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Statins, inflammation & atherogenesis--their failure




Statin’s role in the inflammation process


Big PhARMA bull shit exposed





Goodman and Gilman’s The Pharmacological Basis of Therapeutics, eleventh edition (2006), page 950. 


 Goodman and Gilman found[i] that statins (p 950):

1)  Inhibit monocyte infiltration into the artery wall in rabbits (this is probably a positive effect)

2)  Inhibit the secretion by macrophage of an enzyme which degrades cellular-matrix components that weaken the fibrous cap of atherosclerotic plaques (positive)

3)  Inhibit the proliferation of smooth muscle cells (a process that slows the conversion of unstable plaque to stable and weaken existing caps—negative affect).

4)  Enhance cell apoptosis (death) (a process that could slow the conversion of unstable plaque to stable and weakens existing caps—negative).

5)  Reduces levels of C-reactive protein (an inflammation marker, whose role in atherogenesis is not known—possible positive).

6)  Reduces oxidative modification of LDL which plays a key role in atherogenesis (positive). 

7)  Reduce platelet aggregation; viz., affects thrombi formation (positive). 

[i] I am stating the results in the positive, though of course additional research will modify some of the results. 

Potential Cardio Protective Affects Other Than LDL Lowering (G & G 950):

Although the statins clearly exert their major effects on CHD by lower­ing LDL-C and improving the lipid profile as reflected in plasma cho­lesterol levels (Figure 35-2) (Thompson and Barter, 1999), a multitude of potentially Cardio-protective effects are being ascribed to these drugs (Liao and Laufs, 2005). However, the mechanisms of action for non-lipid-lowering roles of statins have not been established, and it is not known whether these potential pleiotropic [one gene effecting more than one characteristic] effects represent a class-action effect, differ among statins, or are biologically or clinically rele­vant. Until these questions are resolved, selection of a specific statin should not be based on any one of these effects. Nevertheless, the potential importance of the non-lipid roles of statins merits discussion.

Statins and Endothelial Function. A variety of studies have estab­lished that the vascular endothelium [muscle lining of artery] plays a dynamic role in vasoconstriction/relaxation. Hypercholesterolemia adversely affects the pro­cesses by which the endothelium modulates arterial tone. Statin therapy enhances endothelial production of the vasodilator nitric oxide, leading to improved endothelial function after a month of ther­apy (O'DriscolI et al., 1997; Laufs et al, 1998). However, similar results have been observed after a single acute reduction of LDL levels by apheresis (Tamai et al., 1997). In nonhuman primates fed a high-cholesterol diet, statin therapy improved endothelial function independent of significant changes in plasma cholesterol levels (Will­iams et al., 1998).

Statins and Plaque Stability. The vulnerability of plaques to rup­ture and thrombosis is of greater clinical relevance than the degree of stenosis they cause (Corti et al., 2003). Statins may affect plaque stability in a variety of ways. They reportedly inhibit monocyte infiltration into the artery wall in a rabbit model (Bustos et al., 1998) and inhibit macrophage secretion of matrix metalloproteinases in vitro (Bellosta et al., 1998). The metalloproteinases degrade extra-cellular matrix components and thus weaken the fibrous cap of atherosclerotic plaques.

Statins also appear to modulate the cellularity of the artery wall by inhibiting proliferation of smooth muscle cells and enhancing apoptotic cell death (Corsini et al., 1998). It is debatable whether these effects would be beneficial or harmful.  Reduced proliferation of smooth muscle cells and enhanced apoposis could retard initial hyperplasia [abnormal multiplication of cells] and restenosis [reoccurrence of stenosis after corrective surgery], but also could weaken the fibrous cap and destabilize the lesion.  Interestingly, statin-induced suppression of cell proliferation and apoptosis have been extended to tumor biology' statins on isoprenoid biosynthesis and protein phenylation associated with reduced synthesis of the cholesterol precursor may alter the development of malignancies (Davignon and Laaksoren, 1999; Wong et al., 2002; Li et al., 2003).

