If you’ve recently learned that your Lipoprotein(a), commonly written as Lp(a), is elevated, you may feel frustrated. Unlike LDL cholesterol, which responds to diet, exercise, and medication, Lp(a) has long been considered one of the few cardiovascular risk factors that patients and physicians could identify but not treat. That is changing. A promising new class of therapies is in advanced clinical trials, and the results so far have been remarkable.

But first, the most important thing to understand: an elevated Lp(a) does not mean you are powerless. While we wait for targeted therapies, there is a great deal you can do right now to reduce your overall cardiovascular risk.

What Is Lipoprotein(a)?

Lp(a) is a type of lipoprotein particle assembled in the liver. It is structurally similar to LDL cholesterol (often called “bad cholesterol”), but with an additional protein called apolipoprotein(a) attached to it. This unique structure makes Lp(a) both proatherogenic (promoting plaque buildup in arteries) and prothrombotic (promoting blood clot formation) [1].

What sets Lp(a) apart from other cardiovascular risk factors is that it is approximately 80 to 90% genetically determined. Your Lp(a) level is largely set by the genes you inherited, and it remains relatively stable throughout your adult life [2]. Unlike LDL cholesterol, triglycerides, or blood pressure, Lp(a) does not respond meaningfully to changes in diet, exercise, or most currently available medications.

The American Heart Association published a landmark Scientific Statement in 2022 confirming that Lp(a) is "a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease" [1]. The European Atherosclerosis Society and multiple international cardiology guidelines now recommend measuring Lp(a) at least once in every adult’s lifetime to assess cardiovascular risk [3].

How Common Is Elevated Lp(a)?

Far more common than most people realize. As Dr. Steven Nissen, Chief Academic Officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic, noted: "Nearly a quarter of the world’s population has elevated levels of Lp(a), putting them at a significantly higher risk of cardiovascular events such as heart attacks and strokes" [4]. That translates to an estimated 1.4 to 2 billion people worldwide. Yet many have never been tested and remain unaware of their risk. Individuals can have completely normal standard lipid panels and still carry dangerously elevated Lp(a) levels. Because Lp(a) is not included in routine cholesterol screening, this risk factor often goes undetected for decades [5].

Why Elevated Lp(a) Matters

Elevated Lp(a) is an independent risk factor for coronary heart disease, ischemic stroke, and aortic valve stenosis. The risk is level dependent: the higher your Lp(a), the greater your risk. A 2024 pooled analysis of 27,756 participants with an average 21 year follow up found that individuals with Lp(a) levels at or above the 90th percentile had a 46% higher risk of atherosclerotic cardiovascular events, independently of LDL cholesterol levels [6].

The Mayo Clinic has noted that Lp(a) concentrations of 75 nmol/L and above are linearly related to increased risk of cardiovascular events independent of conventional risk markers, and values at or above 125 nmol/L are considered a risk enhancing factor by multiple professional societies [7].

The Frustration: Why Diet and Exercise Don’t Lower Lp(a)

This is the part that understandably frustrates patients. You can eat perfectly, exercise daily, maintain an ideal body weight, and your Lp(a) level will likely remain exactly where it was. "Unfortunately, there are no approved cholesterol-lowering therapies specifically for this genetic risk factor, and lifestyle changes like diet and exercise do not provide meaningful reductions" [4].

Statins, the most widely prescribed cholesterol medications, effectively lower LDL cholesterol but have no clinically significant effect on Lp(a); some studies suggest they may even slightly increase it. PCSK9 inhibitors (such as evolocumab and alirocumab) can reduce Lp(a) by approximately 20 to 27%, but this reduction is modest and these drugs are not specifically approved for Lp(a) lowering [8].

The Breakthrough: Lepodisiran and the New Era of Lp(a) Treatment

This is where the story takes a hopeful turn. Eli Lilly’s investigational drug lepodisiran, a small interfering RNA (siRNA) therapy, has delivered some of the most striking results in cardiovascular medicine in recent years.

