How Common Is Residual Inflammatory Risk?
2017; Lippincott Williams & Wilkins; Volume: 120; Issue: 4 Linguagem: Inglês
10.1161/circresaha.116.310527
ISSN1524-4571
Autores Tópico(s)Adipokines, Inflammation, and Metabolic Diseases
ResumoHomeCirculation ResearchVol. 120, No. 4How Common Is Residual Inflammatory Risk? Free AccessDiscussionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessDiscussionPDF/EPUBHow Common Is Residual Inflammatory Risk? Paul M Ridker Paul M RidkerPaul M Ridker From the Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, MA; and the Harvard Medical School, Boston, MA. Originally published17 Feb 2017https://doi.org/10.1161/CIRCRESAHA.116.310527Circulation Research. 2017;120:617–619After initiating aggressive statin therapy, high-risk atherosclerosis patients can be classified as having residual cholesterol risk (on-treatment low-density lipoprotein cholesterol [LDLC] ≥70 mg/dL), residual inflammatory risk (on-treatment high-sensitivity C-reactive protein [hsCRP] ≥2 mg/L), both conditions, or neither. In contemporary lipid-lowering trials, there are roughly twice as many individuals in whom the principle unmet clinical need is residual inflammatory risk as compared with residual cholesterol risk. As such, continued translational investigation into inflammatory mediators of plaque initiation, progression, and rupture is crucial for the vascular biology community and ultimately for patient care.A critical principle of personalized medicine is to provide the right therapy to the right patient at the right time. Yet, in the treatment of chronic atherosclerosis, statin therapy has proven so effective that all patients should be aggressively treated for life, typically with high-intensity regimens.1Addressing the problem of residual risk after statin therapy has proven complex as differing biological processes drive recurrent events in different patients. On the one hand, individuals treated with statins who, nonetheless, have persistently elevated levels of atherogenic lipoproteins represent a group with residual cholesterol risk where additional lipid-lowering therapies, including PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibition, are likely to prove effective. On the other hand, the majority of patients treated with a higher intensity statins will achieve 50% to 85% reductions in LDLC and apolipoprotein B.2,3 For these individuals in whom cholesterol is no longer the primary problem, the translational research community has long been concerned about the roles of innate and acquired immune function in driving recurrent atherosclerotic events.4–7 Such patients have recently been described as having residual inflammatory risk and might benefit from anti-inflammatory treatments rather than further lipid lowering.8Although knowledge of the relative proportions of atherosclerotic patients with residual cholesterol risk and residual inflammatory risk is important for translational investigators and for drug development, data addressing this issue have been scant. Most data come from clinical trials where lipid-lowering therapy is provided on a per-protocol basis. As examples, in the PROVE-IT trial (Pravastatin or Atorvastatin Evaluation and Infection Therapy) inclusive of 3745 patients with acute coronary syndrome, 44% of those allocated to atorvastatin 80 mg achieved the dual goals of LDLC<70 mg/dL and hsCRP<2 mg/L.9 However, more than twice as many PROVE-IT patients had residual inflammatory risk (defined as an on-treatment LDLC<70 mg/dL and hsCRP≥2 mg/L) as compared with residual cholesterol risk (defined as an on-treatment LDLC≥70 mg/dL and hsCRP 70 mg/dL and hsCRP≤2 mg/L), 16% had only the LDL goal achieved (LDL≤70 mg/dL and hsCRP>2 mg/L), 14% had both goals achieved (LDL≤70 mg/dL and hsCRP≤2 mg/L), and 44% had neither goal achieved (LDL>70 mg/dL and hsCRP>2 mg/L; Figure 1, right).The consistency of observations across 2 trials and a contemporary registry suggests that chronic atherosclerosis patients treated with statin therapy who have residual inflammatory risk are common. This has several immediate implications for the vascular biology and clinical communities.First, while continued LDLC reduction can be achieved with agents, such as PCSK9 inhibitors, the total number of individuals with an absolute need for such reduction may be smaller than anticipated because 27% to 28% of participants in the PROVE-IT and IMPROVE-IT trials had poststatin LDLC levels >70 mg/dL. By contrast, the VIRGO registry data confirm observations that higher-intensity statin therapy is often underutilized in the general community.Second, among those receiving aggressive lipid reduction, larger proportions of atherosclerotic patients had persistently elevated levels of hsCRP than persistently elevated levels of LDLC. This is perhaps not surprising because statin therapy is highly effective at lowering LDLC but only a moderate anti-inflammatory intervention. As such, these data support the ongoing development of agents that reduce the inflammatory response in both chronic atherosclerosis and in acute ischemia.12Finally—and crucial from a biological perspective—these clinical data demonstrate the fundamental need to continue basic investigations into inflammatory mediators of plaque initiation, progression, and rupture, all issues highly relevant to readers of Circulation Research. We have yet to make significant clinical progress on this second crucial part of the vascular prevention paradigm; yet, the success of personalized medicine requires us to look beyond LDLC reduction for novel targets and novel avenues of treatment. Ongoing trials of low-dose methotrexate, colchicine, interleukin-1 inhibitors, and interleukin-6 inhibitors represent the first wave of what will likely be a long series of studies that target residual inflammatory risk rather than residual cholesterol risk.13–15 A positive signal from any of these initial trials will do more than simply close the loop on the inflammatory hypothesis of atherothrombosis. As shown here, the number of individuals in need of such treatments may well exceed the number in need of further lipid reduction.DisclosuresDr Ridker has received investigator-initiated research support from the National Heart Lung and Blood Institute, Novartis, AstraZeneca, Kowa, and Pfizer to conduct clinical trials relevant to this editorial and is listed as a coinventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes mellitus that have been licensed to AtraZeneca and Seimens.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Paul M Ridker, MD, MPH, Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, 900 Commonwealth Ave, Boston, MA 02215. E-mail [email protected]References1. 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February 17, 2017Vol 120, Issue 4 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.116.310527PMID: 28209792 Originally publishedFebruary 17, 2017 KeywordsatherosclerosisC-reactive proteinpreventioncholesterolinflammationPDF download Advertisement SubjectsAtherosclerosisInflammationPrimary Prevention
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