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by Giulia Notarangelo
figures by Abagail Burrus

A drug that might significantly reduce the risk of heart attack and lung cancer is being hailed by researchers as the biggest breakthrough in the treatment of cardiovascular disease since the introduction of cholesterol-lowering drugs called statins over 30 years ago. Despite the fact that drug companies sell over $30 billion worth of statins annually, roughly 600,000 people still die of heart disease each year in the United States (one in every four deaths) and it remains the leading cause of death worldwide. The alternative being studied, canakinumab, is currently sold under the brand name Ilaris by Novartis to treat juvenile rheumatoid arthritis and other rare hereditary disorders. Unlike most treatments against heart disease that almost exclusively target cholesterol, canakinumab provides protection in an entirely different way: it reduces inflammation in the body.

The Failure of the Cholesterol Theory

In the long-lasting fight against heart disease, we have been taught to view cholesterol as public enemy number one; doctors tell us to monitor the amount of saturated fats that we consume and to decrease our intake of cholesterol-rich foods. But what is the actual link between high cholesterol and heart disease?

Cholesterol is a lipid (fat) that is found in all the cells in our body. Because lipids are hydrophobic (i.e. cannot be dissolved in water) and our blood is mostly composed of water, cholesterol must be transported through the bloodstream via water-loving carrier molecules known as lipoproteins. Two major classes of lipoproteins, HDL and LDL, have frequently been referred to as ‘good’ and ‘bad’ cholesterol, respectively. High-density lipoproteins (HDL) facilitate the removal of cholesterol from your blood by transporting it to the liver. Conversely, low-density lipoproteins (LDL) deliver cholesterol to muscle and fat tissue (Figure 1).

Figure 1: HDL vs. LDL in heart disease. HDL and LDL, also known as ‘bad’ and ‘good’ cholesterol, respectively, are types of lipoproteins involved in the transport of cholesterol in the blood. In the context of heart disease, LDL transports cholesterol to the cells in our body and can lead to the accumulation of plaque in the arteries. Conversely, HDL is involved in the removal of excess cholesterol by bringing it back to the liver, which can flush it from the body.
Figure 1: HDL vs. LDL in heart disease. HDL and LDL, also known as ‘good’ and ‘bad’ cholesterol, respectively, are types of lipoproteins involved in the transport of cholesterol in the blood. In the context of heart disease, LDL transports cholesterol to the cells in our body and can lead to the accumulation of plaque in the arteries. Conversely, HDL is involved in the removal of excess cholesterol by bringing it back to the liver, which can flush it from the body.

For decades, researchers have believed that the buildup of cholesterol in the arteries makes it difficult for the heart to pump blood throughout the body. LDL particles that are not absorbed by cells can accumulate in the arteries, leading to the buildup of a substance called plaque. This degenerative material can reduce blood flow and, when disrupted, result in the formation of blood clots. If the clot is large enough to completely block the artery, then it may cause a heart attack.

Despite the connection between cholesterol and heart attacks, drugs that lower cholesterol don’t work for everyone. About a quarter of heart attack survivors will suffer another within five years, even if they take cholesterol-lowering drugs. Furthermore, not only can people have elevated blood cholesterol levels without developing heart disease, but about half of heart disease victims have normal LDL levels. What are we missing? For years, researchers have postulated that inflammation in the body might be another crucial, if not mandatory, contributor to cardiovascular disease.

What is Inflammation?

Inflammation is a protective response to injury that involves immune cells and molecules in the blood, resulting in pain, redness, swelling, and heat. Some of the molecules involved in initiating the inflammatory response are small proteins known as cytokines. Cytokines function by recruiting immune cells to the site of injury and mediating the subsequent clearance of pathogens and damaged cells. Although the word has acquired a negative connotation, inflammation is a fundamental biological response to injury and, without it, our bodies wouldn’t be able to clear bacterial and viral infections.

Like all biological processes, inflammation is highly regulated, and it usually disappears after the infection or injury has been resolved. However, when inflammation gets out of hand or is not properly regulated, it may result in disease. In fact, many common diseases, such as autoimmune disorders, cancer, diabetes, and depression involve persistent, low-grade inflammation.

