Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia
Authors: Mulder Janneke W. C. M. , Tromp Tycho R. , Al-Khnifsawi Mutaz , Blom Dirk J. , Chlebus Krysztof , Cuchel Marina , D’Erasmo Laura , Gallo Antonio , Hovingh G. Kees , Kim Ngoc Thanh , Long Jiang , Raal Frederick J. , Schonck Willemijn A. M. , Soran Handrean , Truong Thanh-Huong , Boersma Eric , Roeters van Lennep Jeanine E. ,   Homozygous Familial Hypercholesterolemia International Clinical Collaborators, Alareedh Mohammed D. , Alieva Rano , Allevi Massimiliano , Altunkeser Bulent B. , Al-Waili Khalid , Al-Zamili Ali F. , Arca Marcello , Atzori Luigi , Averna Maurizio , Ayesh Mahmoud H. , Azar Sami T. , Banderali Giuseppe , Baratta Francesco , Bartuli Andrea , Béliard Sophie , Bianconi Vanessa , Bini Simone , Bin Thani Khalid , Bitar Fadi F. , Blaha Vladimir , Bonomo Katia , Bourbon Mafalda , Branchi Adriana , Brothers Julie A. , Bruckert Eric , Brunham Liam R. , Bruzzi Patrizia , Bucci Marco , Buonuomo Paola S. , Calabrò Paolo , Calandra Sebastiano , Carubbi Francesca , Cassiman David , Casula Manuela , Catapano Alberico L. , Cavalot Franco , Cefalù Angelo B. , Cesaro Arturo , Ceska Richard , Charng Min-Ji , Cipollone Francesco , Cohen Hofit , D'Addato Sergio , Dal Pino Beatrice , Dann Eldad J. , Defesche Joep C. , Del Ben Maria , Demircioglu Sinan , Descamps Olivier S. , Di Costanzo Alessia , Di Taranto Maria D. , Do Doan-Loi , Durst Ronen , Dvorakova Jana , Ebenbichler Christoph F. , Elis Avishay , Emil Sameh , Ezhov Marat V. , Fahed Akl C. , Fasano Tommaso , Ferri Claudio , Fogacci Federica , Formisano Elena , Fortunato Giuliana , Francis Gordon A. , Freiberger Tomas , Galimberti Federica , Gaspar Isabel M. , Genest Jacques , Gentile Marco , Giammanco Antonina , Gokce Cumali , Greber-Platzer Susanne , Grigore Liliana , Groselj Urh , Harada-Shiba Mariko , Hartgers Merel L. , Hegele Robert A. , Horak Pavel , Hori Mika , Hudgins Lisa C. , Hussein Osama , Iannuzzo Gabriella , Ilhan Osman , Iughetti Lorenzo , Kayikcioglu Meral , Kaynar Leyla G. , Kennedy Brooke A. , Khovidhunkit Weerapan , Kolovou Genovefa , Kose Melis , Kuku Irfan , Kurtoglu Erdal , Lalic Katarina S. , Le Hong-An , Le Thanh-Tung , Leitersdorf Eran , Liberopoulos Evangelos , Lyons Alexander R.M. , Madriz Ramón , Mandraffino Giuseppe , Mäser Martin , Mehta Roopa , Mitchenko Olena , Mombelli Giuliana , Montalcini Tiziana , Morace Carmela , Moubarak Elie M. , Muntoni Sandro , Naguib Tarek A. , Nascimbeni Fabio , Nawawi Hapizah , Nemer Georges , Nguyen Mai-Ngoc T. , Notargiacomo Serena , Okutan Harika , Ozcebe Osman I. , Pang Jing , Passaro Angelina , Pavanello Chiara , Pecchioli Lorenzo , Pecchioli Valerio , Pederiva Cristina , Pekkolay Zafer , Pellegatta Fabio , Piro Salvatore , Pirro Matteo , Pisciotta Livia , Pujia Arturo , Ray Kausik K. , Reda Ashraf , Reijman M. Doortje , Reiner Željko , Rhadi Sabah H. , Rizzi Luigi , Romandini Alessandra , Ruel Isabelle , Rymen Daisy , Sadiq Fouzia , Sag Saim , Salcioglu Osman Z. , Santos Raul D. , Sanz Juana M. , Sarzani Riccardo , Sbrana Francesco , Schurr Daniel , Scicali Roberto , Setia Nitika , Shaghee Foaad K. , Shek Aleksandr , Sherman Mark H. , Soska Vladimir , Stevens Christophe A.T. , Stroes Erik S.G. , Stulnig Thomas M. , Suppressa Patrizia , Susekov Andrey V. , Tarugi Patrizia , Temizhan Ahmet , Tichy Lukas , Trenti Chiara , Tromp Tycho R. , Urbanek Robin , Vallejo-Vaz Antonio J. , Vaverkova helena , Verma Ishwar C. , Vrablik Michal , Wang Luya , Watts Gerald F. , Werba José P. , Wiegman Albert , Witters Peter , Yenercag Mustafa , Yilmaz Mehmet , Yilmaz Yasar Hamiyet , Zambon Alberto , Zambon Sabina , Zemek Stanislav , Zenti Maria G. , Zlatohlavek Lukas , Zuurbier Linda 
Published: February 2024

