Author + information
- Michael J. Blaha, MD, MPH∗ ( and )
- Seth S. Martin, MD
- ↵∗Reprint requests and correspondence:
Dr. Michael J. Blaha, Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Carnegie 565A, JHH, 600 North Wolfe Street, Baltimore, Maryland 21287.
There is now indisputable evidence that statins reduce atherosclerotic cardiovascular disease events in a wide variety of patient populations. As a result, up to 200 million people take a daily statin worldwide, including over 30 million people in the United States alone. Now that we have become a statin civilization, perhaps it is time to figure out exactly how these drugs work.
Meta-analyses have tied their favorable mechanism of action to reduction in circulating low-density lipoprotein cholesterol (LDL-C) (1), which is known to play a causal role in atherosclerosis (2). The current National Cholesterol Education Program Adult Treatment Panel III guidelines (3) reflect the central belief in the serum LDL-C measurement, recommending that the choice of who to treat and the intensity of treatment should be inextricably tied to the concentration of LDL-C in the bloodstream. Our mandate has been to “lower the lipoprotein load” and “get to goal.”
However, a consistent stream of data suggests that there are favorable effects of statins independent of their influence on circulating lipoprotein load. For example, statins have been shown to reduce cardiovascular events in both primary and secondary prevention at all levels of serum cholesterol, including in those with so-called normal cholesterol levels (baseline LDL-C <80 mg/dl) (4). When given as a loading dose immediately before coronary revascularization, statins appear to have a nearly immediate effect on lowering periprocedural myocardial infarction (5). As early as 4 months following an acute coronary syndrome, statins reduce the occurrence of unstable angina, suggesting a plaque-level effect rather than cumulative exposure to the circulating lipoprotein load (6). Although controversial, statins may also reduce atrial fibrillation, venous thromboembolism, and neurocognitive diseases such as Parkinson's disease (7).
There are several potential explanations for these apparently nonserum cholesterol mechanisms. For example, statins have been shown to rapidly delipidate atheromas, stripping plaques of their potentially unstable lipid core (8). Statins also appear to reduce systemic inflammation, which is important because subclinical inflammation is now understood to create a proatherogenic milieu (9). They also appear to reduce inflammation within the atherosclerotic plaque itself, which might promote plaque stability (9). Although much work still needs to be done, it is clear that emerging research is taking us beyond the central focus on cholesterol and the bloodstream and instead to the end-effects of statins on peripheral tissue, including the atherosclerotic plaque itself.
These observations are fundamentally changing the way we view statins. Historically, statins have been viewed as exclusively lipid-lowering medications that should be directed to patients with high serum lipid levels. A more modern perspective paints statins as cardiovascular risk-reducing medications with multiple possible mechanisms of action.
Statin mechanism paradigms and their implications
Our understanding of the mechanism of action of statins will have a profound impact on the way we choose to allocate this class of drugs and on the way we evaluate new classes of lipid-modifying therapies. To simplify this important discussion, we propose a taxonomy separating statin mechanisms into 3 nonmutually exclusive paradigms. The question is not which of these paradigms is correct, because they likely all contribute. Rather, the question is which paradigm predominates in which patient population over which time course.
Paradigm 1: “Lipoprotein Load Hypothesis”
The lipoprotein load hypothesis states that statins work primarily by reducing the circulating burden of not only LDL-C, but also all apolipoprotein B–containing lipoproteins (including remnants), which by mass action kinetics leads to less age-related build-up of lipid in the vessel wall. If the lipoprotein load hypothesis predominates, it would seem logical to give statins to patients with high cholesterol as early as possible in life to reduce the exposure to these dose-dependent lipoprotein toxins. Within this framework, the efficacy of new classes of lipid-lowering therapies might be best predicted by conducting detailed analysis of a new drug's effect on the lipid profile.
Paradigm 2: “Systemic Inflammatory Hypothesis”
This hypothesis states that statins preferentially work by reducing systemic subclinical inflammation, such as that seen in the metabolic syndrome or in a condition like rheumatoid arthritis, which promotes the propagation of early atherosclerosis. If the systemic inflammatory hypothesis predominates, statins should be given to patients with elevated levels of serum inflammatory biomarkers, for example, high-sensitivity C-reactive protein (hsCRP), or evidence of extra-arterial inflammation. Within this hypothesis, the efficacy of new antiatherosclerotic drugs might be best predicted by gauging the effect on systemic inflammatory biomarkers.
