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The failure of colchicine to reduce cardiovascular events post–myocardial infarction in a recent trial led some cardiologists to question the role of inflammation in coronary artery disease (CAD) — or, at least, whether treating it with an anti-inflammatory drug would make a difference.

While there is general agreement that inflammation is important in CAD, questions remain about the implications for patient management.

Which Came First: Inflammation or Atherosclerosis?

“The inflammatory theory of CAD posits that chronic, low-grade inflammation plays a crucial role in the initiation, progression, and destabilization of atherosclerotic plaques,” said Pablo Corral, MD, manager of the Lipids and Atherosclerosis area in the Lipid Clinic at the ICM Institute, Buenos Aires, Argentina.

“However, current evidence suggests that inflammation primarily exacerbates atherosclerosis rather than serving as the initial trigger,” he told Medscape Medical News. “The retention and modification of apoB-containing lipoproteins within the arterial wall initiates the process, and inflammation follows as a maladaptive response to this lipid accumulation.”

“Atherosclerosis is caused by vascular inflammation due to cholesterol deposition that occurs with hyperlipidemia,” said Kathryn Moore, PhD, a cardiology professor at New York University Langone Health, New York City. “The immune system recognizes the accumulated lipids as foreign, setting off an inflammatory response in the artery wall, which if not resolved, leads to the formation of plaque.” 

“These plaques can continue to progress over decades, and inflammation is thought to be a key factor in their continued expansion and vulnerability to rupture, which can lead to myocardial infarction or stroke,” she told Medscape Medical News.

“Do people get plaques from cholesterol and does that then trigger inflammation? Or does inflammation trigger the development of plaques? It’s an age-old argument in the field,” said Steven Nissen, MD, of the Cleveland Clinic, Cleveland. “It’s almost impossible to answer that question definitively, and I don’t think we need to.” 

“If you have high cholesterol, you’re going to have events at a higher rate, and if you have evidence of inflammation, you’re also going to have events at a higher rate,” he told Medscape Medical News. Evidence for both, he said, was shown two decades ago, in his study looking at the effects on disease progression from low-density lipoprotein cholesterol (LDL-C) and from C-reactive protein (CRP), a marker of inflammation.

Both LDL-C and CRP levels had a “strong” relationship to disease progression among the study participants on statins, and similar results were seen in another decades-old study led by Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston.

Subsequent studies have confirmed the connection between inflammation and cardiovascular disease events, regardless of etiology.

Obesity and Other Sources of Inflammation

Numerous sources of inflammation can influence vulnerability to CAD events including inflammatory disorders such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease (IBD). Controlling intestinal inflammation has been shown to reduce the risk for atherosclerosis and cardiovascular events in patients with IBD.

“Obesity is also a big driver of inflammation,” Nissen noted. Intra-abdominal fat cells trigger the release of cytokines that in turn travel to the liver, where they trigger an inflammatory reaction. In response, levels of CRP and interleukin-6 (IL-6), another inflammatory marker, go up, he explained. “But if you lose weight, measures of inflammation go down.”

His team has shown that bariatric surgery reduces inflammatory markers, and the ongoing Surmount MMO trial is looking at the effect of tirzepatide on morbidity and mortality in adults with obesity, with data to come on cardiovascular outcomes.

Periodontal diseases and lifestyle factors including smoking, stress, and sedentary behavior can also boost inflammation, according to Corral. And although there is no single, definitive inflammatory phenotype of atherosclerosis, certain features are indicative of atherosclerotic inflammation, he said.

These include elevated levels of high-sensitivity CRP (hsCRP), IL-6; and nucleotide oligomerization domain–, leucine-rich repeat–, and pyrin domain–containing protein 3 (NLRP3) inflammasome activation which is “particularly relevant in residual inflammatory risk and lipid-driven inflammation”; and plaque imaging features such as perivascular fat attenuation index and arterial wall inflammation assessed by PET-CT.

‘More Precise’ Targeting Needed

Does the source of inflammation need to be treated in order for patients to benefit? Probably not, according to the experts interviewed.

Nissen referenced two previous positive trials of colchicine LoDoCo2 and COLCOT that “didn’t require you to have a source of the inflammation,” he said. “Participants just had to have inflammatory biomarkers. And if you have inflammatory biomarkers, there’s no reason to believe that you will not benefit — the source probably doesn’t matter.”

Binita Shah, MD, director of Research in Interventional Cardiology and associate professor at NYU Grossman School of Medicine in New York City, agreed. “There are a wealth of data to show that lower inflammatory levels are associated with lower cardiovascular events, and CANTOS proved it by not only demonstrating a benefit on cardiovascular events but also demonstrating that the patients who achieved on- treatment reductions in inflammatory markers are the patients who derived benefit from the anti-inflammatory therapy,” regardless of the source of the inflammation.

