The article from The Times of India, titled “Explained: How close are we to treating a lipoprotein that can kill?” (published April 9, 2025), discusses the emerging potential to treat high levels of lipoprotein(a), or Lp(a), a genetically determined type of cholesterol linked to sudden and often fatal heart attacks and strokes. Below is a summary and explanation of the key points, addressing how close we are to effectively treating this dangerous lipoprotein:

What is Lipoprotein(a)?

• Lp(a) is a complex particle made of lipids and proteins that transports cholesterol and fatty acids in the body. While cholesterol is essential for cell function, high Lp(a) levels are associated with a significantly increased risk of cardiovascular diseases, including heart attacks and strokes.
• Unlike LDL (“bad” cholesterol), Lp(a) is not effectively lowered by lifestyle changes (diet, exercise) or most existing medications, making it a challenging risk factor to manage.
• Lp(a) is particularly dangerous because it promotes artery plaque buildup, causes inflammation, and increases blood clot formation, contributing to premature cardiovascular events, especially in populations like Indians, who may have higher genetic predisposition.

Why is Lp(a) a Concern?

• Prevalence: An estimated 1.4 billion people globally, including 64 million in the U.S., have elevated Lp(a) levels, with higher risks among individuals of African descent and South Asians, including Indians.
• Genetic Link: Lp(a) levels are largely inherited, with up to 90% of concentrations determined by the LPA gene, making it a significant risk factor for young individuals (under 45 for men, under 50 for women) who may otherwise lack traditional risk factors like diabetes or smoking.
• Undetected Risk: Routine cholesterol tests don’t typically measure Lp(a), so many people are unaware of their elevated levels until a cardiovascular event occurs.
• In India, Lp(a) is increasingly recognized as a key factor behind the high rates of premature heart attacks, which occur about 10 years earlier than in Western populations.

How Close Are We to Treating Lp(a)?

Recent advancements, particularly in experimental drugs, suggest we are on the cusp of breakthroughs for managing Lp(a). Here’s the current state of progress:

1. Experimental Drugs Showing Promise:

• Lepodisiran (Eli Lilly): A single dose of this small interfering RNA (siRNA) drug reduced Lp(a) levels by up to 94% for nearly a year in early trials. It works by targeting the mRNA that instructs the body to produce Lp(a), effectively “shutting down” its production. Phase 3 trials are now enrolling to confirm safety and efficacy in reducing heart attacks and strokes.
• Olpasiran (Amgen): Another RNA-based therapy, olpasiran lowered Lp(a) by at least 95% within nine months in early trials, though some patients, like one mentioned in a trial, received placebos and saw no benefit. Further studies are ongoing.
• Antisense Oligonucleotides (ASOs) and other RNA-targeting therapies are also under investigation, capable of reducing Lp(a) by up to 90% without affecting other lipoproteins.

1. Mechanism of Action:

• These drugs use advanced genetic technologies (siRNA, ASOs) to block the production of apolipoprotein(a), the key protein in Lp(a). Unlike statins, which primarily target LDL cholesterol, these therapies specifically address Lp(a), offering a targeted approach.
• Earlier treatments like niacin or PCSK9 inhibitors (which lower LDL by 60% and Lp(a) by 25–30%) had limited impact on Lp(a), underscoring the need for these new therapies.

1. Clinical Trial Status:

• Lepodisiran: After promising Phase 1 and 2 results, Phase 3 trials are underway to evaluate long-term safety and whether reducing Lp(a) translates to fewer cardiovascular events. Results from these trials will be critical.
• Olpasiran and Others: Similar trials are advancing, with some expecting data within the next few years. If successful, these drugs could be available by the late 2020s or early 2030s.

1. Challenges Ahead:

• Safety: While early trials show these drugs are well-tolerated, long-term safety data from larger populations are needed to confirm no unforeseen side effects.
• Efficacy: It’s not yet proven that lowering Lp(a) directly reduces heart attacks or strokes, though studies like lipoprotein apheresis (which lowers Lp(a) by 60–70%) suggest a link to fewer cardiovascular events. Definitive evidence awaits Phase 3 outcomes.
• Access and Cost: RNA-based therapies are expensive, and ensuring availability, especially in countries like India with high Lp(a) prevalence, will be a hurdle.
• Screening: Widespread Lp(a) testing isn’t standard, so raising awareness among doctors and patients is crucial to identify those who could benefit.

Current Treatment Options

Until these new drugs are approved, managing Lp(a) remains limited:

• Lipoprotein Apheresis: A dialysis-like procedure that physically removes Lp(a) and LDL from the blood, used in severe cases. It’s effective (lowering Lp(a) by 60–70%) but invasive, costly, and not widely available.
• PCSK9 Inhibitors: Drugs like evolocumab reduce Lp(a) modestly (25–30%) alongside LDL but aren’t primarily designed for Lp(a).
• Lifestyle: Diet, exercise, and statins don’t significantly lower Lp(a), but they can manage other risk factors like LDL cholesterol, blood pressure, and diabetes to reduce overall cardiovascular risk.
• Niacin: Can lower Lp(a) by 20–40% in some cases, but side effects (flushing, liver issues) and limited efficacy restrict its use.

Implications for India

• Indians face a unique burden: Lp(a) is implicated in the country’s high rates of premature coronary artery disease, with studies showing a 2–3 times higher risk in young individuals with elevated Lp(a).
• The article highlights that heart attacks in Indians occur nearly a decade earlier than in Western populations, often linked to Lp(a) alongside lifestyle factors like sedentary habits and diet.
• If treatments like lepodisiran succeed, they could be transformative for India, but affordability and access will be critical given the private-heavy healthcare system and insurance challenges.

How Close Are We?

• Timeline: We’re likely 5–10 years from widely available Lp(a)-specific treatments, assuming Phase 3 trials confirm safety and efficacy. Lepodisiran and similar drugs could reach markets by 2030 if all goes well.
• Progress: The ability to reduce Lp(a) by over 90% for extended periods marks a major leap, but proving these reductions prevent heart attacks/strokes is the final hurdle.
• Hope: Cardiologists are optimistic, with experts like Dr. Steven Nissen calling results “remarkable.” For patients with high Lp(a), these therapies could eliminate a previously untreatable risk factor.

Final Thoughts

We’re closer than ever to treating Lp(a), thanks to RNA-based drugs like lepodisiran and olpasiran, which show unprecedented reductions in this deadly lipoprotein. However, we’re not there yet—ongoing trials must confirm that lowering Lp(a) saves lives, and practical challenges like cost and screening need addressing. For now, individuals with a family history of early heart disease should ask their doctors about Lp(a) testing and focus on controlling other risk factors. If you’d like, I can search for more recent updates or dive deeper into a specific aspect, like trial details or implications for India!