Paradigm 3: “Plaque Modulation Hypothesis”
This hypothesis suggests that statins work predominantly by changing the characteristics of early atherosclerotic plaque, including delipidation, regression, reduction of plaque-level inflammation, and plaque stabilization. If the plaque modulation hypothesis predominates, it would follow that statins should be given to patients with subclinical atherosclerosis, particularly those with so-called high-risk plaque features. Within the framework of this hypothesis, the efficacy of new therapies might best be predicted by measuring the direct impact of a new drug on the burden of atherosclerosis and on the inflammatory activity of atherosclerotic plaque.
Measuring the nonlipid effects of statins
Modern imaging techniques have made it possible to directly measure some of the nonlipid effects of statins. For example, intravascular ultrasound and coronary computed tomographic angiography have helped us to understand the effect of statins on total plaque burden and the quantity of lipid-rich, low attenuation plaque. An important prior report by Tawakol et al. (10) highlighted the possibility of using fluorodeoxyglucose (FDG)-positron emission tomography (PET) to visualize plaque-level inflammation. In a feasibility study of 83 patients (67 completed the study) with established atherosclerosis or risk factors randomized to 10 mg versus 80 mg of atorvastatin, the authors demonstrated a dose-dependent reduction in FDG uptake within the walls of the ascending aorta and carotid artery with increasing dose of atorvastatin. This effect was present as early as 4 weeks after initiation of atorvastatin. Importantly, the reduction in plaque inflammation was largely independent of reductions in LDL-C and hsCRP.
In this issue of the Journal, a new analysis from the same FDG-PET study explores the dose-dependent effects of atorvastatin on periodontal inflammation measured using the same scans of the neck as those used for the carotid artery (11). Periodontal disease is an emerging risk factor for atherosclerotic cardiovascular disease, most likely because of a systemic inflammatory response that could directly promote inflammation within atherosclerotic plaques.
A total of 71 of the 83 patients completed the study, and 59 patients provided periodontal images for analysis. The authors show that higher FDG-PET activity indeed identifies more severe periodontal disease, as FDG uptake correlated well with severity of disease by computed tomography. At 12 weeks, there was a reduction of activity in patients randomized to 80 mg versus 10 mg of atorvastatin (p = 0.01). Importantly, those patients with the highest levels of periodontal inflammation at baseline received the greatest reduction with high-dose atorvastatin (p = 0.004). Intriguingly, the differences between the low- and high-dose atorvastatin groups were already evident at just 4 weeks into therapy. Similar to the prior carotid plaque inflammation analysis, reduction in the periodontal uptake was not correlated with either LDL-C or hsCRP reduction. Reduction in FDG update did, however, correlate with reduction in carotid artery FDG activity (r = 0.61, r2 = 0.37, or 37% of the statistical variance explained), although this study does not allow a causal inference between inflammation at these 2 sites.
Several limitations are worth mentioning. Of course, sample size was small. Surprisingly, atorvastatin 10 mg produced no change in periodontal FDG activity—all of the reduction was seen in the atorvastatin 80 mg group. While this could suggest a threshold effect, in general, conclusions would be stronger if a true dose-response curve was demonstrated. The authors attribute the lack of benefit in the atorvastatin 10-mg arm to a majority of patients taking low-dose statins prior to enrollment. Given the short-term follow-up of this study, one cannot determine the durability of the effect of high-dose statins on inflammation past 12 weeks. Further, the clinical significance of an approximately 10% reduction in uptake on FDG-PET imaging is entirely unknown.
The future of atherosclerosis treatment
Should new lipid-lowering drugs undergo testing for so-called pleotropic effects? It is interesting that dalcetrapib, despite markedly increasing high-density lipoprotein cholesterol, did not reduce arterial inflammation by FDG-PET (12). At a minimum, we do not believe that it is safe to assume that a drug that improves lipids (even, for example, such promising therapies as PCSK9 inhibitors) will be guaranteed to proportionally reduce cardiovascular events at the same rate as observed with statins.
Who should be treated with statins over what time course is one of the most hotly debated questions in modern medicine. While statins certainly reduce atherogenic lipoproteins (see Paradigm 1), the 2 reports from this intriguing FDG-PET feasibility study suggest that high-dose statins also reduce extra-arterial inflammation (see Paradigm 2) and inflammation within atherosclerotic plaque (see Paradigm 3). Ultimately, we hypothesize that the relative importance of statin's actions—within the framework of our proposed paradigms—may be population dependent.
We applaud Subramanian et al. (11) for seeking a deeper understanding of the way statins work. This hypothesis-generating research has tremendous potential implications for our philosophy toward statin allocation in primary prevention and for future testing of new antiatherosclerotic drugs.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Martin is supported by the Pollin Fellowship in Preventive Cardiology, as well as the Marie-Josée and Henry R. Kravis endowed fellowship. Dr. Blaha have reported that he have no relationships relevant to the contents of this paper to disclose.
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