On the 31st of July, a drug company found out it had just lost about thirty billion dollars in a single day. Novo Nordisk's stock-market value fell from $229.2 billion to $198.5 billion — a drop of $30.7 billion, on a share price fall of roughly 9 to 10 percent [1].
But their drug worked perfectly to lower inflammation, and inflammation is a key driver of heart disease.
Doesn't make sense, right?
The drug was built to switch off interleukin-6, or IL-6, which your immune system makes to trigger inflammation in response to injury, infection, or stress. This is important because IL-6 has been strongly linked to the aging process itself as well as heart disease. Let me explain, because all of this relates to your own health.
Table of Contents
- The Molecule That Looked Like A Master Switch
- The Genetics Said Go
- CANTOS: The Trial That Worked
- CIRT: The Drug That Never Engaged
- ZEUS: The Fairest Test Anyone Has Built
- Why The Inflammation Hypothesis Isn't Dead
- Target The Cause, Not The Messenger
- References
The Molecule That Looked Like A Master Switch
In 1993, a geriatrician noticed something odd in blood samples. In healthy young people, IL-6 is essentially undetectable. But in older people — no infection, nothing obviously wrong — there it was, sitting in the blood. He called it a cytokine for gerontologists, or for old people [2].
Then in 2000 the idea got bigger. What if this same low-grade, permanent, background inflammation is a driver of ageing itself? It was called inflammaging — ageing involves "a progressive increase in proinflammatory status" [3]. Suddenly IL-6 looked like a master aging switch.
And the observational data kept reinforcing this idea. Pool the studies together and people in the highest band of IL-6 are dying sooner — about a fifty percent higher rate of death from any cause than people in the lowest [4]. They lose strength faster. They lose their independence earlier.
By 2006 all of this was pulled together into a landmark review, where the authors concluded that if high IL-6 proves responsible for the decline of aging — "rather than merely reflecting other processes" — then targeting it could offer a major breakthrough [5].
And the good news just kept coming. Human genetics seemed to confirm it.
The Genetics Said Go
The method is called Mendelian randomisation, and it's simpler than the name. You're dealt your gene variants at conception, at random, before anything about your life has happened. So if some people are dealt a variant that quietly dampens IL-6 signalling, you can look at those people and see what a whole lifetime of slightly-less IL-6 does to them. Nature ran the trial. It started at birth, and nobody could drop out.
In 2012 they got the answer. A hundred and thirty-three thousand people. The variant that dampens IL-6 signalling was protective against coronary heart disease — and not a wobbly signal either, a p-value with four zeros after the decimal point before you get to a number [6].
And it wasn't only hearts. A later analysis pointed the same biology at lifespan, and found people carrying more of the protective version had parents who lived longer. Both parents. The heart signal and the ageing signal agreed [7].
And this is why the field took it so seriously. It's the same method that built the case for LDL-cholesterol and ApoB lowering. Point these methods at cholesterol and it points the same direction the drug trials point — the genetics and the medicines agree [8]. So when these research methods pointed at IL-6 and said protective, that carried real weight.
CANTOS: The Trial That Worked
The next step is an interventional trial to see if this theory worked in the real world. More good news arrived in 2017.
A trial called CANTOS did something nobody had managed before — it lowered inflammation without touching cholesterol at all, and it cut heart attacks. Ten thousand and sixty-one people, all of whom had already survived a heart attack, all of them with a raised CRP. They got an antibody that blocks IL-1 beta, which sits one step upstream of IL-6. Turn off the switch above, and the whole cascade below quietens down.
The result was a hazard ratio of nought point eight five. Which means: for every hundred major cardiovascular events in the placebo group, there were about eighty-five on the drug. A fifteen percent cut. Cholesterol untouched [9]. After twenty-five years of argument, the inflammation hypothesis of heart disease had a randomised trial with its name on it.
But there was a safety signal in this trial: more people died of infection on the drug than on placebo — 0.31 versus 0.18 fatal infections or sepsis per 100 person-years [9]. We'll come back to that shortly.
CIRT: The Drug That Never Engaged
Still, the medical world was excited by the possibility that if we can turn down inflammation, we can lower heart disease rates. So the next step was to see whether an existing and cheap anti-inflammatory could lower heart disease.
It was called CIRT — a different drug entirely. Nearly five thousand people, given low-dose methotrexate. And it came back flat. No change in heart disease.
But then the authors did something important. They went and measured what the drug had actually done to the inflammation — and the answer was nothing. "Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo" [10].