Importance

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by extremely increased low-density lipoprotein (LDL) cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Heterozygous familial hypercholesterolemia (HeFH) is more common than HoFH, and women with HeFH are diagnosed later and undertreated compared to men; it is unknown whether these sex differences also apply to HoFH.

Objective

To investigate sex differences in age at diagnosis, risk factors, lipid-lowering treatment, and ASCVD morbidity and mortality in patients with HoFH.

Design, Setting, and Participants

Sex-specific analyses for this retrospective cohort study were performed using data from the HoFH International Clinical Collaborators (HICC) registry, the largest global dataset of patients with HoFH, spanning 88 institutions across 38 countries. Patients with HoFH who were alive during or after 2010 were eligible for inclusion. Data entry occurred between February 2016 and December 2020. Data were analyzed from June 2022 to June 2023.

Main Outcomes and Measures

Comparison between women and men with HoFH regarding age at diagnosis, presence of risk factors, lipid-lowering treatment, prevalence, and onset and incidence of ASCVD morbidity (myocardial infarction [MI], aortic stenosis, and combined ASCVD outcomes) and mortality.

Results

Data from 389 women and 362 men with HoFH from 38 countries were included. Women and men had similar age at diagnosis (median [IQR], 13 [6-26] years vs 11 [5-27] years, respectively), untreated LDL cholesterol levels (mean [SD], 579 [203] vs 596 [186] mg/dL, respectively), and cardiovascular risk factor prevalence, except smoking (38 of 266 women [14.3%] vs 59 of 217 men [27.2%], respectively). Prevalence of MI was lower in women (31 of 389 [8.0%]) than men (59 of 362 [16.3%]), but age at first MI was similar (mean [SD], 39 [13] years in women vs 38 [13] years in men). Treated LDL cholesterol levels and lipid-lowering therapy were similar in both sexes, in particular statins (248 of 276 women [89.9%] vs 235 of 258 men [91.1%]) and lipoprotein apheresis (115 of 317 women [36.3%] vs 118 of 304 men [38.8%]). Sixteen years after HoFH diagnosis, women had statistically significant lower cumulative incidence of MI (5.0% in women vs 13.7% in men; subdistribution hazard ratio [SHR], 0.37; 95% CI, 0.21-0.66) and nonsignificantly lower all-cause mortality (3.0% in women vs 4.1% in men; HR, 0.76; 95% CI, 0.40-1.45) and cardiovascular mortality (2.6% in women vs 4.1% in men; SHR, 0.87; 95% CI, 0.44-1.75).

Conclusions and Relevance

In this cohort study of individuals with known HoFH, MI was higher in men compared with women yet age at diagnosis and at first ASCVD event were similar. These findings suggest that early diagnosis and treatment are important in attenuating the excessive cardiovascular risk in both sexes.