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Many patients receive a standardized lipid panel as part of their annual physical examination, which includes testing for high-density lipoprotein (HDL) and low-density lipoprotein (LDL). However, most people are unfamiliar with another type of cholesterol, lipoprotein(a) or Lp(a), which is not included in the standard lipid panel but is an independent risk factor for cardiovascular disease.

In a Q&A session, Yale clinicians and researchers provided insights into Lp(a), guidance for managing patients with elevated levels, and new approaches to improve testing.

**What is lipoprotein(a)?**

"Lp(a) – pronounced as 'lp little a' – is a lipoprotein whose serum level is genetically determined without much fluctuation after early childhood," explained Erica Spatz, MD, MHS, associate professor of cardiovascular medicine and epidemiology. "We’ve known for many years that it is an independent risk factor for cardiovascular disease. It contributes to atherosclerosis (plaque buildup in the heart arteries), thrombosis (blood clotting), and early aortic stenosis (narrowing of the valve that connects the main chamber of the heart to the rest of the body). It can also lead to major adverse cardiovascular events like heart attacks."

**How is Lp(a) tested?**

"It is checked with a simple blood test that is often covered by insurance," said Spatz. "However, today only about 0.5% of people in the United States are tested for Lp(a). This is because we haven’t had therapies to reduce Lp(a). It is not lowered by lifestyle interventions and statins, which are first-line agents for high cholesterol. So, it hasn’t been on most physicians’ radar to check."

**How can providers care for patients with elevated Lp(a) levels?**

Although no targeted therapies are available, providers specializing in preventive cardiology can work with patients to reduce risk factors. "In our practice, we double down on all other modifiable risk factors like lifestyle and other LDL cholesterol," said Spatz. "If a person has cardiovascular disease and elevated Lp(a) levels, we may use non-statin medications like PCSK9 inhibitors because clinical trials showed greater benefit for these patients. We also recommend family members get tested."

**What research is in progress to help us better understand Lp(a)?**

"We are excited about research in the pipeline that may give us new knowledge about how to treat patients with elevated Lp(a)," said Spatz. "I hope we will soon have some targeted treatment options. But the field of medicine needs to be prepared for a potential change in caring for these patients."

"Unfortunately, enrollment in these clinical trials is slow," added Rohan Khera, MD, MS, assistant professor of medicine and biostatistics and director of the Cardiovascular Data Science Lab. "Only one in eight people have elevated levels; thus researchers need to test many people just to identify one eligible for trial enrollment. To speed up research, we need a more efficient way to determine who would most benefit from testing."

To address this issue, they recently published a paper in Nature Cardiovascular Research outlining an approach using algorithmic diagnostics to improve health promotion at the population level.

**How was the new screening tool developed?**

The team developed a machine learning model utilizing structured clinical elements from electronic health records to identify patients likely having elevated Lp(a) levels.

"While Lp(a) is an independent risk factor for cardiovascular disease, it does have company that it tends to keep," Khera explained. "For example, we found that people with high Lp(a) were more likely women or Black individuals and had hypertension or premature heart disease before age 60. They were also more likely to have a family history of ASCVD."

The model's analysis drew from large datasets including UK Biobank, ARIC, CARDIA, and MESA studies.

"We evaluated the model to ensure it did not introduce bias regarding social determinants of health such as age, sex, race or ethnicity," said Arya Aminorroaya, MD MPH postdoctoral associate at CarDS Lab and first author of the paper. "The good news is that its performance remains consistent across all clinical subgroups."

**How can the new screening tool be used?**

"This tool isn't diagnostic; you still need tests," Khera stated. "But we've found we can conduct half as many tests while identifying the same number of patients with elevated levels."

Khera along with Spatz Aminorroaya hopes this tool will assist researchers leading clinical trials in selecting participants effectively while aiding hospitals or health systems deciding which patients might benefit most from screening.

"I also see potential taking this tool directly towards patient awareness allowing them better gauge their risks prioritizing those higher at-risk cases," Spatz mentioned.

"This tool won’t replace universal screening recommended by European guidelines National Lipid Association but helps accelerate trial progress determining benefiting screenings better,” Aminorroaya concluded.

Other study authors include Lovedeep S Dhingra MBBS Evangelos K Oikonomou MD DPhil Phyllis Thangaraj MD PhD Sumukh Vasisht Shankar Yale Seyedmohammad Saadatagah Baylor College Medicine

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