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Multicenter Study
. 2025 Mar 24;46(12):1127-1140.
doi: 10.1093/eurheartj/ehae791.

Overweight, obesity, and cardiovascular disease in heterozygous familial hypercholesterolaemia: the EAS FH Studies Collaboration registry

Amany Elshorbagy  1   2 , Antonio J Vallejo-Vaz  1   3   4   5 , Fotios Barkas  1   6 , Alexander R M Lyons  1 , Christophe A T Stevens  1 , Kanika I Dharmayat  1 , Alberico L Catapano  7   8 , Tomas Freiberger  9   10 , G Kees Hovingh  11   12 , Pedro Mata  13 , Frederick J Raal  14 , Raul D Santos  15 , Handrean Soran  16 , Gerald F Watts  17   18 , Marianne Abifadel  19 , Carlos A Aguilar-Salinas  20   21 , Khalid F Alhabib  22 , Mutaz Alkhnifsawi  23   24 , Wael Almahmeed  25 , Fahad Alnouri  26 , Rodrigo Alonso  27 , Khalid Al-Rasadi  28 , Ahmad Al-Sarraf  29 , Marcello Arca  30 , Tester F Ashavaid  31 , Maurizio Averna  32   33 , Maciej Banach  34   35   36 , Marianne Becker  37 , Christoph J Binder  38 , Mafalda Bourbon  39   40 , Liam R Brunham  41 , Krzysztof Chlebus  42 , Pablo Corral  43 , Diogo Cruz  44 , Kairat Davletov  45 , Olivier S Descamps  46 , Bambang Dwiputra  47 , Marat Ezhov  48 , Urh Groselj  49   50 , Mariko Harada-Shiba  51 , Kirsten B Holven  52 , Steve E Humphries  53 , Meral Kayikcioglu  54 , Weerapan Khovidhunkit  55 , Katarina Lalic  56 , Gustavs Latkovskis  57 , Ulrich Laufs  58 , Evangelos Liberopoulos  59 , Marcos M Lima-Martinez  60 , Vincent Maher  61 , A David Marais  62 , Winfried März  63   64   65   66 , Erkin Mirrakhimov  67   68 , André R Miserez  69   70 , Olena Mitchenko  71 , Hapizah Nawawi  72 , Børge G Nordestgaard  73 , Andrie G Panayiotou  74 , György Paragh  75 , Zaneta Petrulioniene  76 , Belma Pojskic  77 , Arman Postadzhiyan  78 , Ashraf Reda  79 , Željko Reiner  80 , Ximena Reyes  81 , Fouzia Sadiq  82 , Wilson Ehidiamen Sadoh  83 , Heribert Schunkert  84   85 , Aleksandr B Shek  86 , Erik Stroes  87 , Ta-Chen Su  88 , Tavintharan Subramaniam  89 , Andrey V Susekov  90 , Myra Tilney  91   92 , Brian Tomlinson  93 , Thanh Huong Truong  94 , Alexandros D Tselepis  95 , Anne Tybjærg-Hansen  96 , Alejandra Vázquez-Cárdenas  97 , Margus Viigimaa  98 , Branislav Vohnout  99 , Shizuya Yamashita  100 , Kausik K Ray  1
Affiliations
Multicenter Study

Overweight, obesity, and cardiovascular disease in heterozygous familial hypercholesterolaemia: the EAS FH Studies Collaboration registry

Amany Elshorbagy et al. Eur Heart J. .

Abstract

Background and aims: Overweight and obesity are modifiable risk factors for atherosclerotic cardiovascular disease (ASCVD) in the general population, but their prevalence in individuals with heterozygous familial hypercholesterolaemia (HeFH) and whether they confer additional risk of ASCVD independent of LDL cholesterol (LDL-C) remains unclear.

Methods: Cross-sectional analysis was conducted in 35 540 patients with HeFH across 50 countries, in the EAS FH Studies Collaboration registry. Prevalence of World Health Organization-defined body mass index categories was investigated in adults (n = 29 265) and children/adolescents (n = 6275); and their association with prevalent ASCVD.

Results: Globally, 52% of adults and 27% of children with HeFH were overweight or obese, with the highest prevalence noted in Northern Africa/Western Asia. A higher overweight/obesity prevalence was found in non-high-income vs. high-income countries. Median age at familial hypercholesterolaemia diagnosis in adults with obesity was 9 years older than in normal weight adults. Obesity was associated with a more atherogenic lipid profile independent of lipid-lowering medication. Prevalence of coronary artery disease increased progressively across body mass index categories in both children and adults. Compared with normal weight, obesity was associated with higher odds of coronary artery disease in children (odds ratio 9.28, 95% confidence interval 1.77-48.77, adjusted for age, sex, lipids, and lipid-lowering medication) and coronary artery disease and stroke in adults (odds ratio 2.35, 95% confidence interval 2.10-2.63 and odds ratio 1.65, 95% confidence interval 1.27-2.14, respectively), but less consistently with peripheral artery disease. Adjusting for diabetes, hypertension and smoking modestly attenuated the associations.

Conclusions: Overweight and obesity are common in patients with HeFH and contribute to ASCVD risk from childhood, independent of LDL-C and lipid-lowering medication. Sustained body weight management is needed to reduce the risk of ASCVD in HeFH.

Keywords: Adiposity; Atherosclerosis; Dyslipidaemia; Insulin resistance.

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Figures

Structured Graphical Abstract
Structured Graphical Abstract
Overweight and obesity are common in patients with heterozygous familial hypercholesterolaemia and are associated with higher LDL cholesterol and greater risk of atherosclerotic cardiovascular disease, independent of lipid-lowering medication. BMI, body mass index; CI, confidence interval; HDL-C, HDL cholesterol; LDL-C, LDL-cholesterol; OR, odds ratio.
Figure 1
Figure 1
Prevalence of underweight, normal weight, overweight, and obesity in people with heterozygous familial hypercholesterolaemia pooled globally (A), by country-income category (B), and by United Nations sub-regions (C). Adults were aged 18 years or older; children and adolescents were aged 5 to <18 years. Body mass index categories were defined by World Health Organization body mass index cut-offs (see Methods section for details). In B and C, underweight individuals are pooled with the normal weight category; data are sorted in descending order of combined overweight and obesity prevalence. No formal statistical comparisons are conducted as these prevalence are for descriptive purposes only. 1n = 5 adults from Nigeria were not included in this analysis
Figure 2
Figure 2
A-G: Estimated means and 95% confidence intervals of different lipid fractions by body mass index z-score (in children and adolescents aged 5 to <18 years; left panels) and body mass index in adults (aged ≥18 years; right panels) with adjustment for age, sex, and use of lipid-lowering medication. The vertical lines (green, yellow, and red) mark the beginning of the normal weight, overweight, and obese BMI ranges, respectively. The lowest and highest 1% of the independent variable are not shown. Note the different scales on the y-axes for children and adults. BMI, body mass index; TRL-C, triglyceride-rich lipoprotein cholesterol
Figure 3
Figure 3
A-D: Odds ratios and 95% confidence intervals for the presence of different types of cardiovascular disease in adults with heterozygous familial hypercholesterolaemia at registry entry by body mass index category. Models are adjusted for the following variables: Model 1, age and sex; Model 2, age, sex, lipid-lowering medication, LDL cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol × lipid-lowering medication interaction; Model 3, all Model 2 variables, plus diabetes, hypertension, and smoking. Body mass index categories were defined by World Health Organization body mass index cut-offs (see Methods section for details)
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