The Inflammation Theory

What led people to believe that inflammation might be a contributing factor to cardiovascular disease? Inflammation has been observed at the sites of plaque formation for centuries. Moreover, a growing body of evidence suggests that measures of C-reactive protein (CRP), a biological indicator of inflammation, may be even more effective than cholesterol at predicting the risk of heart disease. The source of this chronic low-level inflammation is not completely understood. Several factors, however, such as smoking, alcohol consumption, diabetes, poor diet, stress, depression, physical inactivity, and modified LDL are thought to be major contributors to the inflammatory process.

Recent studies have suggested that, in order to promote heart disease, LDL has to first become modified, either via the formation of needle-like structures or through a chemical process known as oxidation. Modified LDL is believed to then recruit immune cells to the arterial walls, driving the process of plaque formation. Our immune system perceives this plaque as foreign, and so it releases inflammatory cytokines with the hope of removing the modified cholesterol. Elevated cytokine levels can cause harm by injuring blood vessels and disrupting the plaque surface, leading to heart attacks, strokes, and in some cases death (Figure 2).

FIgure 2: Schematic overview of the inflammation theory. LDL diffusion into blood vessel walls (1) leads to the accumulation of lipids in the arterial walls (2). LDL becomes modified via oxidation or through the formation of needle-like structures (3). Modified cholesterol recruits immune cells (4), leading to the release of inflammatory cytokines (5) and the formation of plaque (6). Finally, plaque destabilization and rupture can result in a stroke (7).
Figure 2: Schematic overview of the inflammation theory. LDL diffusion into blood vessel walls (1) leads to the accumulation of lipids in the arterial walls (2). LDL becomes modified via oxidation or through the formation of needle-like structures (3). Modified cholesterol recruits immune cells (4), leading to the release of inflammatory cytokines (5) and the formation of plaque (6). Finally, plaque destabilization and rupture can result in a stroke (7).

CANTOS Trial

Despite the accumulation of evidence suggesting that inflammation may be a major driver of cardiovascular disease, the so-called inflammation theory had never been proven. This led to several clinical trials designed to test it, and Novartis may have finally taken the prize. Their four-year clinical trial CANTOS involved over 10,000 participants with a history of heart attacks from 39 countries. The goal of the study was to test whether the drug canakinumab could lower the incidence of cardiovascular disease in patients with high CRP (i.e. an elevated inflammatory response).

The study, which was published in the New England Journal of Medicine, reported that patients on the medium dose of the drug were 15% less likely to suffer a heart attack than those receiving the placebo. Moreover, the drug also cut the risk of the patient being hospitalized with chest pain (by 37%) or needing expensive interventional procedures like bypass surgery (by 32%). Importantly, these results are more dramatic than the reduction in risk seen after taking statins, despite patients’ cholesterol levels remaining the same throughout the treatment.

The Best Side Effect

If the results of the CANTOS trial were not exciting enough already, a follow-up study published in The Lancet revealed that the drug had a surprising side effect: the treatment sharply reduced rates of lung cancer. When administered at the highest dose, canakinumab decreased the incidence of lung cancer by a startling 67%. Patients on the highest dose also showed a 50% reduction in cancer mortality compared to those who received a placebo.

A prior history of heart attacks and high CRP levels were the only major criteria to enroll in the clinical trial; no patients had a prior history of cancer. So why did the investigators decide to look at lung cancer? It turns out that many of the patients who have had a heart attack have also smoked cigarettes, raising their risk for lung cancer. Although these preliminary findings are exciting, future studies are needed to validate the role of the drug in preventing lung cancer, as the CANTOS trial was primarily exploratory and not directly designed to study lung cancer.

Unfortunately, not all side effects were as welcome as the benefits shown for lung cancer. One in every 1,000 patients treated with canakinumab was at risk of dying from an infection, likely due to the fact that the drug suppresses part of the body’s immune response. Once infections were taken into account, all-cause mortality did not differ between the drug and placebo groups.

Final Thoughts

The results of the CANTOS trial are undoubtedly exciting. CANTOS is the first trial to convincingly show that inflammation plays a role in cardiovascular disease in a cholesterol-independent way. These results broaden our understanding of both heart disease and cancer and could lead to a new generation of treatments. It will be interesting to see how the drug can be combined with other therapies or inflammation-lowering lifestyle changes to reduce the rate of cardiovascular disease even further.

Giulia Notarangelo is a second-year graduate student in the Biological and Biomedical Sciences Ph.D. program at Harvard Medical School.

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