By Ron Winslow

The drug colchicine has been used for more than 2,000 years to treat the fiery joint-pain ailment called gout. It also is a remedy for a genetic disorder called familial Mediterranean fever, and for pericarditis, an inflammation of the sac around the heart.

Now colchicine may be set for a surprising new role. In June, the Food and Drug Administration approved a new low-dose version of the drug as the first-ever medicine to treat cardiovascular inflammation, marking a new approach for heart-attack prevention.

Several things could limit the adoption of colchicine by cardiologists, at least at first, including side-effect concerns and the emergence of several other new options for reducing the risk of heart attacks. But the drug’s approval provides fresh validation for a concept that has been gaining momentum in cardiology over the past 25 years—that inflammation is a key culprit in atherosclerosis, the artery-clogging disease, and that treating it can reduce the risk of a heart attack.

The bedrock strategy for heart-attack prevention has long been lowering LDL cholesterol with drugs called statins. Adding low-dose colchicine—which in one study reduced cardiovascular risk by 31% in patients already treated with statins and other preventive medicines—would enable doctors to simultaneously hit two biological targets that cause heart attacks.

“This is about combining therapies” that are both effective ways to reduce risk, says Dr. Paul Ridker, director of the Center for Cardiovascular Disease Prevention at Harvard-affiliated Brigham and Women’s Hospital, Boston. “They’re not in conflict, they’re synergistic.”

Ridker is a scientific adviser to Agepha Pharma, the company that owns the rights to market 0.5-milligram colchicine for cardiovascular-risk reduction, but wasn’t involved in the studies that led to the drug’s approval.

Making it personal

More broadly, colchicine is now part of a burgeoning arsenal of medicines that will enable cardiologists to personalize treatment as they seek to maximize heart protection for their high-risk patients beyond that achieved with statins. For example, new drugs that treat diabetes and obesity, two major risk factors for cardiovascular disease, are among medicines doctors say could play an important role in reducing heart risk. Nonstatin drugs that lower cholesterol are also in the mix.

“The pivot here is to precision cardiology as opposed to one-size-fits-all cardiology,” says Dr. Richard Kovacs, a professor at Indiana University School of Medicine, Indianapolis, and chief medical officer of the American College of Cardiology. Instead of routinely doubling down on cholesterol-lowering for most patients already taking statins, “we need to tailor treatment to the individual risk factors of the patient.”

The baseline strategy for high-risk patients won’t change, doctors say: statins, blood-pressure control, and aspirin or anti-platelet drugs to prevent clots. Add to that quitting smoking, a healthy diet and regular exercise.

“After that, it’s personalized approaches,” says Dr. Michael Blaha, director of clinical research at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore.

He envisions a scenario in which doctors consider inflammatory risk—which can be measured with a high-sensitivity test for a marker called C-reactive protein—cholesterol levels and diabetes and weight status to determine what’s driving a patient’s risk and then prescribe a drug best targeted to address that risk.

“Preventive cardiology is undergoing a renaissance,” he says. “We can do more than ever for our patients who have high risk.”

Like Ridker, Blaha is a scientific adviser to Agepha Pharma but wasn’t involved in the studies that led to the drug’s approval.

Hurdles to clear

Colchicine is cheap and safe and would be an effective option for many patients, study data indicate. But it faces challenges carrying the banner for a potentially important shift in medical practice. Diarrhea is associated with much higher doses typically used to treat gout flares and could make doctors hesitant, though researchers said it wasn’t a big issue with the once-a-day low dose tested in the heart-related trials. Updated treatment guidelines from the American College of Cardiology and American Heart Association gave colchicine a weak endorsement.

Another hurdle: lack of pharmaceutical companies marketing muscle to get the word out to clinicians and patients. The FDA gave approval for the drug to Agepha Pharma, a tiny family-owned company based in Dubai that has neither a sales force nor a presence in the U.S. market. It hasn’t been able to find a partner to co-promote the drug, which it calls Lodoco.

The potential market for an anti-inflammatory agent to reduce heart risk is huge. Data from clinical trials indicate that about half of patients with atherosclerosis have elevated levels of C-reactive protein, or CRP, despite being on intensive statin therapy. Such patients are significantly more likely to suffer a heart attack or other cardiovascular event than those with low CRP and low LDL.

