Metabolic syndrome predicts cardiovascular risk and mortality in familial hypercholesterolemia

Elsevier

Available online 22 March 2023

Journal of Clinical LipidologyAuthor links open overlay panel, , , , , , , , ABSTRACTBackground

The association between familial hypercholesterolemia (FH) and premature atherosclerotic cardiovascular disease (ASCVD) is well established. Several risk factors other than the cumulative low-density lipoprotein cholesterol (LDL-C) have been shown to modulate the severity of the phenotype in these patients. However, the effect of the metabolic syndrome (MetS) on ASCVD risk in FH remains to be determined.

Objectives

The objective was to study the association between the presence of MetS and the incidence of different ASCVD endpoints and all-cause mortality.

Methods

This prospective follow up study used data from 5 independent FH cohorts from Europe and North America. We analysed data of 2401 adult heterozygous FH without history of a prior ASCVD event (21,139 person-years of follow-up). Multivariate Cox proportional hazards regression was used to estimate the association between MetS and the incidence of the different endpoints.

Results

The prevalence of MetS was 14% in the study population. The presence of MetS was a significant predictor of incident 10-year ASCVD after adjustment for traditional cardiovascular risk factors (HR 2.07, 95% CI 1.34-3.19), as well as of 10-year major adverse cardiovascular event (MACE) (HR 4.59, 95% CI 2.27-9.30), 10-year myocardial infarction (MI) (HR 4.29, 95% CI 1.91-9.63), and 30-year all-cause mortality (HR 4.87, 95% CI 1.99-11.89).

Conclusion

Our findings suggests that FH patients with MetS, have an increased cardiovascular risk that is independent from LDL-C and other traditional risk factors. Future studies are required to determine the most appropriate strategy to reduce the cardiovascular burden associated with MetS in this population.

Section snippetsINTRODUCTION

Familial hypercholesterolemia (FH) is one of the most prevalent forms of genetic dyslipidemias with an estimated prevalence of ∼1/300 worldwide1,2, but with considerable variability in some populations3,4. FH is an autosomal co-dominant genetic disease associated with extremely elevated low-density lipoprotein cholesterol (LDL-C) (>95th percentile for age and sex) and premature atherosclerotic cardiovascular disease (ASCVD) if left untreated5, 6, 7. This inherited lipid disorder is mainly

Study Population and Data Collection

This was a prospective observational study involving 2401 patients with a diagnosis of FH from 5 registries from Canada, United Kingdom, and France. Extensive details about these cohorts have been reported elsewhere10. Eligibility criteria included a genetic diagnosis of heterozygous FH (likely pathogenic or pathogenic variant in LDLR, APOB or PCSK9 genes) or a probable/definite diagnosis of FH according to the Dutch Lipid Clinic Network criteria (≥6 points). Methodological aspects concerning

Baseline characteristics

A total of 186 patients came from the Montreal Clinical Research Institute FH cohort (8%), 319 from the FH registry from British Columbia (13%), 492 from the UK Biobank (20%), 98 from the Robarts Research Institute in Ontario (4%), and 1306 from the REFERCHOL FH registry from France (54%). Baseline characteristics according to the occurrence of ASCVD are presented in Table 1. A total of 157 patients experienced a first ASCVD over 10 years of follow-up, whereas 2,244 patients remained free of

DISCUSSION

Since its first definition in 1998 by the World Health Organization (WHO)22, MetS has been used as a clinical indicator for the identification of subjects with hyperinsulinemia and insulin resistance. Many large studies have shown that in the general population, the presence of MetS is strongly and independently associated with ASCVD risk12.

This large population-based study of prospective and multinational cohorts provides evidence that the insulin resistance phenotype, as indicated by the

CONCLUSIONS

Our findings have important clinical implications for ASCVD risk prediction in FH. Indeed, this study suggests that having an insulin resistance phenotype, as indicated by the presence of MetS, confers a 2-fold increased risk of ASCVD and a >4-fold increased risk of MI, MACE, and all-cause mortality that is independent from LDL-C and other traditional risk factors. However, we believe that the findings from this study underscore the need for additional research to determine the best clinical

FUNDING SOURCES

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CONTRIBUTORS’ STATEMENT

Conceptualization: A.B., M.P.

Data curation: M.P.

Formal analysis: M.P.

Interpretation of data: All authors

Writing - Original Draft: M.P.

Writing - Review & Editing: All authors

Final approval of the version to be published: All authors

Agreement to act as guarantor of the work: All authors

Dr. Baass had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis

DATA AVAILABILITY

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Declaration of Competing Interest

A.B. received research grants from Akcea, Amgen, Astra Zeneca, Fondation Leducq, Fondation Yvan Morin, Merck Frosst, and Sanofi. He has participated in clinical research protocols from Acasti Pharma Inc., Akcea, Amgen, Astra Zeneca, Ionis Pharmaceuticals, Inc., The Medicines Company, Merck Frosst, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., and Sanofi. He has served on advisory boards and received honoraria for symposia from Akcea, Amgen, and Sanofi. S. Bernard received research grants

ACKNOWLEDGEMENTS

The authors want to thank the Montreal Clinical Research Institute research team and the nursing staff for their everyday help, support, and implication.

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© 2023 Published by Elsevier Inc. on behalf of National Lipid Association.

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