Statins and Inflammation. Appreciation of the importance of inflammatory processes in atherogenesis is growing (Libby, 2002), and statins may have an anti-inflammatory role (Libby and Atkins 2003). Statins decreased the risk of CHD and levels of C-reactive protein (CRP, an independent marker for inflammation and high risk) independently of cholesterol lowering (Libby and Aikawa, Libby and Ridker, 2004). Body weight and the metabolic syndrome are associated with elevated levels of highly sensitive CRP, leading some to suggest that the CRP may simply be a marker of inflammation and insulin resistance (Peason et al., 2003).  It remains to be determined whether the C-reactive is simply a marker of inflammation, or if it contributes to obesity insulin resistance (Pearson et al., 2003). It remains to be whether the C-reactive protein if it contributes to the pathogenesis of atherosclerosis. The clinical utility of measuring CRP with "highly sensitive" assays appears to be limited to those primary prevention subjects with a moderated (10% to 20%) 10-year risk of sustaining a CHD event. Values of highly sensitive CRP above 3 mg/L suggests that such patients should be managed as secondary prevention patients (Pearson et al., 2003).

Statins and Lipoprotein Oxidation. Oxidative modification of LDL appears to play a key role in mediating the uptake of lipoprotein cholesterol by macrophages and in other processes, including cyto-toxicity within lesions (Steinberg, 1997). Statins reduce the susceptibility of lipoproteins to oxidation both in vitro and ex vivo (Hussein et al., 1997).

Statins and Coagulation. Statins reduce platelet aggregation (Hussein et al., 1997) and reduce the deposition of platelet thrombi in the porcine aorta model (Lacoste et al.. 1995). In addition the different statins have variable effects on fibrinogen levels, the significance of which remains to be determined (Rosenson and Tangney, 1998).  Elevated plasma fibrinogen levels are associated with an increase in the incidence of CHD (Ernst and Resch, 1993); however it remains to be determined whether fibrinogen is a contributor to or a marker of disease.  



JK’s trail of the smoking gun:

 The lack of research upon Statins and their effect upon inflammation in the coronary arteries and on clotting leading to thrombosis makes me suspect that the marketing has decided not to use this mechanism for to sell statins.  They have decided to concentrate on the reduction of LDL, for to do otherwise would promote for some the choice of aspirin.  Aspirin like statins lowers the marker for inflammation, C-reactive protein (CRP).  Aspirin lowers the risk of MI by nearly 25%; the same cannot be made of statins alone.  The role of inflammation has been known since the 80s and there is currently extensive market-oriented research on inflammation markers; however, most of the research has as its primary goal the establishment of a new class of at-risk people, who of course should be on statins.  Since big PhARMA does most of the funding, there is scant basic research on the role of statins upon the inflammation process. I suspect they were hiding something.    


I thus reread (11/08) the section on inflammation in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11 Edition.  There I found the details of how statins profoundly affect the inflammatory process—the mechanism for atherogenesis--see also. “The vulnerability of plaques to rupture and thrombosis is of greater relevance than the degree of stenosis they cause.  Stains may affect plaque stability in a variety of ways (950)”.  Goodman and Gilman confirmed my skepticism.  This was my speculation as to why statins, which profoundly effect LDL levels, do not significantly prolong life.  The good they do by lowering LDL is counterbalanced by exacerbating unstable plaque.  Now I knew why there was minimal reduction of MI at best[i].    There is for the highest risk groups a modest benefit, for others the results are equivocal. 

[i]   First few studies include stats about MI and longevity.  And those that find little benefit.  Moreover, big Pharma manipulates the contents of the research they fund as to content.  A study published in NEGM of 39 drugs, which compared the raw data given the FDA to published results, found an average positive bias of 32%. Journals do not get raw data.  I can only presume that this process of manipulation is universal.  


Big PhARMA is doing research to both justify and expand the use of statins.  They have waged a war against aspirin (as they also do against all off patent and all over the counter preparations).  Given the intrusion of the market place into research including positive bias, one must look carefully at the putative effects of stains as to the affect upon the inflammation process.  Marketers use biochemical processes to promote sales.  Two questions need to be answered:  Are the effects upon the inflammation process clinically significant, and are there safer alternatives?  To the first question the answer seems to be negative.  Statins seem to promote rupture of unstable plaque probably by slowing the process by which it is converted to stable plaque. This would explain why that though statins create a much better lipid profile there is little if any effect upon the prognosis of patients.  Secondly I have come to believe that what little positive outcome statins have is due to its effect upon platelets in the formation of clots (thrombi).  Given the side effects of statins there are thus better ways to improve lipid profile and aspirin is a better way to reduce clotting. 

