Sex differences and similarities in largest global HoFH registry study


A retrospective cohort study of 751 patients with homozygous familial hypercholesterolemia (HoFH) showed no sex differences in age at diagnosis, treatment, and CVD risk factors, except for smoking. However, men were more likely to have an MI and undergo PCI.

This summary is based on the publication of Mulder JWCM, Tromp TR, Al-Khnifsawi M, et al. - Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia. JAMA Cardiol. 2024 Apr 1;9(4):313-322. doi: 10.1001/jamacardio.2023.5597

Introduction and methods


Patients with homozygous familial hypercholesterolemia (HoFH) have extremely increased LDL-c levels and therefore a very high risk of premature ASCVD [1]. In heterozygous FH, female patients exhibit excess ASCVD morbidity and mortality compared with males [2,3], which could be related to women with heterozygous FH often being diagnosed later and treated differently [4-8]. It is unknown whether these sex differences also exist in HoFH.

Aim of the study

The study aim was to investigate possible sex differences in age at diagnosis, risk factors, lipid-lowering therapy, and ASCVD morbidity and mortality in patients with HoFH.


In this retrospective cohort study, data from 751 HoFH patients who were alive in or after 2010 were collected from the HoFH International Clinical Collaborators registry, the largest global HoFH dataset spanning 88 institutions across 38 countries.

Main results

Patient characteristics at diagnosis

  • The median age at diagnosis was 13 years (IQR: 6–26) in female patients (n=389) and 11 years (IQR: 5–27) in male patients (n=362) (P=0.53).
  • Mean ± SD untreated LDL-c levels were similar in females and males (579 ± 203 vs. 596 ± 186 mg/dL).
  • In women, mean untreated HDL-c levels were higher than in men (42 ± 17 vs. 38 ± 16 mg/dL; P=0.007), whereas median untreated triglyceride levels were lower (100 mg/dL; IQR: 75–140 vs. 115 mg/dL; IQR: 79–161; P=0.013).

Patient characteristics during follow-up

  • After a median clinical follow-up duration of 9 years (IQR: 1–20), the prevalence of smoking was lower in females than males (14.3% vs. 27.2%; P<0.001), but the frequencies of other CVD risk factors (BMI, diabetes, hypertension, and CKD) were similar in both sexes (all P>0.05).
  • Almost all females (94.9%) and males (96.5%) received lipid-lowering therapy (P=0.49), and there were no sex differences in the type or number of lipid-lowering therapies.
  • During treatment, mean LDL-c levels were also similar in females and males (321 ± 179 vs. 323 ± 176 mg/dL), and only few patients reached the recommended LDL-c goals (4.0% of women vs. 3.1% of men; P=0.82).
  • In females, mean treated HDL-c levels were higher than in males (44 ± 18 vs. 41 ± 16 mg/dL; P=0.022), but there was no sex difference in median treated triglyceride levels (91 mg/dL; IQR: 62–131 vs. 96 mg/dL; IQR: 70–143; P=0.09).
  • At the latest clinical evaluation, fewer females than males had experienced an MI (8.0% vs. 16.3%; P<0.001), although the mean age at first MI was similar (39 ± 13 vs. 38 ± 13 years; P=0.81).
  • The prevalence and age of onset of aortic stenosis, angina pectoris, ischemic stroke or TIA, and peripheral artery disease did not differ between sexes (all P>0.05).
  • Fewer females than males had undergone PCI (8.7% vs. 15.7%; P=0.005), but the frequencies of other ASCVD interventions (CABG, aortic valve replacement, and carotid intervention) did not differ between the sexes (all P>0.05).
  • In total, 18 women (5.3%) and 19 men (6.1%) died (P=0.77), with no difference in median age at death (32 years; IQR: 23–48 vs. 43 years; IQR: 16–54; P=0.89).

Cumulative incidence of ASCVD morbidity, intervention, and mortality

  • Sixteen years after the HoFH diagnosis was made, the cumulative incidence of first MI was lower in females than in males (5.0% vs. 13.7%; subdistribution HR (SHR): 0.37; 95%CI: 0.21–0.66), as was the cumulative incidence of first PCI (6.5% vs. 15.0%; SHR: 0.42; 95%CI: 0.26–0.69).
  • The cumulative incidence of all-cause mortality did not differ between females and males (3.0% vs. 4.1%; HR: 0.76; 95%CI: 0.40–1.45), nor did the cumulative incidence of CV death (2.6% vs. 4.1%; SHR: 0.87; 95%CI: 0.44–1.75).


In this retrospective cohort study of the largest global registry of HoFH patients, there were no sex differences in age at diagnosis, lipid-lowering therapy, LDL-c levels (before and during treatment), and CVD risk factors—except for smoking prevalence. The prevalence and incidence of MI and PCI were higher in males than females, but the rates of other ASCVD morbidity, interventions, and mortality were similar.

The authors conclude their “findings indicate that both women and men with HoFH have a very high risk of premature ASCVD, suggesting that early diagnosis and treatment are important steps in attenuating excessive cardiovascular risk in both sexes.”

Find this article online at JAMA Cardiol.


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  2. Ahmad Z, Li X, Wosik J, et al. Premature coronary heart disease and autosomal dominant hypercholesterolemia: increased risk in women with LDLR mutations. J Clin Lipidol. 2016;10(1):101-108.e1-3. doi:10.1016/j.jacl.2015.09.003
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  8. Zamora A, Masana L, Comas-Cufí M, et al; XULA and ISV-Girona groups. Familial hypercholesterolemia in a European Mediterranean population-Prevalence and clinical data from 2.5 million primary care patients. J Clin Lipidol. 2017;11(4):1013-1022. doi:10.1016/j.jacl.2017.05.012

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