“My approach to patient care has always been to encourage healthy diet, exercise, dental hygiene, smoking cessation, lipid control, diabetes control, etc.,” she told Medscape Medical News. “Despite that, some patients remain with cardiovascular events, and to target their residual inflammatory risk, an anti-inflammatory therapy should provide that additional benefit.”

Corral believes anti-inflammatory drugs may offer only partial or transient benefit if the underlying cause is not addressed. “Targeting inflammation alongside aggressive lipid lowering and lifestyle modifications may be the best strategy moving forward. Future treatments might focus on early intervention, lipid-lowering combined with inflammation resolution, and selective IL-6/NLRP3 inhibitors rather than nonspecific immunosuppressive strategies,” he said referring to the failure of broad anti-inflammatory strategies like methotrexate and colchicine in certain trials.

Beyond Colchicine: CRP Testing and Novel Drugs

Looking ahead, Ridker advocates for universal screening of hsCRP, the same way we have universal screening for LDL-C and for blood pressure. He had patents on CRP tests that ran out more than a decade ago and currently neither he nor his hospital benefit financially in any way from hsCRP testing. “I can’t look across the room and guess who has an elevated hsCRP any better than I can look across the room and guess who has elevated LDL cholesterol,” he said, adding that “there’s no reason to be guessing.”

Ridker added that “we’ve been able to show over and over that once you’re on a statin, CRP is much more predictive of recurrent heart attacks and recurrent strokes and cardiovascular death than is LDL cholesterol, yet our guidelines still tell us to focus entirely on LDL.”

Indeed, Ridker’s recent study of 30-year cardiovascular outcomes in women showed that hsCRP was a stronger predictor of the likelihood of having a heart attack, stroke, or dying of a cardiovascular event than measures of either LDL-C or lipoprotein (a).

Currently colchicine, is the only anti-inflammatory drug approved by the US Food and Drug Administration for CAD. Novel drugs are on the horizon. For example, a recent review discussed new entities targeting the NLRP3 inflammasome and IL-1, as well as potential new roles for colchicine and for SGLT2 inhibitors.

In a discussion on Medscape, the principal investigator of the negative colchicine trial, Sanjit Jolly, MD, said that when asked if the inflammatory hypothesis of CAD is dead, his response is “absolutely not”. He thinks that the focus should now be on different parts of the inflammatory pathway and is really interested to see what the IL-6 story tells us.

Ridker is leading studies of ziltivekimab (Novo Nordisk), a monoclonal antibody that targets IL-6. Three trials of the drug are ongoing in patients with heart failure, myocardial infarction, and chronic kidney disease.

“Hopefully, they all may present us with some novel new ways, beyond colchicine, to lower the risk of heart attack, stroke and, cardiovascular death in some very high-risk patients,” Ridker said.

Shah had received grant funding from the VA Office of Research and Development and previously had received grant funding from the NIH; she currently is a consultant for Novo Nordisk on the ARTEMIS trial, serves on the advisory board for Philips Volcano, and serves on the steering committee for Magenta Medical’s Elevate trial.

Ridker had received institutional research grant support from Kowa, Novartis, Amarin, Pfizer, Esperion, Novo Nordisk, and the NHLBI; during the past 3 years he has served as a consultant to Novartis, Agepha, Ardelyx, Arrowhead, AstraZeneca, CSL Behring, Janssen, Civi Biopharm, Glaxo Smith Kline, SOCAR, Novo Nordisk, Eli Lilly, New Amsterdam, Boehringer-Ingelheim, Cytokinetics, Nodthera, Tourmaline Bio and Cardio Therapeutics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and received compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston). Nissen reported that the Cleveland Clinic Center for Clinical Research (C5Research) had received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen, Arrowhead, Bristol Myers Squibb, Cardigan, CRISPR Therapeutics, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics; Nissen is involved in conducting these clinical trials but had received no personal remuneration for his participation, and although he consults for these pharmaceutical companies, he does not accept compensation. Moore reported no conflicts of interest. Corral had received grants or contracts from Amgen and PTC Therapeutics; honoraria from Amgen, Novartis, Boehringer Ingelheim, Pfizer, PTC, and TEVA; payment for expert testimony from PTC and Novartis; and support to attend meetings from Novartis and Boehringer Ingelheim. Jolly had received grant support from Boston Scientific, and honoraria from Teleflex, Abiomed, and Shockwave.

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.