ASCVD prevalence related to overweight/obesity in HeFH

In a cross-sectional analysis of the global EAS FHSC registry among patients with heterozygous familial hypercholesterolemia (HeFH), ~50% of the adults had increased BMI, and this was associated with higher odds of having ASCVD.

This summary is based on the publication of Elshorbagy A, Vallejo-Vaz AJ, Barkas F, et al. - Overweight, obesity, and cardiovascular disease in heterozygous familial hypercholesterolaemia: the EAS FH Studies Collaboration registry. Eur Heart J. 2025 Jan 13:ehae791 [Online ahead of print]. doi: 10.1093/eurheartj/ehae791

Introduction and methods

Background

In patients with heterozygous familial hypercholesterolemia (HeFH), increased BMI is a predictor of CVD risk [1,2]. However, in most world regions, the prevalence of overweight and obesity in this patient population is unknown. It is also not clear whether overweight and obesity confer additional risk of developing ASCVD independent of LDL-c levels and the use of lipid-lowering medication (LLM), which are major risk drivers in FH.

Aim of the study

The authors investigated the prevalences of overweight and obesity in patients with HeFH in different world regions and their relationships with prevalent ASCVD independent of LDL-c exposure and LLM use.

Methods

This was a cross-sectional analysis of individual-level data from 35,540 patients with a clinical and/or genetic diagnosis of HeFH and baseline BMI measurement across 50 countries who were enrolled in the European Atherosclerosis Society (EAS) FH Studies Collaboration (FHSC) registry from October 5, 2015, until December 20, 2022 [3,4]. At enrollment, 4237 children and adolescents (69%) and 9096 adults (32%) were not treated with LLM.

In adults, the WHO definition was used to categorize their BMI: underweight (BMI <18.5 kg/m²), normal weight (BMI 18.5–24.9 kg/m²), overweight (BMI 25.0–29.9 kg/m²), and obesity (BMI ≥30.0 kg/m²) [5,6]. For children/adolescents, a BMI z-score was calculated based on each individual’s height, weight, age, and gender using the WHO growth reference data [6], which was then used to define the following categories: underweight (BMI z-score <−2SD), normal weight (BMI z-score >−2SD and <+1SD), overweight (BMI z-score >+1SD and <2SD), and obesity (BMI z-score >+2SD).

Outcomes

The endpoint was the prevalence of ASCVD, comprising coronary artery disease (CAD), premature CAD (diagnosis at age <55 years in men and <65 years in women), stroke peripheral arterial disease, and (PAD).

Main results

Prevalences of overweight and obesity

• Overall, 36% of the adult patients with HeFH (n=29,265) were overweight and 16% were obese. In children/adolescents with HeFH (n=6275), the proportions were 18% and 9%, respectively.
• In adults, the highest prevalence of overweight or obesity was found in the Northern Africa and Western Asia region (82%), whereas Western Europe showed the lowest combined prevalence (46%).
• Children/adolescents in the Latin American/Caribbean region had the highest prevalence of overweight or obesity (47%), and those in Western Europe were least likely to be considered overweight or obese (19%).
• In non–high-income countries, a higher proportion of adults had overweight or obesity compared with those in high-income countries (63% vs. 50%).
• The median age at HeFH diagnosis was 49 years (25th–75th percentiles: 38–58) in adults with obesity, 48 years (25th–75th percentiles: 37–59) in those with overweight, and 40 years (25th–75th percentiles: 28–53) in those with normal weight (P<0.001).
• In both children/adolescents and adults, total cholesterol, LDL-c, non–HDL-c, and triglyceride levels and the atherogenic index were overall higher across higher BMI categories, whereas HDL-c levels were lower, irrespective of the use of LLM.

Associations of overweight and obesity with ASCVD

• Multivariate logistic regression analysis adjusted for age, sex, lipid levels, and LLM use showed obesity in children/adolescents was associated with higher odds of CAD compared with normal weight (0.7% vs. 0.07%; OR: 9.28; 95%CI: 1.77–48.77; P=0.008).
• In adults, obesity was associated with increased odds of premature CAD (21% vs. 6.5%; OR: 2.27; 95%CI: 1.98–2.61; P<0.001), CAD (30% vs. 11%; OR: 2.35; 95%CI: 2.10–2.63; P<0.001), stroke (3.7% vs. 1.6%; OR: 1.65; 95%CI: 1.27–2.14; P<0.001), and PAD (7.4% vs. 3.8%; OR: 1.86; 95%CI: 1.41–2.45; P<0.001). Further adjustment for diabetes, hypertension, and smoking attenuated these associations, and the ORs for stroke and PAD were no longer statistically significant.
• Similar results were observed for adults with overweight versus normal weight, although the ORs were lower.

Conclusion

This cross-sectional analysis of individual-level data from the global EAS FHSC registry demonstrated that half of the adults with HeFH and 1 in 4 pediatric HeFH patients were overweight or obese. In both adults and children/adolescents with HeFH, overweight and obesity were associated with a more atherogenic lipid profile and higher odds of having ASCVD, independent of lipid levels and use of LLM. The authors conclude that, “[g]iven their already augmented risk of ASCVD, patients with FH should be prioritized from the point of FH diagnosis for intensive lifestyle management aimed at maintaining a healthy weight, to reduce their lifetime risk of CVD events.”

Find this article online at Eur Heart J.

References

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2. Perez de Isla L, Alonso R, Mata N, Fernandez-Perez C, Muniz O, Diaz-Diaz JL, et al. Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study). Circulation 2017;135: 2133–44. https://doi.org/10.1161/CIRCULATIONAHA.116.024541
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5. World Health Organization. WHO Factsheets: Obesity and Overweight 2021. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight (May 2024, date last accessed).
6. World Health Organization. BMI-for-age (5–19 years). https://www.who.int/toolkits/growth-reference-data-for-5to19-years/indicators/bmi-for-age (January 2024, date last accessed).