Lepodisiran works by using gene silencing technology to reduce the liver’s production of apolipoprotein(a), the protein component that makes Lp(a) so harmful. The results were dramatic [9]:

A single 400 mg dose of lepodisiran reduced Lp(a) levels by 93.9% over the 60 to 180 day period after treatment. Two doses given six months apart achieved a 94.8% reduction sustained over a full year. Even 540 days (approximately 18 months) after the second dose, Lp(a) levels remained 74.2% below baseline [4, 9].

To put that in perspective: a therapy given just twice a year could reduce Lp(a) by more than 90%, a level of reduction that was unimaginable even five years ago.

The safety profile has also been encouraging. There were no serious adverse events related to the drug. The most common side effect was mild, temporary injection site reactions in up to 12% of participants [9]. "Reducing the inherited cardiovascular risk for patients with high Lp(a) has long been a critically unmet need. These results offer hope for a long-term, durable treatment option" [4].

Dr. Leslie Cho, Co Section Head of Preventive Cardiology at Cleveland Clinic, added: "This is an exciting time in Lp(a) research, with an antisense oligonucleotide agent, several small interfering RNA agents, and one Lp(a) lowering oral medication all in clinical trials. We eagerly await results of the cardiovascular outcomes trials to learn whether lowering Lp(a) lowers cardiovascular risk" [10].

What Comes Next: The ACCLAIM Lp(a) Phase 3 Trial

The Phase 3 ACCLAIM Lp(a) trial (NCT06292013) is currently enrolling 12,500 participants worldwide. This will be the first large scale cardiovascular outcomes trial specifically designed to answer the critical question: does lowering Lp(a) actually reduce heart attacks, strokes, and cardiovascular deaths? The trial, led by Dr. Nissen in collaboration with Cleveland Clinic, is expected to provide results by 2029 [10].

Other companies are also developing Lp(a) lowering therapies. Novartis’s pelacarsen and Amgen’s olpasiran are in their own Phase 3 trials with results expected as early as 2026. This means that within the next few years, patients with elevated Lp(a) may have multiple treatment options available for the first time in history.

What You Can Do Right Now

While we wait for these therapies to complete clinical trials and receive regulatory approval, there is meaningful action you can take today. The strategy is straightforward: since you cannot yet control Lp(a) directly, focus aggressively on controlling every other cardiovascular risk factor within your power. This approach is supported by leading cardiologists and institutions worldwide.

Optimize Your LDL Cholesterol

Because Lp(a) adds risk on top of LDL driven risk, lowering your LDL cholesterol becomes even more important. Work with your physician to achieve the lowest attainable LDL level through statins, ezetimibe, or PCSK9 inhibitors. The Mayo Clinic Proceedings have recommended that "aggressive low-density lipoprotein reduction should be the primary focus of lipid-modifying therapies" in patients with elevated Lp(a) [11].

Manage Blood Pressure

Hypertension compounds the arterial damage that elevated Lp(a) promotes. Keeping blood pressure within optimal range through medication, dietary sodium reduction, and regular exercise reduces the cumulative burden on your arteries.

Address Inflammation

Chronic inflammation accelerates atherosclerosis. Monitoring inflammatory markers like CRP and working to reduce systemic inflammation through diet, exercise, stress management, and appropriate medical treatment can meaningfully lower your overall cardiovascular risk.

Improve Metabolic Health

Insulin resistance, elevated blood sugar, and metabolic syndrome all amplify cardiovascular risk. Addressing these through diet (particularly reducing refined carbohydrates and increasing fiber), regular physical activity, and weight management provides substantial risk reduction independent of Lp(a).

Exercise Consistently

Regular physical activity improves nearly every cardiovascular risk factor simultaneously: it lowers blood pressure, improves lipid profiles, reduces inflammation, enhances insulin sensitivity, and supports healthy body weight. Aim for at least 150 minutes of moderate intensity aerobic activity per week, combined with resistance training twice weekly.

Adopt a Heart Healthy Diet

A Mediterranean style eating pattern, rich in fish, olive oil, nuts, vegetables, and whole grains while low in processed foods and added sugars, has been consistently shown to reduce cardiovascular events regardless of Lp(a) status.