Colchicine “is the first practical option we have now” for these patients, Kovacs says. Danish drugmaker Novo Nordisk is among several companies with new anti-inflammatory drugs in development to reduce heart risk.

Anti-Inflammatory Trial

In a randomized trial, roughly 5,500 patients with chronic coronary disease were divided into two equal groups; one received 0.5 mg of colchicine once daily, the other a placebo. The results showed a reduction in cardiovascular incidents, including heart attacks, for the patients taking colchicine.

Establishing a link

Inflammation is a normal part of the immune system’s response to injury and generally subsides once its healing work is done. But when the walls of the coronary arteries are under constant assault—from LDL cholesterol or, say, the effects of smoking or dietary fat—the inflammation that comes with the immune system’s response doesn’t subside. It becomes a chronic part of a process that causes accumulation of fatty deposits in the artery walls called plaques, which can rupture and cause heart attacks. Cholesterol can also crystallize in atherosclerosis, further provoking an immune-system response.

As research brought the link between inflammation in the coronary arteries and the risk of heart attacks into focus, the question was, would a drug that targeted inflammation lower that risk?

The answer came in a 10,061-patient study called Cantos, published in 2017 and led by Ridker, that tested canakinumab, an antibody from Novartis that targets an inflammatory immune-system protein called interleukin 1 beta. In patients with elevated CRP already on statin therapy, those treated with canakinumab had a 15% reduction in major cardiovascular events compared with those on a placebo, even though the drug had no effect on LDL cholesterol.

Dr. Steven Nissen, chief academic officer at the Heart Institute, Cleveland Clinic, who wasn’t involved in the study, says the result was “a landmark” because it was the first to show that inhibiting inflammation could reduce cardiovascular risk without lowering cholesterol.

“The more you look and the deeper you look, you have to believe that inflammation matters,” he says.

Dangerous Combination

When found together in the blood, increasing levels of C-reactive protein, a marker for inflammation, and higher ratios of total cholesterol (including LDL, HDL, and triglycerides) to HDL raise the risk of cardiovascular disease.

Winning approval

But canakinumab was already on the market under the brand name Ilaris for several rare diseases at a price that would be prohibitive for use as a preventive therapy. The drug also sharply reduced new cases of lung cancer, but led to a slightly higher number of fatal infections, compared with a placebo. Novartis ultimately decided against pursuing an FDA indication for heart-risk reduction for the drug, leaving cardiologists with a proven new target but no drug to use against it.

Enter colchicine. Its path to FDA approval began in a hospital ward in Western Australia in 2006, where Dr. Mark Nidorf, a cardiologist at the Harry Perkins Institute of Medical Research, in Perth, was treating a patient with severe pericarditis. He gave him a single dose of colchicine.

“The next day he just felt fantastic,” Nidorf says. He wondered if a drug that had such a rapid impact on pericarditis might be useful against atherosclerosis by treating arterial inflammation.

He recruited a group of his own patients who were on statins and had high CRP levels and randomly allocated them to take colchicine or no colchicine. A month later, CRP levels of those given the drug had come down “quite dramatically,” Nidorf says.

Nidorf was also struck by research describing the role of cholesterol crystals in cardiovascular inflammation. Colchicine treats gout pain, which is caused by a similar biology—uric-acid crystals that attack the joints.

On that basis, he and his colleagues launched—without drug-company funding—a four-year pilot study called Lodoco that recruited some 500 patients from his own practice, using a commonly available 0.5 milligram dose of colchicine.

The results, which Nidorf presented at an American Heart Association conference in 2012, were so encouraging that the Australian team, together with colleagues in the Netherlands, mounted a major randomized double-blind study, called Lodoco2. They enrolled 5,522 patients with stable cardiovascular disease.

About the same time, researchers in Canada mounted their own colchicine study, called Colcot. It enrolled 4,745 patients to test whether colchicine added to statin therapy would reduce recurrent events in patients who had suffered a heart attack within the previous 30 days.

The positive canakinumab results came out in 2017, part way through Lodoco2. “We were thrilled,” Nidorf says. Colchicine works differently, but hits canakinumab’s main target, providing optimism that the Lodoco2 trial would be positive too.

