Thursday, April 30, 2009

Luck that Looks Like Logic? Statins (Rosuvastatin), the Cholesterol Hypothesis, and Causal Pathways

The Cholesterol Hypothesis (CH), namely that the association between elevated cholesterol (LDL) and cardiovascular disease and events is a CAUSAL one, and thus that intervening to lower cholesterol prevents these diseases has seduced mainstream medicine for decades. However, much if not most of the evidence for the causality of cholesterol in atherogenesis and its reversal by lowering cholesterol derives from studies of "Statins" or HMG-CoA-reductase inhibitors; indeed the evidence that lowering LDL cholesterol (or raising HDL) through other pathways has salutary effects on cardiovascular outcomes is scant at best as has been chronicled on this blog (see posts on torcetrapib and ezetimibe/Vytorin). Not myself immune to the beguiling allure of the CH, I admit that I take Niacin, in spite of normal HDL levels and scant to no trustworthy evidence that, in addition to raising HDL and lowering LDL, it will have any primary (or secondary or tertiary) preventative effects for me.

In yesterday's NEJM, Glynn et al report the results of analysis of data on a secondary endpoint from the JUPITER trial of Rosuvastatin. ( .) The primary aim of the trial was to determine if Rosuvastatin was effective for primary prevention of cardiovascular events in people with normal cholesterol levels and elevated CRP levels. The secondary endpoint described in the article was the occurrence of venothromboembolism during the study period. Because I see no obvious evidence of foul play, and because this study was simply impeccably designed, conducted, and reported, I'm going to hereafter ignore the fact that it was industry sponsored, and that there is probably some motive of "off-label promotion by proxy" ( .) here...

Lo and behold: Rosuvastatin lowered venothromboembolism rates. The difficulties posed by ascertainment of this outcome notwithstanding, this trial has convincing evidence of a statistically significant reduction in DVT and PE event rates (which were very low - ~0.2%/100 persons/year) during the four year period of study. And this does not make a whole lot of sense from the standpoint of the CH. There's something more going on. Like an anti-inflammatory property of Statins. Which is very interesting and noteworthy and worthwhile in its own right. But I'm more interested in what kind of light this sheds on the validity of the CH.

Because of my interest in the fraility of the normalization hypothesis/heuristic (the notion that you just measure something and then raise or lower it to the normal range and make things ALL better) I am obviously a reserved skeptic of the Cholesterol Hypothesis, which was bolstered by if not altogether reared by data from trials of statins. And these new data, combined with emerging evidence that statins may have salutary effects on lung inflammation in ARDS and COPD, among perhaps others, make me wonder - was it just pure LUCK rather than a triumph of LOGIC that the first widely tested and marketed drug for cholesterol happened to both reduce cardiovascular endpoints AND lower cholesterol, even though not necessarily as part of the same causal pathway? Is it just "true, true, and unrelated?" Are they the anti-inflammatory properties or some other piece of the complex biochemical effects of these drugs on the body that leads to their clinical benefits? Other examples come to mind: Is blood pressure lowering just an epiphenomenon of another primary ACE-inhibitor effect on heart failure? Because these effects appear to be superficially and intuitively related does not mean that they are an obvious causal pathway.

What if things had happened another way. What if Statins had eluded discovery for another 20-30 years. What if study of the cholesterol hypothesis meanwhile proceeded through evaluation of Cholestyramine, Cholestipol, Niacin, and other drugs, and what if it had been "disconfirmed" by failure of these agents to reduce cardiovascular outcomes? These hypotheticals will be answerable only after more study of Statins and other drugs as well as their mechanisms. The data presented by the Harvard group as well as their other work with CRP are but one leg of a long journey toward elucidation of the biological mechanisms of atherogenesis, coagulation, and downstream clinical events.


  1. In my opinion, it is likely that statins work through both LDL-lowering and pleiotropic effects. The following study shows evidence for pleiotropic effects of statins.

    Circulation. 2009;119:131-138

    Evidence for Statin Pleiotropy in Humans

    Differential Effects of Statins and Ezetimibe on Rho-Associated Coiled-Coil Containing Protein Kinase Activity, Endothelial Function, and Inflammation

    Ping-Yen Liu, MD, PhD; Yen-Wen Liu, MD; Li-Jen Lin, MD; Jyh-Hong Chen, MD, PhD; James K. Liao, MD
    From the Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (P.-Y.L., J.K.L.), and Division of Cardiology, Internal Medicine, National Cheng Kung University Medical Center, Tainan, Taiwan (P.-Y.L., Y.-W.L., L.-J.L., J.-H.C.).

    Correspondence to James K. Liao, MD, Brigham and Women’s Hospital, 65 Landsdowne St, Room 275, Cambridge, MA 02139. E-mail

    Received August 6, 2008; accepted October 21, 2008.

    Background— By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins not only reduce cholesterol biosynthesis but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho-associated coiled-coil containing protein kinase (ROCK) pathway. Increased ROCK activity has been implicated in endothelial dysfunction and vascular inflammation. We hypothesize that ezetimibe, which inhibits intestinal cholesterol absorption, may not exert similar cholesterol-independent or pleiotropic effects of statins and, when used with a lower dose of statin, have less effect on ROCK activity than a higher dose of statin.