All NSAIDs also affect COX-1 and COX-2, which are prostaglandins that are involved in the inflammation process.  All NSAIDs reduce inflammation, however, at the same time they promote (all but aspirin) atherogenesis (see the American Heart Association’s warning) by a process of prolongation.  They block the shutoff signal.  .  Thus as a consequence only aspirin of the NSAIDs reduces thrombi and doesn’t promote atherosclerosis. 

The third reason to take aspirin is a reduction of 20% or more of at least 9 common cancers.  This is through an enhancement of apoptosis of abnormal cells (it is dose related with a maximum reduction of 60% for colon cancer).   Given the sum total of effects, the type of research being done, the very significant side effects of statins, their cost, I have come to the conclusion that for those at risk the best intervention--besides change of lifestyle and diet—is to take daily a 325 mg coated aspirin[i] and if the lipid profile is a concern at least 1.5 grams of niacin. 



Articles below on Statins and COX-2 expression and the various inflammation factors, especially CRP (C-reactive protein).  There was little on this, Google search.



Anti-inflammatory effects of simvastatin in subjects with hypercholesterolemia.  International Journal of Cardiology, Volume 77, Issue 2 - 3, Pages 247 - 253 J, 2003.


Aims: Beneficial effects of statins in preventing cardiovascular events may depend, at least in part, on their anti-inflammatory action. The aim of the study was to assess the influence of simvastatin and aspirin on serum levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in hypercholesterolemic subjects. Methods and results: In 33 asymptomatic men with total cholesterol (TC) >6.5 mmol l−1 and in 25 men with coronary heart disease and borderline-high cholesterol levels (between 5.2 and 6.5 mmol l−1) chronically treated with low-dose aspirin (75 mg/d), serum levels of CRP, TNF-α, IL-6, and IL-8 were determined before and after a 3-month simvastatin therapy (20–40 mg daily). In the former group, these markers of inflammation were also measured before and after a 2-week treatment with aspirin (300 mg/d), implemented prior to and in combination with simvastatin. A distinct reduction of CRP and TNF-α was found in both groups; IL-6 levels were decreased only in subjects with marked hypercholesterolemia. Aspirin had no effect on the anti-inflammatory action of simvastatin. Conclusions: In men with hypercholesterolemia simvastatin treatment lowers serum levels of CRP and pro-inflammatory cytokines. Low-dose aspirin does not add to the anti-inflammatory action of simvastatin.






Originally published In Press as doi:10.1074/jbc.M104197200 on October 8, 2001

J. Biol. Chem., Vol. 276, Issue 50, 46849-46855, December 14, 2001

Modulation of COX-2 Expression by Statins in Human Aortic Smooth Muscle Cells

Frédéric Degraeve §, Manlio Bolla , Stéphanie Blaie , Christophe Créminon , Isabelle Quéré**, Patrice Boquet , Sylviane Lévy-Toledano , Jacques Bertoglio§§, and Aïda Habib ¶¶

From the  Commissariat à l'Energie Atomique (CEA), Service de Pharmacologie et d'Immunologie, 91191 Gif sur Yvette, France, the ** Department of Internal Medicine B, St. Eloi Hospital, 34295 Montpellier, France,  INSERM U 452, 06107 Nice, France, §§ INSERM U 461, 92296 Chatenay-Malabry, France, and  INSERM U 348, Institut Férératif 6-Circulation-Paris 7, Hôpital Lariboisière, 75010 Paris, France

Cyclooxygenase (COX)-2 and COX-1 play an important role in prostacyclin production in vessels and participate in maintaining vascular homeostasis. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, which is crucial in cholesterol biosynthesis. Recently, cholesterol-independent effects of statins have been described. In this study, we evaluated the effect of two inhibitors of HMG CoA reductase, mevastatin and lovastatin, on the production of prostacyclin and the expression of COX in human aortic smooth muscle cells. Treatment of cells with 25 µM mevastatin or lovastatin resulted in the induction of COX-2 and increase in prostacyclin production. Mevalonate, the direct metabolite of HMG CoA reductase, and geranylgeranyl-pyrophosphate reversed this effect. GGTI-286, a selective inhibitor of geranylgeranyltransferases, increased COX-2 expression and prostacyclin formation, thus indicating the involvement of geranylgeranylated proteins in the down-regulation of COX-2. Furthermore, Clostridium difficile toxin B, an inhibitor of the Rho GTP-binding protein family, the Rho selective inhibitor C3 transferase, and Y-27632, a selective inhibitor of the Rho-associated kinases, targets of Rho A, increased COX-2 expression whereas the activator of the Rho GTPase, the cytotoxic necrotizing factor 1, blocked interlukin-1 -dependent COX-2 induction. These results demonstrate that statins up-regulate COX-2 expression and subsequent prostacyclin formation in human aortic smooth muscle cells in part through inhibition of Rho




