Impact of Providing Future Cardiovascular Risk Based on Genetic Testing on Low-Density Lipoprotein Cholesterol in Patients with Familial Hypercholesterolemia (GenTLe-FH): A Randomized Wait-list Controlled Open-Label Trial

Abstract

Background and Aims: Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disease characterized by high low-density lipoprotein cholesterol (LDL-C) levels. Although carrying causative FH variants is associated with coronary heart disease (CHD), it remains unclear whether disclosing its associated cardiovascular risk affects outcomes in patients with FH. Here, we evaluated the efficacy of providing future cardiovascular risk based on genetic testing in addition to a standard FH education program. Methods: We conducted a randomized, wait-list controlled, open-label, single-center trial. In the intervention group, we reported a future cardiovascular risk based on the genetic testing adding to standard FH education at week 0. In the wait-list control group, we only disseminated standard FH education according to the guidelines at week 0; they later received a genetic testing-based cardiovascular risk assessment at week 24. The primary endpoint of this study was the plasma LDL-C level at week 24. Results: Fifty eligible patients with clinically diagnosed FH, without a history of CHD, were allocated to the intervention group (n=24) or the wait-list control group (n=26). At week 24, the intervention group had a significantly greater reduction in LDL-C levels than the wait-list control group (mean changes, -13.1 mg/dL vs. 6.6 mg/dL; difference, -19.7 mg/dL; 95% confidence interval, -34 to -5.6; p=0.009). This interventional effect was consistent with FH causative variant carriers but not with non-carriers. Conclusions: In addition to standard FH care, providing future cardiovascular risk based on genetic testing can further reduce plasma LDL-C levels, particularly among FH causal variant carriers.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

jRCTs042180027

Clinical Protocols

https://bmjopen.bmj.com/content/8/12/e023636

Funding Statement

This trial was supported by a Clinical Research Grant from Kanazawa University Hospital, JSPS KAKENHI (18K08064, 19K08553, 20H03927), the Astellas Foundation for Research on Metabolic Disorders, the ONO Medical Research Foundation, the Ministry of Health, Labour and Welfare of Japan (Research Grant for Rare and Intractable Diseases), and the Japanese Circulation Society (Project for Genome Analysis in Cardiovascular Diseases).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The institutional Review Board of Kanazawa University Hospital (Kanazawa, Japan) gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

The data in this trial are available from the corresponding author upon reasonable request.

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