Know Your Numbers: Why Comprehensive Testing Matters

Dr. Nissen has emphasized: "Many people with high Lp(a) don’t experience symptoms, and unfortunately, it is not frequently tested. It is important for patients with a personal or family history of heart disease to speak with their physician about having an Lp(a) blood test" [10].

Beyond Lp(a) itself, comprehensive cardiovascular testing that includes advanced markers such as Apolipoprotein B, homocysteine, inflammatory indices, and metabolic health markers provides a complete picture of your cardiovascular risk and identifies every lever you can pull to protect your heart while we await targeted Lp(a) therapies.

The Bottom Line

If you have elevated Lp(a), you are not alone, and you are not without options. The science is advancing rapidly. Lepodisiran and other investigational therapies represent the most significant progress in Lp(a) treatment in the six decades since this risk factor was first discovered. A future where elevated Lp(a) is a treatable condition, not just a diagnosis, is closer than ever.

In the meantime, the most empowering thing you can do is take control of every risk factor within your reach. Get tested comprehensively. Optimize your LDL, blood pressure, inflammation, and metabolic health. Work closely with your physician. Every percentage point of risk you reduce in the areas you can control makes elevated Lp(a) a smaller part of your overall cardiovascular picture.

Your genes are not your destiny. They are your starting point.

References

[1] Reyes-Soffer G, Ginsberg HN, Berglund L, et al. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42:e48–e60. https://www.ahajournals.org/doi/10.1161/ATV.0000000000000147 

[2] Nordestgaard BG, Langsted A. Lipoprotein(a) and cardiovascular disease. The Lancet. 2024;404(10459):1255–1264. https://doi.org/10.1016/S0140-6736(24)01308-4 

[3] Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111–188. https://doi.org/10.1093/eurheartj/ehz455 

[4] Eli Lilly and Company. Lilly’s lepodisiran reduced levels of genetically inherited heart disease risk factor, lipoprotein(a), by nearly 94% from baseline at the highest tested dose. Press Release, March 30, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-lepodisiran-reduced-levels-genetically-inherited-heart 

[5] Understanding Elevated Lipoprotein(a): A Focus on Cardiovascular Risk and Screening Recommendations. AJMC. Presented at AHA Scientific Sessions 2023, featuring Leslie J. Donato, PhD, Mayo Clinic. https://www.ajmc.com/view/understanding-elevated-lipoprotein-a-a-focus-on-cardiovascular-risk-and-screening-recommendations 

[6] Wong ND, Fan W, Hu X, et al. Lipoprotein(a) and Long-Term Cardiovascular Risk in a Multi-Ethnic Pooled Prospective Cohort. J Am Coll Cardiol. 2024;83(16):1511–1525. https://doi.org/10.1016/j.jacc.2024.02.031 

[7] Mayo Clinic Laboratories. Lipoprotein(a), Serum: Test Overview (LIPA1). https://www.mayocliniclabs.com/test-catalog/overview/615007 

[8] An Update on Lipoprotein(a): The Latest on Testing, Treatment, and Guideline Recommendations. American College of Cardiology. 2023. https://www.acc.org/Latest-in-Cardiology/Articles/2023/09/19/10/54/An-Update-on-Lipoprotein-a 

[9] Nissen SE, Ni W, Shen X, et al. Lepodisiran — A Long-Duration Small Interfering RNA Targeting Lipoprotein(a). N Engl J Med. 2025;392(17):1673–1683. https://doi.org/10.1056/NEJMoa2415818 

[10] Cleveland Clinic Newsroom. Experimental Gene-Silencing Drug Produces Long-Duration Reduction in Lipoprotein(a), an Important Heart Disease Risk Factor. March 30, 2025. https://newsroom.clevelandclinic.org/2025/03/30/experimental-gene-silencing-drug-produces-long-duration-reduction-in-lipoproteina-an-important-heart-disease-risk-factor 

[11] Lipoprotein(a), Cardiovascular Disease, and Contemporary Management. Mayo Clinic Proceedings. 2013;88(11):1294–1311. https://www.mayoclinicproceedings.org/article/S0025-6196(13)00795-7/fulltext