Sure enough, Lodoco2’s 31% relative reduction in cardiovascular events was reported in 2020. A few months earlier, the Colcot study found a 23% reduction in risk. In absolute terms, Colchicine prevented 2.5 to 3 heart attacks or other events for every 100 patients treated.

Agepha Pharma, which had acquired rights to market 0.5-milligram colchicine for cardiovascular-risk reduction from an Australian company, used the data to make its case for FDA approval.

The company launched the drug in the U.S. earlier this month at a list price of $99 a month. It is still negotiating arrangements with insurers, but plans to make it available at no charge to anyone who can’t afford it. Lacking a sales force or a budget for television marketing, it began promoting the drug to cardiologists online last week.

“We’re a small company trying to do big things for patients,” says Antonia Riel-Köllmann, Agepha’s managing director.

A tough market

Colchicine faces a challenging market. Other potential candidates for risk reduction beyond statins include Wegovy, from Novo Nordisk, and other so-called GLP-1 agonists that treat obesity and diabetes, as well as another class of diabetes drugs known as SGLT2 inhibitors. Full details on their risks and benefits in heart prevention aren’t yet known.

Amgen’s Repatha and Regeneron’s Praluent, drugs known as PCSK9 inhibitors, and bempedoic acid, marketed as Nexletol by Esperion Therapeutics, are other options. They are nonstatins that achieved modest additional reductions in LDL and heart risk in clinical studies when added to intensive statin treatment.

At $99 a month, Lodoco is much cheaper than drugs such as Wegovy, which lists for more than $1,600 a month at a Walgreens drugstore (before insurance coverage or discounts), or a PCSK9 inhibitor such as Repatha, which runs about $650 a month. Studies suggest the relative reduction in heart risk achieved with Lodoco is at least as large as with any of the other options.

Caveats and hesitation

Ridker and other cardiologists familiar with the drug say doctors may take it slow in prescribing it. The drug “is not for everybody,” Ridker says. It shouldn’t be given to patients with kidney or liver disease, for instance.

The approved once-a-day 0.5-milligram dose is slightly lower than 0.6-milligram generic colchicine already on the U.S. market and may mitigate kidney risks associated with the higher dose. But there are other reasons cardiologists may take time to get used to colchicine before adopting it as a regular option for their patients.

One is the history of other anti-inflammatory treatments. The painkiller Vioxx, once viewed as a potential candidate to curb cardiovascular inflammation, was pulled from the market in 2004 after it was found to have caused heart attacks and death from heart attacks. And soon after canakinumab’s success in reducing coronary events was reported, Ridker presented data from another study showing methotrexate, a generic drug for treating the inflammatory disorder rheumatoid arthritis, failed to curtail heart risk.

The updated treatment guidelines from the American College of Cardiology and the American Heart Association, issued in July, acknowledged inflammation’s role in the development of atherosclerosis for the first time. But the guidelines stopped short of recommending colchicine, saying only that “it may be considered” as an option to reduce “recurrent” cardiovascular events. Citing among other reasons potential interactions with other drugs and a slight increase in non-heart-related deaths, the guidelines say use of colchicine should be limited to patients at very high risk “until further data become available.”

Cleveland Clinic’s Nissen, who has been prescribing the 0.6-milligram dose for selected patients, says he’ll likely give one of the two versions (depending on price) to more patients in the wake of FDA approval.

“I think it is going to have a role to play, but it’s going to come after we’ve done other things we can do,” he says.

Indiana University’s Kovacs cautions that high-risk patients already on several medicines may resist adding another, especially one that while potentially reducing a serious risk, doesn’t make them feel better, a challenge facing many preventive drugs.

Dr. Roger Blumenthal, director of the Ciccarone Center for the Prevention of Cardiovascular Disease at Hopkins, says given the lukewarm advice from the new guidelines, he’ll likely urge patients to work harder on healthy lifestyle changes—quitting smoking, weight loss and exercise all lower inflammation—before prescribing the drug.

With growing interest in Wegovy and other obesity drugs, colchicine “is going to enter a crowded space,” Hopkins’s Blaha says. “But it will be a unique drug—the only anti-inflammatory drug approved for heart disease.”