C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseases .  Medical Hypotheses , Volume 62 , Issue 4 , Pages 499 - 506 J . Li


Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis and mediate many of the stages of atheroma development from initial leukocyte recruitment to eventual rupture of the unstable atherosclerotic plaque. C-reactive protein (CRP), an acute phase reactant that reflects different degree of inflammation, has been indicated an independent risk factor in a variety of cardiovascular disease (CVD), especially in unstable coronary syndrome. Our data have showed that increased level of CRP in patients with unstable angina was associated with short-term clinical outcomes, response for conventional therapy, and activation of nuclear factor-kappa B (NF-κB), but it is not correlated to coronary artery stenosis as well as lipid profile.

Traditionally, CRP has been thought of as a bystander marker of vascular inflammation, without playing a direct role in the CVD. More recently, accumulating evidence suggest that CRP may have direct pro-inflammatory effects, which is associated with all stages of atherosclerosis. In our recent study, the results demonstrate that monocytes exhibit an enhanced production of interleukin-6 (IL-6) in response to CRP, and this response is significantly inhibited by simvastatin in a dose-dependent manner. This may be of important interest in the connection between CVD and CRP.

Based on those evidence, we hypothesis that CRP is not only an inflammatory marker but also a direct cause of CVD, and treatments that reduce CRP should be benefit for primary and secondary prevention of CVD. Administration of several agents, especially statin has been showed to modify CRP concentrations with a concurrent fall in cardiovascular events. Our clinical investigation suggested that treatment with a single high-dose or a short-term common dose of simvastatin could rapidly reduce CRP level. Those data indicated that the benefit to the vascular endothelium might occur quickly in patients with CVD, which is critical issue for high-risk subgroup. Other interventions, such as lifestyle changes, weight loss, and stop smoking are also warrant attention.



[i] Aspirin lowers at least 9 common cancers over 25%, and this effect is dose related. 

Those who have a financial interest in the outcome manipulate the results, Major study finds that all 37 journal articles positive effects over stated; the average was 32%. Statins cause erectile dysfunction, cognitive imparement, and cancer.  

Lipitor (2011) lifetime sales $131 billion, tops all drugs.  Plavix at $60 billion is second.



52% short term


LA Times, Health section, July 21, 2008  --  excerpts

Vytorin, the combination drug (simvastatin (better known by its commercial name Zocor) and ezetimibe--known as Zetia) prescribed to lower cholesterol, sustained another blow today, when the author of a major clinical trial announced that the medication had failed to drive down hospitalization and death due to heart failure in patients with narrowing of the aortic valve. In the process, researchers in Norway detected a significant blip in cancers in the 1,800 subjects they followed

Today's findings suggested something more ominous: the incidence of cancer -- and of dying of cancer -- was significantly higher in the patients taking Vytorin. Altogether, 67 patients on placebo developed cancer during the trial. Among subjects on Vytorin, 102 developed cancers of various kinds.*  This is the second adverse press—the first being in March 08, when the ENHANCE trial found that Vytorin fared no better than a placebo at reducing plaque buildup on the walls of patients' arteries.* *

Comments by jk

Simvastatin (Zocor) is off patent.  Thus in a scramble for profits a combination drug (on patent) was introduced.  Direct to consumer market cost $155 in 07—mainly TV ads. 

*  The pressing issue is that since the development  of Statins, the very first animal studies in the 60s it has been known that Statins increase the incidents of cancer.  However, nearly all studies done thereafter have not included cancer. 

*  Several studies have failed to find a reduction in the build of plaque, even thought the statins including Zocor, reduce LDL and cholesterol.  Few studies include the principle reason for taking a statin, namely a reduction in the death rate.  Claims for such reduction probably entail a failure to control the contravening variable, aspirin usage.  Given a pile of evidence, including the very mechanism of plaque formation, which involves inflammation process, I must conclude that the use of statins is highly suspect.  Given the harm done including cognitive impairment, weakness, and cancer, if my skepticism is born out, the harm done by statins as a course of treatment will far surpass that of VIOXX which killed over 200,000 people world wide by accelerating atherosclerosis.