Familial hypercholesterolemia (FH), characterized by lifelong elevations in low-density lipoprotein cholesterol (LDL-C), is the most common autosomal-dominant genetic disorder in the world. Without treatment, individuals with FH, compared with those without FH, are at 10- to 20-times higher risk of early coronary artery disease and subsequent premature death. With appropriate and aggressive treatment this impact can be greatly reduced.

There are two types of FH, including the more prevalent heterozygous familial hypercholesterolemia (HeFH) impacting one in every 250 individuals, and the less common, but significantly more deadly, homozygous familial hypercholesterolemia (HoFH), affecting one in 250,000 individuals.

Over the last three years, the ACC has been working to increase awareness of FH, and particularly HoFH, through the development of patient and clinician education and resources to encourage early screening and optimal treatment. Supported by Regeneron, these efforts have involved the creation of CardioSmart infographics and worksheets to aid in patient understanding of the disease and how to mitigate disease progression.

Clinician education has also been a focus, with the creation of a free, online course that includes expert analyses, podcasts, webinars, videos and more, designed to provide best practices and information on topics such as when to refer to a specialist, how to leverage genetic testing and cascade screening, and how to maximize the use of new and evolving treatment options and strategies for ongoing management of the FH patient.

A new ACC survey of cardiologists suggests that, while there is still room for improvement, these efforts are beginning to bear fruit when it comes to both diagnosing and treating this high-risk patient population. The survey is a follow-up to a similar ACC survey conducted in 2021 to gauge practice patterns and better understand the needs of clinicians and patients.

What's the Diagnosis?

In current guidelines a common threshold for HoFH is an untreated LDL-C ≥400 mg/dL. While the majority of cardiologists surveyed said they had not yet diagnosed a patient with HoFH, 75% reported they would diagnose a patient presenting with untreated LDL-C ≥400 mg/dL with HoFH.

When asked the same question in 2021, only 67% of cardiologists surveyed said they would make that same diagnosis (Table 1). Of those cardiologists with previous experience diagnosing HoFH, this percentage increased significantly, with 94% saying they would diagnose a patient with LDL-C ≥400 mg/dL with HoFH, compared with 75% in 2021.

When asked about diagnosing a patient with a parent with an LDL-C ≥400 mg/dL and all other offspring having an LDL-C of 160-400 mg/dL, nearly three-fourths of survey respondents (73%) said they would diagnose either HoFH or HeFH, compared with less than half (44%) of cardiologists when asked a similar question in 2021.

Tackling Treatment

When considering treatment for a patient with untreated LDL-C ≥400 mg/dL, cardiologists continue to be more likely to prioritize medication as well as reviewing the patient's family history and screening offspring.

However, survey respondents were divided on their typical treatment goal for a patient diagnosed with HoFH. One-fourth (25%) reported a goal of either <100 mg/dL or <70 mg/dL, while one-third (35%) felt that it would depend upon the patient scenario.

In addition, one-third of cardiologists (32%) indicated they would often refer patients with LDL-C ≥400 mg/dL to a lipid specialist. When asked about screening, 46% of those surveyed said cascade screening lipid-level testing for first-degree relatives is performed more than half of the time – an opportunity for continued clinician education and a finding that will continue to be tracked going forward.

In terms of treatment, highly familiar options such as PCSK9 inhibitors (i.e., alirocumab, evolocumab) were considered by survey respondents to be the most effective treatment options for HoFH (77%), followed closely by high-dose statins (67%), and 25% said cholesterol absorption inhibitors (i.e., ezetimibe) are very effective as well (Table 2).

In addition to medications, 38% of cardiologists indicated that the procedure of lipoprotein (LDL) apheresis (38%) is very effective, particularly among those who previously diagnosed HoFH (49%). Diet and exercise also continued to rank among the most effective treatments among 28% of survey respondents. While diet and exercise are important for everyone with cardiovascular risk, they are a smaller part of the overall LDL-C reduction due to the genetic nature of HoFH.

Awareness of newer treatment options that act independently of the LDL receptor such as evinacumab, an angiopoietin-like 3 inhibitor (ANGLPT3i) approved by the U.S. Food and Drug Administration, as an adjunct to other lipid-lowering therapies to treat HoFH patients who are 5 years of age and older still show room for improvement.

Only 11% of cardiologists indicated they were very or extremely familiar with this therapy. However, among cardiologists who have diagnosed HoFH, familiarity with ANGLPT3i therapies did increase from 12% in 2021 to 24% in the new survey.

Driving Forward

Looking ahead, most cardiologists surveyed continue to underscore the need for increased awareness of FH in the broader clinical community, as well as a focus on screening and/or testing of children with a family history of cardiovascular disease.

Additional simplified clinical guidance and increased amplification and dissemination of the College's 2022 Expert Consensus Decision Pathway (ECDP) on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk was also identified as an area for improvement. Only one-third of cardiologists surveyed said they were very or extremely familiar with the ECDP.

"Education is always helpful as keeping up to date with conditions such as HoFH and how to monitor and treat is very important to caring for our patients," said one survey participant. With lipid specialists not always available, another participant noted that "education is critical to identify affected individuals and their families."

FH Resources

Click here for the ECDP on Nonstatin Therapies.

Click here for the ACC's FH Online Course and related resources.

Click here to access CardioSmart patient education materials.

Click here for more details from the 2021 ACC Survey.

Click here to download ACC's Nonstatin Strategies Therapies for LDL-C Lowering Pocket Guide.

Clinical Topics: Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins

Keywords: Cardiology Magazine, ACC Publications, Homozygous Familial Hypercholesterolemia, Coronary Artery Disease, Genetic Testing, Cholesterol, LDL