Is Chronic Inflammation Really Behind Heart Disease?

For twenty-five years, a large group of scientists has been convinced of something that sounds almost too simple. Your immune system, quietly overactive for years without you ever feeling sick, may be aging your arteries, your brain, and your colon. Turn down that slow burn, the thinking went, and you should be able to prevent not just heart attacks but a whole family of diseases that otherwise look nothing alike.

At the end of July, that theory took its biggest hit yet. A large, closely watched trial of a new anti-inflammatory drug from Novo Nordisk came back with the result nobody wanted. The hazard ratio was 0.99, in other words, there was no difference between the number of heart attacks, strokes and cardiovascular deaths in the two groups. Cardiologists who built careers on this idea are now asking out loud whether they got it wrong.

Smoke without fire, or fire without smoke?

Picture your blood vessels as old pipes. Cholesterol is the sludge that builds up inside them. For decades doctors have fought that sludge with statins, and it works. But some researchers noticed something odd. Even patients whose cholesterol was perfectly controlled kept having heart attacks. Something else was going on.

That something, the theory goes, is inflammation, the immune system’s alarm response, normally reserved for fighting infections and healing wounds. In some people the alarm never fully shuts off. It smolders for years, and that smoldering is what turns a stable patch of cholesterol sludge into a raw, unstable wound that can rupture and trigger a heart attack or stroke.

The evidence behind this was strong, and it came from several directions at once. Scientists cutting into diseased arteries found that the most dangerous plaques were not necessarily the biggest ones. They were the ones swarming with immune cells. Blood tests showed that a marker of inflammation called C-reactive protein predicted future heart attacks even in people with normal cholesterol. Geneticists found that people born with a natural glitch that dials down one particular inflammatory signal, a protein called interleukin-6 or IL-6, have measurably less heart disease over a lifetime. That last clue is hard to explain away, since nobody’s genes are shaped by their future health habits.

And when researchers gave people anti-inflammatory drugs in large trials, some of them worked. A 2017 trial of canakinumab cut heart attacks and strokes by 15 percent. Two later trials of colchicine, a cheap old gout medicine, cut events by 23 and 31 percent. The theory was not just plausible. It had trial data behind it.

The big bet

So when Novo Nordisk built a drug called ziltivekimab to block IL-6 directly, at the source of the inflammatory signal, expectations ran high. This was not a long shot. It targeted the exact pathway the genetics pointed to, in the patients most likely to benefit: over 6,300 people with established cardiovascular disease, chronic kidney disease, and clear evidence of ongoing inflammation.

And the drug did its job. Free IL-6 fell. C-reactive protein fell. Everything the researchers measured under the hood said the treatment was working as designed.

Then came the outcomes. Heart attacks, strokes, cardiovascular deaths: statistically identical between drug and placebo, with a confidence interval that ran from 0.88 to 1.11. Not a near miss. No signal at all.

The question everyone is really asking

Scientists are now split into two camps. Was this a good theory undone by a flawed experiment, or is the theory itself the problem?

The case for a bad drug or a bad design is strong. The trial enrolled people with advanced disease, arteries already thick with hardened, calcified plaque, and many with failing kidneys. By that stage inflammation may no longer be the main event. It may be a bystander at a scene where the real damage was done years earlier. There is also a targeting problem. IL-6 does not only fuel disease, it also helps repair tissue and regulate metabolism, so blocking it high up in the signaling cascade may knock out helpful effects along with harmful ones. The earlier successful drugs hit a narrower piece of the same pathway, further downstream. And the trial mixed cardiac patients with kidney patients, whose cardiovascular risk often comes from irregular heart rhythms or vascular calcification rather than from inflamed plaque. That alone could dilute a real benefit into statistical invisibility.

But the case for rethinking the theory cannot be waved away either. This is not the first anti-inflammatory drug to fail. A methotrexate trial failed in 2018. A 7,000-patient colchicine trial, the same drug that succeeded twice before, failed in 2025, in nearly the same population that made colchicine look so promising the first time. When the successes and failures start splitting this evenly, it stops looking like bad luck.

The honest answer is probably both. The theory survives, but in a narrower and more demanding form. Inflammation appears to matter for the right target, in the right patients, at the right stage of disease. It is not a switch you can flip in anyone with a heart problem.

Why this matters far beyond the heart

Here is what makes this trial bigger than cardiology. The same slow-burning immune activation implicated in heart disease has been blamed for a long list of conditions that, on the surface, have nothing in common.

I should say where I sit in this. The chronic low-grade immune activation hypothesis has been promoted by functional medicine practitioners, by social media personalities, and by a growing number of scientists, clinicians, and authors. I am one of them. I have also spent my career as a skeptic, and I have never been fully comfortable with the idea that so many different health problems trace back to a single cause. A theory that explains everything is usually a theory that needs more scrutiny, not less.

Chronic inflammation in the gut is a known driver of colon cancer, especially in people with inflammatory bowel disease, where the constantly activated immune system appears to nudge normal cells toward becoming malignant. In the brain, immune cells called microglia are suspected of accelerating Alzheimer’s and other dementias, not just responding to the damage but possibly causing some of it. The same low-grade inflammatory signature shows up in type 2 diabetes, obesity, and frailty in old age. Scientists have a term for it: inflammaging, the idea that much of what we call aging is the slow accumulation of immune system static.

If low-grade inflammation really does run underneath all of these diseases, it would be one of the most useful ideas in modern medicine, a single lever that moves cancer, dementia, diabetes, and heart disease at once. It would also connect disease risk directly to diet, through the gut-associated immune system, which is where much of the immune activation begins.

That is why this failure stings, and also why it would be a mistake to read too much into it. A drug that failed to help people with advanced heart disease says very little about whether calming inflammation could help someone with early colon polyps, or a brain just beginning to accumulate the plaques of Alzheimer’s. Those conditions have their own genetic and biological evidence pointing at inflammation.

The bottom line

This was not the story anyone wanted, and it is not proof that inflammation was a dead end. What it shows is that the question was never whether inflammation causes disease. The question is which inflammation, in which patients, at which point in the disease, and which piece of the immune system you block. That makes for a worse headline than either “inflammation theory confirmed” or “inflammation theory busted.” It is also very likely the true one, and it is where the next round of trials will have to aim, including two more ziltivekimab studies, HERMES in heart failure and ARTEMIS after acute heart attack, both due to report in the first half of 2027.