<p>Familial hypercholesterolemia (FH) leads to a lifelong predisposition toward atherosclerotic cardiovascular disease (ASCVD). Several presentations at the recent <strong>American Heart Association (AHA) Scientific Sessions 2025</strong> provided information on the role of genetics in both the identification and treatment of FH.</p> <p><br></p> <p><em>Following these presentations, featured expert Seth Martin, MD, MHS, was interviewed by </em>Conference Reporter<em> Associate Editor-in-Chief Mona Shah, PharmD. Clinical perspectives from Dr Martin on these findings are presented here.</em></p>

The genes involved in FH have been well described, and a single pathogenic mutation in the LDLR, APOB, or PCSK9 can lead to high low-density lipoprotein cholesterol (LDL-C) levels from birth and therefore put someone at risk for ASCVD. Clinical genetic testing in patients with suspected FH can confirm the diagnosis by identifying a pathogenic mutation, while facilitating cascade testing in the family, facilitating earlier diagnoses in future generations, and motivating optimal treatment.

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I have seen a rise in the use of genetic testing in clinical practice. We have been offering it to our patients for the past decade, and we are very fortunate to have a genetic counselor who has been the key to the availability of genetic testing in our clinic primarily for the evaluation of FH. At the AHA Scientific Sessions 2025, there were several studies presented on this topic.

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For example, a study presented by Matthew E. Levy, PhD, and colleagues at the meeting looked at population-level genomic screening for FH, followed by downstream lipid management and control (poster Su4019). The study included 9 US health systems and used a propensity score matched design. FH-positive patients were matched 1:4 with FH-negative patients, and patients had similar baseline LDL-C levels and risk factor profiles. They were followed over time for lipid management and LDL-C level achievement. Of the 1155 FH-positive patients, 74% had mutations in the LDLR, 25% in APOB, and 1% in PCSK9. FH-positive patients were approximately threefold more likely than FH-negative patients to receive new or adjusted lipid-lowering therapies within the first year after genetic screening, which led to better outcomes. FH-positive patients were also more likely to be treated with combination lipid-lowering therapy, which is what we expect individuals with FH to need to optimize their LDL-C levels. Finally, FH-positive patients were more likely to achieve target primary and secondary prevention LDL-C levels within 2 years following genetic testing.

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I thought that this was an interesting study showing that making a genetic diagnosis of FH is linked to better downstream treatment. Although this was not a randomized trial, the authors attempted to enhance causal inference with the propensity score matched design. The demonstration of the improved use of lipid-lowering therapies and improved LDL-C levels, if sustained long-term, could ultimately be expected to translate into better CV outcomes. It is interesting to consider the practicality of implementing FH genetic testing at a broader population-level scale. It would face barriers, but I do think that this could be done in certain health care settings. These are encouraging results in terms of the connection to the quality of care that is delivered.

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Another important presentation at the AHA Scientific Sessions 2025 was from Shoshana H. Bardach and colleagues on the FIND FH Collaborative Learning Network from the Family Heart Foundation (abstract 4369036). FIND stands for: flag, identify, network, and deliver. It is about applying a machine learning algorithm to electronic health records data to find patients who appear to have a higher likelihood of FH. The use of machine learning in clinical care to drive quality improvement is an exciting area. The FIND FH program flagged approximately 4500 individuals using the algorithm. Of those, more than 800 patients were contacted and 209 had appointments, which ultimately led to 175 new diagnoses of definite, probable, or possible FH. These results indicate that the algorithm was picking up quite a large number of people who have clinical FH but were being missed. It is an important initiative that I hope can continue to be expanded.

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The AHA Scientific Sessions 2025 also included discussions on several studies of enlicitide, an oral PCSK9 inhibitor with encouraging data. Although patients do well on our currently available PCSK9 inhibitor injectables, an oral option would give flexibility and would be a welcome addition to clinical practice.

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Positive data for enlicitide were presented from the phase 3 CORALreef Lipids trial by Ann Marie Navar, MD, PhD, et al (abstract 4391578). This trial was not exclusive to patients with FH, as it included adults with or at risk for ASCVD. There was also a phase 3, double-blind, randomized, placebo-controlled trial in patients with heterozygous FH presented by Christie M. Ballantyne, MD, and colleagues at this year’s AHA meeting (abstract 4391641). Patients were randomized 2:1 to 1 year of once-daily treatment with enlicitide 20 mg or placebo, in addition to moderate- or high-intensity statin therapy with or without other lipid-lowering therapies. The authors reported impressive results for the primary end point of mean percent change in LDL-C from baseline at week 24. There was an approximately 60% reduction in LDL-C levels with enlicitide at week 24, which was maintained out to week 52. The APOB reduction was approximately 50%, and lipoprotein(a) reduction was approximately 27%. Additionally, enlicitide appeared to be well tolerated, with a similar incidence of adverse events between the enlicitide and placebo groups. This is similar to the favorable safety profiles of the existing PCSK9 injectable therapies.

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Positive results from both the dedicated heterozygous FH study and the bigger, broader CORALreef Lipids trial indicate that enlicitide is on track to make its way into clinical practice in the future as an oral agent with PCSK9 monoclonal antibody–like efficacy.