HomeCirculationVol. 141, No. 10From CANTOS to CIRT to COLCOT to Clinic Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBFrom CANTOS to CIRT to COLCOT to ClinicWill All Atherosclerosis Patients Soon Be Treated With Combination Lipid-Lowering and Inflammation-Inhibiting Agents? Paul M Ridker, MD Paul M RidkerPaul M Ridker Paul Ridker, MD, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave, Boston, MA 02215. Email E-mail Address: [email protected] Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Search for more papers by this author Originally published9 Mar 2020https://doi.org/10.1161/CIRCULATIONAHA.119.045256Circulation. 2020;141:787–789Lipid lowering is the cornerstone of atherosclerosis prevention such that every 1 mmol/L reduction in low-density lipoprotein cholesterol is associated with a 20% reduction in future cardiovascular events. Yet, 3 recent randomized, double-blind, placebo-controlled clinical trials indicate that aggressive inhibition of inflammation is also a crucial therapeutic target for secondary prevention in high-risk patients.In 2017, CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) provided proof-of-principle that inflammation inhibition in the absence of lipid lowering can significantly reduce cardiovascular event rates.1 Among 10 061 patients who had stable atherosclerosis with residual inflammatory risk who were already on statin therapy, those allocated to higher doses of canakinumab, a monoclonal antibody that binds interleukin-1β, experienced a 15% reduction in major adverse cardiovascular events and a 17% reduction in major adverse cardiovascular events plus urgent revascularization in comparison with placebo. CANTOS helped to define the inflammatory pathway from interleukin-1 to interleukin-6 to C-reactive protein (CRP) as a central target for atheroprotection, with the magnitude of clinical benefit for individual patients tracking with the degree of inflammation inhibition as assessed by on-treatment levels of both interleukin-6 and CRP.In contrast, in 2018, the National Institutes of Health–sponsored CIRT (Cardiovascular Inflammation Reduction Trial) of 4786 patients who had stable atherosclerosis with diabetes mellitus or metabolic syndrome reported that low-dose methotrexate did not reduce major adverse cardiovascular events.2 Yet, low-dose methotrexate also failed to reduce plasma levels of interleukin-1β, interleukin-6, or CRP. As such, in the context of CANTOS, CIRT can be viewed as providing informative neutral data supporting the concept that adequate inhibition of the interleukin-1β to interleukin-6 pathway of innate immunity is necessary to secure long-term cardiovascular benefits.Then, in late 2019, COLCOT (Colchicine Cardiovascular Outcomes Trial) provided exciting independent affirmation of the inflammation hypothesis of atherosclerosis by using the repurposed anti-inflammatory agent colchicine.3 Colchicine is an antimitotic agent that inhibits tubulin polymerization and microtuble generation. As a consequence, part of colchicine’s anti-inflammatory effect is likely to derive from its ability to inhibit NLRP3 inflammasome assembly and thus indirectly reduce interleukin-1β activation, leading to downstream reductions in both interleukin-6 and CRP.4 It is for this reason that colchicine has been used to treat and prevent classical inflammasome/interleukin-1β activation disorders, including gout and familial Mediterranean fever.In COLCOT, treatment with colchicine 0.5 mg daily in comparison with placebo over a 2-year period among 4745 patients after myocardial infarction resulted in a 23% relative reduction in the primary trial end point inclusive of myocardial infarction, stroke, resuscitated cardiac arrest, urgent hospitalization for angina leading to revascularization, and cardiovascular death (95% CI, 0.61–0.96; P=0.02). Although the benefit of colchicine was significant only for the coronary revascularization and stroke components of this primary end point, all cardiovascular outcomes were directionally consistent, providing reassurance. Furthermore, the effects in COLCOT were of greater magnitude in analyses including all postrandomization cardiovascular events, and first events, as well. These benefits came with modest risk because colchicine was associated with increases in pneumonia, nausea, and flatulence. Colchicine, however, is widely available and relatively inexpensive. Thus, if benefit is confirmed in the ongoing LoDoCO2 (Low Dose Colchicine after Myocardial Infarction) and CLEAR-SYNERGY trials (Colchicine and Spironolactone in Patients with STEMI/SYNERGY Stent Registry), colchicine could provide an important adjunctive therapy for high-risk patients with atherosclerosis. Because of renal excretion, chronic use of colchicine may be contraindicated for those with significant kidney dysfunction.On the basis of CANTOS, CIRT, and COLCOT, it can be anticipated that several novel anti-inflammatory and anticytokine agents that also target the