Managing extreme LDL-C: Targeted therapies for genetic dyslipidemias
Industry Buzz
Extremely high LDL in a young person (especially those with a strong family history or early heart disease) can be a red flag that this is not just a lifestyle issue.
—Meena Malhotra, MD
FH patients typically require intensive, specialized therapies beyond standard statins.
—Brett A. Sealove, MD
Your patient has extremely elevated levels of low-density lipoprotein (LDL) cholesterol. They’re young. They have a family history of heart disease. And they have a healthy lifestyle. What do you do?
Healthy LDL levels should sit somewhere below 100 mg/dL. With a family history of atherosclerosis, the goal should be 70 mg/dL or lower. Extreme LDL is classified as anything above 190 mg/dL.[]
“Extremely high LDL in a young person (especially those with a strong family history or early heart disease) can be a red flag that this is not just a lifestyle issue,” says Meena Malhotra, MD, double board-certified physician in Internal Medicine and Obesity Medicine. In many cases, it’s genetic.
Familial hypercholesterolemia (FH) is marked by extremely high LDL cholesterol. It is among the most common genetic disorders, but 70% of people with FH remain undiagnosed.[] The average patient with FH will have a cardiac event around age 47.
What can be done to diagnose and treat FH?
Identifying FH is key to treating it. Accordingly, the Family Heart Foundation established a multi-year initiative designed to increase detection of FH. The program utilized the Flag-Identify-Network-Deliver (FIND™) strategy, establishing the FIND HF™ program in 2016.[] A collaborative learning network component was added in 2022.
The FIND HF study employed machine learning models alongside targeted quality improvement strategies at five healthcare sites. It identified high-risk patients, pinpointed diagnostic care gaps, and engaged patients for follow-up.
The researchers found that by integrating machine learning into real-time clinical workflows—incorporating lipid levels, family history, and clinician notes—more FH diagnoses could be made.
The researchers project further applications of the FIND methods. “Future work should explore opportunities to spread and scale learnings to the related genetic dyslipidemia,” they wrote (ie, elevated Lp[a]). “Future machine learning models may be developed to facilitate precision screening for both conditions.”
Moving beyond statins Beyond identifying FH, treating it requires serious care. “FH patients typically require intensive, specialized therapies beyond standard statins,” says Brett A. Sealove, MD, Chair of Cardiology at Hackensack Meridian Jersey Shore University Medical Center.
Olivia Hollyer, PA-C, with Manhattan Cardiology, agrees, noting the distinction between homozygous FH—more severe and inherited from both parents, versus heterozygous FH. “Homozygous FH patients often need lipoprotein apheresis, a dialysis-like procedure to filter cholesterol from blood,” she says.
Recently, major advances in FH treatment have been made, extending survival by years, according to a 2025 review published in Current Atherosclerosis Reports.[]
PCSK9 inhibitors (a monoclonal antibody) have been shown to significantly lower LDL cholesterol and extend life expectancy when combined with statins and cholesterol absorption inhibitors (like ezetimibe). New therapies, like ANGPTL3-inhibiting evinacumab (another monoclonal antibody), have been paired with lomitapide to reduce LDL levels in patients with even the most severe FH with success. RNA-based therapies and gene-editing approaches are on the future frontier as well.