    Methods and Results— In a prospective, randomized, observer-blinded study, we treated 60 dyslipidemic subjects without cardiovascular disease with simvastatin 40 mg/d, simvastatin/ezetimibe 10/10 mg/d, or placebo tablets for 28 days (n=20 in each arm). We evaluated baseline demographics and lipid levels, ROCK activity, C-reactive protein, and flow-mediated dilation before and after treatment. Compared with the placebo group, both treatment regimens decreased low-density lipoprotein cholesterol by 38% and C-reactive protein by 38% to 40% after 28 days (P<0.01 for both compared with placebo). Although the low-density lipoprotein cholesterol and C-reactive protein reductions were comparable with either lipid-lowering regimen, only simvastatin 40 mg reduced ROCK activity and improved flow-mediated dilation (P<0.01 for both compared with baseline). Reduction in ROCK activity with simvastatin 40 mg remained significant even after controlling for changes in low-density lipoprotein cholesterol (P=0.01) and correlated with improvement in flow-mediated dilation (R2=–0.78, P<0.01). No correlation was found between changes in flow-mediated dilation and changes in low-density lipoprotein cholesterol or C-reactive protein.

    Conclusion— These results indicate that high-dose statin monotherapy exerts greater effects on ROCK activity and endothelial function, but not on C-reactive protein, than low-dose statin plus ezetimibe. These findings provide additional evidence of statin benefits beyond cholesterol lowering.

  2. I did not have access to the full article, but we even calculate the 10 year risk of a heart attack based on the Framinghan study. I agree that statins likely have additional properties that protect patients from developing coronary events, but I am not sure if can complete disregard the causal effect on cholesterol

    JAMA. 1987 Apr 24;257(16):2176-80.Links
    Cholesterol and mortality. 30 years of follow-up from the Framingham study.Anderson KM, Castelli WP, Levy D.
    From 1951 to 1955 serum cholesterol levels were measured in 1959 men and 2415 women aged between 31 and 65 years who were free of cardiovascular disease (CVD) and cancer. Under age 50 years, cholesterol levels are directly related with 30-year overall and CVD mortality; overall death increases 5% and CVD death 9% for each 10 mg/dL. After age 50 years there is no increased overall mortality with either high or low serum cholesterol levels. There is a direct association between falling cholesterol levels over the first 14 years and mortality over the following 18 years (11% overall and 14% CVD death rate increase per 1 mg/dL per year drop in cholesterol levels). Under age 50 years these data suggest that having a very low cholesterol level improves longevity. After age 50 years the association of mortality with cholesterol values is confounded by people whose cholesterol levels are falling--perhaps due to diseases predisposing to death.

  3. Further to my comment above: this study shows a lack of effect of niacin on endothelial function. Statins, by contrast, improve endothelial function. Endothelial dysfunction, or the loss of proper endothelial function, is a hallmark for vascular diseases, and often leads to atherosclerosis. Endothelial dysfunction is very common in patients with diabetes mellitus, hypertension, hypercholesterolemia, or other cardiovascular risk factors. One of the main mechanisms of endothelial dysfunction is the diminishing of nitric oxide.

    Statins inhibit rho kinase, which is part of the mevalonate pathway. Rho kinase has inflammatory vascular effects. Thus, the "pleiotropic," or antiinflammatory, effects of statins.

    In addition, the results of statin trials with clinical endpoints are much more impressive than trials of nonstatins.

    Atherosclerosis, Volume 204, Issue 1, Pages 216-221 (May 2009)

    Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: Results of the randomized, double-blind, placebo-controlled INEF study

    Ascan Warnholtza1, Philipp Wilda1, Mir Abolfazl Ostada, Veronika Elsnera, Fabian Stiebera, Reinhard Schinzelb, Ulrich Walterc, Dirk Peetzd, Karl Lacknerd, Stefan Blankenberga, Thomas Munzela

    Received 15 March 2008; received in revised form 12 July 2008; accepted 5 August 2008. published online 26 September 2008.

    High-density-lipoproteins-cholesterol (HDL-C) is invertedly related to the incidence of cardiovascular events. Recent studies suggest that HDL-C directly improves endothelial function. Nicotinic acid (niacin) effectively raises serum HDL-C. We therefore hypothesized that treatment with niacin improves endothelial dysfunction in patients with coronary artery disease (CAD). One hundred seven patients with CAD were randomly assigned to double-blinded treatment for 12 weeks with extended-release (ER)-niacin 1000mg/day (N) or placebo (C), respectively. Flow-mediated dilation (FMD) of the brachial artery, nitroglycerin-mediated endothelium-independent dilation (NMD) and serum lipid concentrations were measured before and after treatment. Triglycerides (P=0.013), low-density-lipoprotein-cholesterol (LDL-C) (P=0.013) and HDL-C (P<0.0001) were altered by N compared to C. Niacin treatment was without effect on FMD or NMD, respectively, compared to placebo. However, post-hoc subgroup analysis revealed an improvement in FMD in patients with low HDL-C at baseline (absolute change in FMD (mean±S.D.) N: +3.25±3.88%, C: +1.03±2.71% in low tertile HDL-C ≤45mg/dl. P=0.047). The present findings indicate that ER-niacin treatment improves endothelial dysfunction in patients with CAD and low HDL-C, but not with normal HDL-C.

    Keywords: Endothelium, Niacin, Flow-mediated dilation, Coronary artery disease
    a Department of Medicine II, Johannes Gutenberg-University Mainz, Mainz, Germany

    b vasopharm BIOTECH GmbH, Würzburg, Germany

    c Department of Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Wuerzburg, Germany

    d Department of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg-University Mainz, Mainz, Germany

    Corresponding author at: II. Medizinische Klinik und Poliklinik, Klinikum der Johannes Gutenberg-Universität Mainz, Langenbeckstraße 1, D-55101 Mainz, Germany. Tel.: +49 6131 17 3747; fax: +49 6131 17 6428.

    1 A.W. and P.W. contributed equally to this study and should therefore be considered as first author.

    PII: S0021-9150(08)00547-9


  4. You definitely come with exceptional articles.