An experimental drug cuts genetic heart disease risk by 94% in trial: What we know

A potential breakthrough in cardiovascular medicine has emerged with the development of lepodisiran, an experimental drug by pharmaceutical company Eli Lilly.

The drug has demonstrated an unprecedented ability to lower levels of lipoprotein(a), or Lp(a), a genetically inherited risk factor for cardiovascular disease.

In a mid-stage clinical trial, patients who received either one or two 400-milligram doses of lepodisiran saw an average reduction of 93.9 per cent in their Lp(a) levels compared to those given a placebo.

These findings, which were presented at the American College of Cardiology’s annual meeting in Chicago and simultaneously published in the New England Journal of Medicine, have generated widespread attention among cardiologists and researchers.

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Unlike LDL cholesterol, which can be managed through diet and statin therapy, there are currently no approved treatments to lower Lp(a). Elevated levels of Lp(a) are associated with an increased risk of heart attacks, strokes, narrowing of the aortic valve, and peripheral artery disease.

Given that an estimated 1.4 billion people worldwide — including 64 million in the United States — have high Lp(a) levels, the development of an effective treatment has long been a priority in cardiovascular medicine.

The science behind Lipoprotein(a) and its dangers

Lipoprotein(a) is a complex particle composed of lipids and protein. It has been recognised as a risk factor for heart disease since 1974, but its hereditary nature has made it particularly challenging to address.

Unlike other cardiovascular risk factors influenced by lifestyle, Lp(a) levels are almost entirely determined by genetic inheritance.

This means that individuals with high Lp(a) levels often have a family history of unexplained heart disease, early-onset heart attacks, or strokes despite having normal cholesterol levels and blood pressure.

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People with moderately elevated Lp(a) levels have a 25 per cent greater risk of heart attack or stroke, while those with significantly high levels — found in roughly 10 per cent of the population — face up to double the risk.

Studies have shown that individuals of African ancestry are at the highest risk of elevated Lp(a) levels.

Dr. Steven Nissen, a preventive cardiologist at the Cleveland Clinic and the academic leader of the lepodisiran trial, highlighted the significance of this drug, stated in an interview, “What we have is a drug that can lower lipoprotein(a) with very infrequent administration.”

How Lepodisiran works

The experimental drug functions by targeting the body’s production of Lp(a), leading to sustained reductions over a six-month period following a single injection. Notably, the trial results showed that lepodisiran was well tolerated, with no serious adverse events reported.

However, while the drug has demonstrated a substantial reduction in Lp(a) levels, the key question remains: will this reduction translate into fewer heart attacks and strokes?

To answer this, Eli Lilly has initiated a large-scale Phase 3 clinical trial to assess whether lowering Lp(a) levels with lepodisiran leads to a tangible decrease in cardiovascular events. The results of this trial are expected in 2029.

Other pharmaceutical companies are also actively developing Lp(a)-targeting treatments. Silence Therapeutics is working on zerlasiran, while Amgen is testing olpasiran. Novartis is conducting trials on pelacarsen, which is administered through monthly injections.

Eli Lilly is additionally investigating muvalaplin, the only oral drug currently in clinical trials designed to lower Lp(a) levels. In a separate development, Merck has partnered with Jiangsu Hengrui Pharmaceuticals to test an experimental Lp(a)-lowering pill called HRS-5346.

Dr. David Maron, a preventive cardiologist at Stanford University who was not involved in the Lilly research, described the drug’s ability to drastically reduce Lp(a) levels as “thrilling.” reported The New York Times (NYT).

NYT also quoted Dr. Martha Gulati, a cardiologist at Cedars-Sinai Medical Center who also praised the study as “really elegant.”

The urgent need for Lp(a) testing

Despite the well-established link between high Lp(a) levels and cardiovascular disease, testing for this genetic risk factor remains rare. Research has found that only 0.3 per cent of the US population has been tested for Lp(a), and just 3 per cent of individuals diagnosed with heart disease have undergone the test.

Many doctors do not routinely check for Lp(a) because, until now, there were no treatment options available.

Nissen believes that testing for Lp(a) should become a standard part of cardiovascular risk assessments. “If you go into the coronary care unit and see someone who is 40 years old with an acute myocardial infarction, you need to know the level of their Lp(a),” he said, referring to heart attacks.

According to him, many of these patients have Lp(a) levels of 250 nanomoles per liter or higher, well beyond the normal threshold of 75.

Maron echoes this sentiment, noting that his clinic sees numerous patients who were unaware of their high Lp(a) levels until they had already experienced cardiovascular issues.

One such patient is Monte Wooden, a 71-year-old retired firefighter who had his first heart attack in 2006 despite having normal blood pressure and only moderately elevated LDL cholesterol levels, reported NYT.

After years of uncertainty, Maron tested Wooden’s Lp(a) levels and found them to be over 400 — an extreme elevation. Further investigation revealed a family history of early heart attacks, underscoring the hereditary nature of the condition.

Although lepodisiran and other emerging treatments offer hope for high-risk patients like Wooden, preventive cardiologists stress the importance of managing all other modifiable risk factors.

“We say: You have a disorder with serious implications. I want to take every risk factor you have off the table,” Nissen stated.

Until these drugs are widely available and proven effective in preventing heart attacks and strokes, physicians point out that patients should aggressively manage their LDL cholesterol, blood pressure, and overall cardiovascular health.

If late-stage clinical trials confirm the ability of Lp(a)-lowering drugs to reduce cardiovascular events, it could mark one of the most significant advancements in heart disease treatment in decades.

Unlike past efforts to alter cardiovascular risk factors — such as drugs that raised HDL, or “good cholesterol,” but failed to prevent heart disease — scientists are hopeful that these new drugs will provide tangible benefits.

With heart disease remaining the leading cause of death globally, any breakthrough in this field could have a profound impact on millions of lives.

With inputs from Reuters