Opportunistic Genomic Screening for Familial Hypercholesterolemia to Improve Low-Density Lipoprotein Cholesterol: A...

The clinical benefit of opportunistic genomic screening for familial hypercholesterolemia (FH) has not been demonstrated in a randomized clinical trial (RCT).

To evaluate the impact of returning clinically confirmed FH-associated genetic results on low-density lipoprotein cholesterol (LDL-C) levels.

This RCT was performed within the Veterans Health Administration, a large national health care system, and linked to the Million Veteran Program (MVP), a research biobank. Participants were MVP enrollees suspected to have an FH-associated genetic variant, as identified in their research data. Recruitment occurred from February 27, 2020, to September 20, 2022, and 6-month follow-up was completed October 21, 2024.

Delivery of clinical genetic confirmation testing and telegenetic counseling at baseline (immediate results arm) vs after 6 months (delayed results arm).

Change in LDL-C levels (primary outcome) and proportions with treatment intensification and achievement of LDL-C target levels at 6 months (secondary outcomes).

The trial randomized 112 participants across 28 US states (mean age, 65.9 [range, 36-91] years; 94 [83.9%] men). Baseline mean (SD) LDL-C level was 109.5 (55.5) mg/dL, and 86 participants (76.8%) were already receiving therapy to lower lipid levels. At 6 months, the between-arm difference in LDL-C level reduction was -10.5 (95% CI, -21.9 to 1.0) mg/dL (P = .07; Cohen d = 0.34). Bayesian analysis suggested a high probability of benefit but was exploratory. Treatment was intensified in 11 of 55 participants (20.0%) in the immediate results arm vs 5 of 57 (8.8%) in the delayed results arm (P = .09). Fifteen participants (27.3%) in the immediate results arm vs 14 (24.6%) in the delayed results arm (P = .74) achieved LDL-C target levels. Thirty of 49 participants (61.2%) in the immediate results arm who completed this information shared their genetic result with a total of 98 relatives.

In this RCT, opportunistic genomic screening for FH plus telegenetic counseling did not result in a statistically significant improvement in LDL-C levels and clinical management; however, the findings suggest that there may be a small to moderate benefit favoring the immediate results arm. Further research should be conducted to confirm these findings, optimize implementation strategies, and assess the long-term effects on cardiovascular outcomes.

ClinicalTrials.gov Identifier: NCT04178122.