypass was associated with a dramatic early reduction in low-density lipoprotein (LDL) cholesterol but no early reduction in clinical events.6 Plus, a number of trials suggest that the apparent benefit from statin therapy is often delayed a year or more.7
What potential mechanisms might explain the
early effects of statin therapy? Statins inhibit HMG-CoA reductase, which is responsible for the reduction in circulating LDL ch
olesterol beginning one to two weeks after therapy initiation. Statins also inhibit HMG-CoA reductase within endothelial cells, vascular smooth muscle cells, and inflammatory cells (the monocyte/macrophage system), which affects important signaling pathways. In cell culture, animal, and clinical studies, these effects appear within hours after statin administration and may be dose dependent.3,8
The PROVE IT-TIMI 22 authors cited median C-reactive protein (CRP) level at 30-days (1.6 mg/l in the atorvastatin group compared with 2.3 mg/l in the standard therapy arm; p<0.001) as supporting greater early anti-inflammatory pleiotropic effects with intensive statin therapy.9,10
Another marker of inflammation was evaluated in the MIRACL trial, which evaluated intensive atorvastatin therapy given early after ACS. Patients in the placebo group with initial levels of
soluble CD40 ligand (sCD40-L) above the 90th percentile had a higher risk of recurrent events compared with patients with sCD40-L concentrations
at or below the 90th percentile. However, the increased risk associated with high initial sCD40-L was completely abrogated by treatment with atorvastatin.
Recent studies have shown that the severity of endothelial dysfunction also relates to cardiovascular risk. A number of interventions, including statins, have been shown to improve endothelial function,11,12 but is this effect just a response to LDL lowering or is it more? Consistent evidence suggests that reduction of plasma LDL improves endothelial function, which has been observed when LDL is lowered by nonpharmacologic means such as diet in animals, and with bile acid resins, plasma apheresis, and statins. Yet there is evidence, too, that pleiotropic effects of statins may be relevant based on reduced cellular concentrations of important and biologically active intermediates that influence endothel
ial phenotype. Statins directly enhance expression, phosphorylation state, and activity of the endothelial isoform of nitric oxide (NO) synthase, and CR
P reduces NO synthase expression, suggesting a mechanism by which statins may specifically protect against the adverse effects of inflammation on the vasculature.
In the most recent study, published March 2006 in JACC, investigators reported that peripheral arterial disease (PAD) patients on statins have less annual decline in lower-extremity performance than PAD patients who were not taking statins. In this prospective study, the benefits in performance were evident during three years of follow-up and remained after adjusting for a number of known and potential confounders.13
Are the pleiotropic effects of statin therapy proved? In late 2005, a meta-regression analysis was published in JACC suggesting that the regression lines for non-statin and statin trials were similar and consistent with a one-to-one relationship betw
een LDL-cholesterol lowering and cardiovascular disease (CVD) and stroke reduction over five years of treatment.14 The authors concluded that the pleiotropic effects
of statins do not seem to contribute an additional cardiovascular risk reduction benefit beyond that expected from the degree of LDL-cholesterol lowering observed in other trials that primarily lowered LDL.
Interpretation
Regarding the PROVE IT-TIMI 22 data, Dr. Halcox said, What was interesting is that subjects with lower cholesterol but higher CRP appeared to do exactly as well as those with higher cholesterol and lower CRP, suggesting that CRP was as important a predictor of outcome as LDL cholesterol (Slide 5).
Also, he emphasized, subjects with the greatest number of uncontrolled risk factors (e.g., smoking, hypertension, high triglycerides, body mass index greater than 25) had high levels of
CRP even if they were receiving intensive atorvastatin therapy. According to Dr. Halcox, this underscores the need to target global risk and not assume that aggressive cholesterol-lowering will ma
ke up for uncontrolled risk factors.
How should the pleiotropic effects of statins be used in clinical practice? Dr. Halcox recommends:
- Use statin dosing to achieve aggressive LDL targets.
- Optimize global risk management (e.g., aggressive lifestyle interventions, with or without additional drug therapy for residual risk factors)
- Await results of randomized trials addressing inflammation as a specific target in CVD prevention.