Why FH Matters Particularly to the VA An estimated 90% of FH cases in the United States remain undiagnosed, a remarkable figure for a condition that is both common, treatable and potentially deadly. Within the VA system, that diagnostic gap translates into potentially hundreds of thousands of veterans at elevated cardiovascular risk who may not be receiving appropriately aggressive therapy. Recognizing this opportunity, VA researchers have been at the forefront of efforts to close the gap through genomic screening. The Million Veteran Program Return Of Actionable Results (MVP-ROAR) Study, led by Jason L. Vassy, MD, MPH, MS, a research health scientist at the Massachusetts Veterans Epidemiology Research and Information Collaborative (MAVERIC) and the Boston VAMC, was designed precisely to address this challenge. The study identified MVP enrollees with probable pathogenic variants in FH-associated genes (LDLR, APOB, LDLRAP1, PCSK9) who had no molecular diagnosis of FH, then recontacted and invited them to receive clinical confirmatory gene sequencing and telehealth genetic counseling. “Participants who received their results lowered LDL cholesterol by an average of 10.5 mg/dL more than those who waited—suggesting that genomic screening improves care, even in already treated populations. The trial was stopped before target enrollment due to pandemic delays and funding constraints, but Bayesian analysis suggests this LDL difference would have met statistical significance,” said Vassey.5 “Notifying MVP participants that they might carry an undiagnosed FH-associated genetic variant has the potential to improve the lives of both the veteran and their family,” the investigators wrote.6 A notable secondary finding: 61% of participants who received their results shared the information with an average of 98 relatives, creating a beneficial cascade of screening that professional organizations and the CDC endorse as an efficient method for detecting undiagnosed cases.5 Separately, a VA quality improvement program presented at the American Heart Association’s 2025 Scientific Sessions, by Vassey’s colleague at MAVERIC, Luc Djoussé, MD, demonstrated a 32% increase in veterans with cardiovascular disease reducing LDL-C below 70 mg/dL. In addition, medication prescribing rose from 78% to 88% and adherence climbing from 65% to 77% of participants.7 Treatment: A Stepped Approach The 2025 VA/DoD Clinical Practice Guideline on Lipid Management recommends that treatment intensity for FH be guided by LDL-C and global cardiovascular risk. The initial treatment goal is LDL-C reduction of at least 50%, with target levels of less than 100, 70, or 55 mg/dL depending on individual ASCVD risk. Statins remain first-line pharmacologic therapy for veterans with FH, with high-intensity agents such as rosuvastatin and atorvastatin preferred. Evidence supports their ability to reduce cardiovascular events even in HoFH patients, though the average LDL-C reduction in HoFH with statins alone is approximately 25%.8 The next step involves adding ezetimibe to statin therapy. Dosed at 10 mg orally once daily, this well- tolerated generic agent provides an additional 18% to 25% LDL-C reduction and has demonstrated ASCVD risk reduction in a major cardiovascular outcomes trial. In combination with a high-intensity statin, ezetimibe is recommended as first-line combination therapy for HoFH patients. PCSK9 Inhibitors: Potent Options With Favorable Profiles When statins and ezetimibe prove insufficient, a com- mon scenario in FH, PCSK9 inhibitors represent a major therapeutic advance. By blocking PCSK9, these agents increase the density of LDL receptors on liver cells, dra- matically enhancing the liver’s ability to clear LDL from the bloodstream. LDL-C reductions in the range of 48% to 64% have been demonstrated across this drug class. Three PCSK9 inhibitor modalities have FDA approval: • Monoclonal antibodies, alirocumab (Praluent) and evolocumab (Repatha), work extracellularly to sequester the PCSK9 protein in plasma and are injected every two to four weeks. • Lerodalcibep is a recombinant fusion protein that sequesters PCSK9 in the bloodstream, preventing it from degrading LDL receptors. It is administered monthly. • Inclisiran, a small interfering RNA (siRNA), takes a fundamentally different approach. Instead of neutralizing circulating PCSK9 protein, it silences the PCSK9 gene at the mRNA level inside liver cells, preventing PCSK9 from being produced in the first place. The Dosing Advantage Inclisiran was first approved by the FDA in December 2021 for adults with HeFH or clinical ASCVD requiring additional LDL-C lowering on maximally tolerated statin therapy. In August 2025, the FDA expanded its label to 2 0 2 6 C O M P E N D I U M O F F E D E R A L M E D I C I N E 3 7
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