So the inflammation hypothesis of heart disease was still alive. The methotrexate study maybe just tested the wrong concept. The obvious next move was to hit IL-6 properly.
ZEUS: The Fairest Test Anyone Has Built
Which brings us to the new ZEUS trial, which tested a drug that removes IL-6 directly. This is the big trial that combines all of the exciting work together. Remember, IL-6 is linked to the aging process itself. It's linked to higher rates of heart disease.
They designed the trial brilliantly. Six thousand three hundred and seventy-six people. All had residual inflammation as measured by CRP. They were on cholesterol treatment, with an average LDL of seventy-seven milligrams per decilitre — treated, though not all the way down to the target we'd aim for [11]. So a lot of what was left over was the residual risk from inflammation.
And the drug worked. It knocked down CRP. It knocked down IL-6.
So why did the company's share price crash thirty billion dollars? Despite the drug doing what it was supposed to do, there was no reduction in cardiovascular events. A hazard ratio of 0.99 — so not even a hint that heart disease might be reduced by this new drug [12].
There were also high rates of infection. Consistent with targeting IL-6 inhibition, a higher proportion of people treated with the drug had serious infections compared to placebo. No difference in all-cause mortality was observed [12].
Why The Inflammation Hypothesis Isn't Dead
But this trial does not mean that the inflammation hypothesis of heart disease is dead and buried. And this result ties back to your own health. Let me explain.
IL-6 and CRP are messengers that rally the immune system to fight infection or to help in the repair process. So in the right context, they can be great. We want them to help fight infection. And it's no wonder that the CANTOS trial and the new ZEUS trial saw higher rates of infection, since those drugs dampened down the immune response.
But it's not just fighting off infection that matters here. It matters too for exercise.
In 2019, researchers looked at people who carried a lot of belly fat — and their belly fat pumps out IL-6. They randomised them two ways at once: twelve weeks of cycling or no cycling, and an IL-6 blocker or a placebo. Exercise did what exercise does — it shrank their visceral fat. Except in the group whose IL-6 was blocked. In them, the benefit vanished. Same training. No fat loss.
The researchers' conclusion was that "IL-6 is required for exercise to reduce visceral adipose tissue mass" [13].
So the thing we called the problem — the inflammatory messengers — turns out to be part of how exercise makes you healthier.
So my read is this. Inflammation is a real modifier of this disease. But we have to target the actual reason why inflammation is raised, and not just knock down the messengers.
Target The Cause, Not The Messenger
Go back to the visceral fat around your organs that pumps out IL-6.
In the clinic when I help people lose weight, their IL-6 and CRP levels plummet, because we've removed the actual reason why IL-6 and CRP are raised. We haven't just shot the messenger.
GLP-1 medications play a large role here, and they shift visceral fat hard. In a post hoc analysis of one trial, in Japanese adults, the abdominal visceral fat area fell forty percent, against seven percent on placebo [14]. And the inflammatory markers follow it down. Across the semaglutide trials CRP fell by around forty percent [15].
To me, the inflammation heart hypothesis is not dead. We just need to target the cause of why inflammation is high in the first place.
And after helping a patient reach their target weight, if they still have residual inflammation, we can consider using low-dose colchicine, which is a cheap anti-inflammatory. In a meta-analysis involving over 21,800 patients, colchicine reduced heart disease rates by 25 percent — though the authors graded the variation between the individual trials as high [16].
And we need to lower the other heart disease risk factors: visceral fat, insulin resistance, blood pressure, stress, smoking, and ApoB.
References
2. https://pubmed.ncbi.nlm.nih.gov/8426042/
3. https://pubmed.ncbi.nlm.nih.gov/10911963/
4. https://pubmed.ncbi.nlm.nih.gov/28866452/
5. https://pmc.ncbi.nlm.nih.gov/articles/PMC2645627/
6. https://pubmed.ncbi.nlm.nih.gov/22421340/
7. https://doi.org/10.1038/s41525-019-0097-4
8. https://pubmed.ncbi.nlm.nih.gov/23083789/
9. https://pubmed.ncbi.nlm.nih.gov/28845751/
10. https://pubmed.ncbi.nlm.nih.gov/30415610/
11. https://pubmed.ncbi.nlm.nih.gov/41369941/
13. https://pubmed.ncbi.nlm.nih.gov/30595477/
14. https://pubmed.ncbi.nlm.nih.gov/40189961/
