Twenty-two years ago, the landmark 4S trial demonstrated that statin therapy could reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among secondary prevention patients with overt hyperlipidaemia.1 Since that time, large-scale statin trials have shown that an exceptionally wide range of patients benefit from statins, including those without evidence of underlying vascular disease or hyperlipidaemia. Yet many statin-treated patients continue to suffer from life-threatening vascular events, an issue commonly described in the clinical literature as the problem of ‘residual risk’.

One side of the residual risk coin undoubtedly relates to further reduction in low-density lipoprotein cholesterol (LDLC). Ever more aggressive cholesterol reduction is the cornerstone for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors that dramatically lower LDLC among those on statins, among those with statin intolerance, and among those with forms of familial hyperlipidaemia characterized by residual LDL receptor function.2–4 In contrast, therapies addressing residual cholesterol risk on the basis of high triglycerides or low HDL cholesterol have not to date proved effective for event reduction in randomized clinical trials.

Yet focusing solely on ‘residual cholesterol risk’ among statin-treated patients ignores the fact that these agents have anti-inflammatory as well as lipid-lowering properties. As consistently shown in the CARE, AFCAPS/TexCAPS, REVERSAL, PROVE-IT, ASCOT, A to Z, and JUPITER trials,5–11 on treatment measures of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) are as important a determinant of residual risk as on-treatment levels of LDLC. For example, among secondary prevention patients in the PROVE-IT trial treated with aggressive statin therapy, those who achieved LDLC levels <70 mg/dL and hsCRP levels <2 mg/L had substantially lower rates of recurrent vascular events when compared with those who achieved only one or neither of these independent treatment targets (Figure 1, left).8 This concept of ‘dual targets’ was very recently confirmed in the IMPROVE-IT trial of simvastatin plus ezetimibe.12 This latter confirmation is important since the addition of ezetimibe to statin therapy not only further reduces LDLC but also further reduces hsCRP. Thus, like analyses preceding it, IMPROVE-IT looks at the obverse side of the residual risk coin and suggests that ‘lower is better’ not only for LDLC but also for biomarkers of vascular inflammation (Figure 1, right).

Figure 1

Recurrent cardiovascular event rates according to whether or not trial participants achieved the ‘dual goals’ of LDL reduction (<1.8 mmol/L [<70 mg/dL]) and hsCRP reduction (<2 mg/L) following initiation of statin therapy (PROVE-IT, left) or the combination of statin therapy and ezetimibe (IMPROVE-IT, right). Data from Ridker et al.5 (PROVE-IT) and Bohula et al.12 (IMPROVE-IT).

Figure 1

Recurrent cardiovascular event rates according to whether or not trial participants achieved the ‘dual goals’ of LDL reduction (<1.8 mmol/L [<70 mg/dL]) and hsCRP reduction (<2 mg/L) following initiation of statin therapy (PROVE-IT, left) or the combination of statin therapy and ezetimibe (IMPROVE-IT, right). Data from Ridker et al.5 (PROVE-IT) and Bohula et al.12 (IMPROVE-IT).

How might recognition of ‘residual inflammatory risk’ as being distinct from ‘residual cholesterol risk’ impact on clinical care? First, recognition that there are two sides to the residual risk coin emphasizes the continued importance of LDLC reduction while bringing to the fore fundamental discoveries regarding inflammation as a core driver of atherogenesis and eventual plaque rupture. In this manner, the LDL hypothesis and the inflammatory hypothesis do not stand in opposition to each other but rather are presented as inter-related issues each in need of aggressive clinical attention.

Second, weight loss, exercise, and smoking cessation all reduce inflammation. Thus, the concept of ‘residual inflammatory risk’ can immediately be used to promote critical concepts in primordial prevention and lifestyle improvement. As shown in the PREDIMED trial, simple dietary supplements such as olive oil and nuts reduce vascular event rates, and both of these interventions have anti-inflammatory properties.13

Finally, addressing the obverse side of the residual risk coin may lead to new opportunities for personalized medicine. Ongoing trials of PCSK9 inhibitors (which markedly lower LDLC without clear anti-inflammatory effects) are exceptionally promising and will teach the cardiovascular community if further aggressive LDLC reduction alone reduces rates of heart attack and stroke. At the same time, ongoing trials of agents such as low-dose methotrexate, canakinumab, anakinra, colchicine, and salsalate will teach the cardiovascular community if targeted anti-inflammatory treatments that reduce inflammation (but have little or no impact on LDLC) might also reduce cardiovascular event rates.14–18

Consider the patients outlined in Figure 2, both of whom have known cardiovascular disease and baseline LDLC of 3.8 mmol/L (150 mg/dL) and hsCRP of 4.5 mg/L. Each is initially treated with high-intensity statin therapy. Despite aggressive statin therapy, the patient on the left has an on-treatment LDLC of 2.8 mmol/L (110 mg/dL) and an hsCRP of 1.8 mg/L. Here, the per cent reduction in LDLC with statin therapy is modest and residual cholesterol risk dominates the clinical picture. As such, the addition of ezetimibe would appear warranted, or potentially a PCSK9 inhibitor should these agents prove effective at event reduction. In contrast, for the patient on the right, aggressive statin therapy reduced LDLC by 70% to 1.15 mmol/L (45 mg/dL), yet the hsCRP remains elevated at 3.8 mg/L. Here, residual inflammatory risk dominates the clinical picture and the consideration of inflammation inhibitors might be the more thoughtful approach if ongoing trials of anti-inflammatory therapy also prove effective at event reduction.

Figure 2

Differential secondary prevention treatment options for statin-treated patients with ‘Residual Inflammatory Risk’ when compared with ‘Residual Cholesterol Risk’.

Figure 2

Differential secondary prevention treatment options for statin-treated patients with ‘Residual Inflammatory Risk’ when compared with ‘Residual Cholesterol Risk’.

In 1997, professor Attilio Maseri commented that initial studies linking inflammatory biomarkers to future cardiovascular risk were a glimpse ‘at the hidden side of the moon’.19 In the near future, we may be lucky enough to have targeted therapies for residual inflammatory risk that parallel those being developed for residual cholesterol risk. If so, the evolving concepts of residual inflammatory risk and residual cholesterol risk have the potential to advance personalized cardiovascular care in which the selection of secondary prevention agents for atherosclerotic protection will link the most appropriate intervention to the most appropriate patient.

Author's contributions

P.M.R. performed statistical analysis, handled funding and supervision, acquired the data, conceived and designed the research, drafted the manuscript, and made critical revision of the manuscript for key intellectual content.

Conflict of interest: P.M.R. has received investigator-initiated research support from the National Heart Lung and Blood Institute, Novartis, AstraZeneca, and Pfizer to conduct clinical trials relevant to this editorial, and is listed as a co-inventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AtraZeneca and Seimens.

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Author notes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

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