NLRP3 to interleukin-1 to interleukin-6 to CRP pathway will be developed for atherosclerosis5(Figure). These will likely include, but will not be limited to, direct upstream inhibitors of the NLRP3 inflammasome (which would additionally lower interleukin-18 activation), and direct inhibitors of interleukin-6, as well. Interleukin-6 is widely seen as the central mediator of the proinflammatory atherosclerotic response and a probable causal target on the basis of Mendelian randomization analyses. Indeed, interleukin-6 levels remain a potent marker of cardiovascular risk even after interleukin-1β inhibition.Download figureDownload PowerPointFigure. Potential therapeutic targets in the NLRP3 inflammasome to interleukin-1 to interleukin-6 to C-reactive protein (CRP) signaling pathway. In response to various proinflammatory stimuli and crystalline structures (including cholesterol crystals), the proteinase caspase-1 contained in the NLRP3 inflammasome cleaves pro–interleukin-18 and pro–interleukin-1β into activated interleukin-18 and interleukin-1β, triggering robust proinflammatory signaling through interleukin-6. Interleukin-18, interleukin-1β, and interleukin-6 have direct vascular effects, whereas interleukin-6 also induces the acute phase response and concomitant hepatic production of CRP. CRP, when measured with high-sensitivity assays (hsCRP), is used in clinical practice as a biomarker to detect residual inflammatory risk in comparison with residual cholesterol risk. Yellow boxes indicate targets of this signaling pathway and, where available, approved agents that potentially could be repurposed as vascular therapeutics. IL-1β indicates interleukin-1β; IL-1βmAB, interleukin-1β monoclonal antibody; IL-1Ra, interleukin-1 receptor antagonist; IL-1 TRAP, dimeric fusion protein of an interleukin-1 receptor component and an IL-1 receptor accessory protein; IL-6, interleukin-6; IL-18, interleukin-18; and NLRP3 inflammasome, NOD-like receptor family pyrin domain containing 3 inflammasome.Whether alternative (non–interleukin-1 to interleukin-6) pathways of innate immunity can be modulated for atheroprotection is uncertain. To date, trials evaluating agents that inhibit tumor necrosis factor, adhesion molecules, leukotrienes, secretory phospholipases, and inflammation-associated antioxidants have been ineffective for event reduction. The research community needs to develop a more precise lexicon with which to differentiate inflammatory pathways with diverse vascular effects; the broad term anti-inflammatory is insufficient to describe agents targeting interleukin-1 and interleukin-6 while also being used to describe agents such as aspirin, ibuprofen, and celecoxib, which have markedly different vascular effects.At this time, the use of any targeted anti-inflammatory agent (including colchicine) should be considered only as an adjunct to statin therapy. In the future, more intensive low-density lipoprotein cholesterol–lowering agents will be coupled with anti-inflammatory therapies to maximize vascular benefit. Bempedoic acid, an agent that provides concomitant low-density lipoprotein cholesterol and high-sensitivity CRP lowering, is currently being evaluated in outcome trials. Ezetimibe monotherapy (which lowers low-density lipoprotein cholesterol but not high-sensitivity CRP) augments CRP reduction when combined with statin therapy. More potent combinations might include, as examples, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor (evolocumab, alirocumab) or a small interfering RNA (inclisiran) given in combination with an interleukin-1 inhibitor (canakinumab, gevokizumab, anakinra, rilonacept) or an interleukin-6 inhibitor (tocilizumab, sarilumab, sirukumab, olokizumab; Figure). The production of bispecific or trispecific therapeutic monoclonal antibodies targeting these pathways in a single chemical entity could provide an additional method for industry to move forward. Given well-described interactions between lipids and innate immunity, it is possible that the magnitude of clinical benefit deriving from intensive combination therapy will exceed the sum of the parts. Such an hypothesis could be evaluated in thoughtfully designed 2×2 factorial trials.The future of atherosclerosis therapy will involve a combination of intensive lipid lowering and intensive inflammation inhibition; the challenge is how to get there as quickly as possible.DisclosuresDr Ridker served as the Principle Investigator of the CANTOS and CIRT trials discussed in this commentary, which were funded by Novartis and the National Heart, Lung, and Blood Institute, respectively. Dr Ridker has served as a consultant to Novartis, Inflazome, Agepha, and Corvidia, entities that have inhibitors of the NLRP3 to interleukin-1 to interleukin-6 pathway in development.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circPaul Ridker, MD, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave, Boston, MA 02215. Email [email protected]harvard.edu