Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia.

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.

Lipid metabolism during pregnancy: consequences for mother and child.

PURPOSE OF REVIEW: Accommodating fetal growth and development, women undergo multiple physiological changes during pregnancy. In recent years, several studies contributed to the accumulating evidence about the impact of gestational hyperlipidemia on cardiovascular risk for mother and child. This review aims to provide a comprehensive overview of the current research on lipid profile alterations during pregnancy and its associated (cardiovascular) outcomes for mother and child from a clinical perspective. RECENT FINDINGS: In a normal pregnancy, total and LDL-cholesterol levels increase by approximately 30-50%, HDL-cholesterol by 20-40%, and triglycerides by 50-100%. In some women, for example, with familial hypercholesterolemia (FH), a more atherogenic lipid profile is observed. Dyslipidemia during pregnancy is found to be associated with adverse (cardiovascular) outcomes for the mother (e.g. preeclampsia, gestational diabetes, metabolic syndrome, unfavorable lipid profile) and for the child (e.g. preterm birth, large for gestational age, preatherosclerotic lesions, unfavorable lipid profile). SUMMARY: The lipid profile of women during pregnancy provides a unique window of opportunity into the potential future cardiovascular risk for mother and child. Better knowledge about adverse outcomes and specific risk groups could lead to better risk assessment and earlier cardiovascular prevention. Future research should investigate implementation of gestational screening possibilities.

Sex Differences in Familial Hypercholesterolemia.

PURPOSE OF REVIEW: This review aims to summarize the existing research on sex differences in familial hypercholesterolemia (FH) across the lifespan. RECENT FINDINGS: From childhood onward, total- and low-density lipoprotein cholesterol (LDL-C) levels in girls are higher than those in boys with FH. By the age of 30 years, women with FH have a higher LDL-C burden than men. In adulthood, women are diagnosed later than men, receive less lipid-lowering treatment, and consequently have higher LDL-C levels. An excessive atherosclerotic cardiovascular disease risk is reported in young female compared to male FH patients. The periods of pregnancy and breastfeeding contribute to treatment loss and increased cholesterol burden. Earlier initiation of treatment, especially in girls with FH, and lifelong treatment during all life stages are important. Future research should aim to recruit both women and men, report sex-specific data, and investigate the impact of the female life course on cardiovascular outcomes. Future guidelines should include sex-specific aspects.

First clinical experiences with inclisiran in a real-world setting.

BACKGROUND AND OBJECTIVE: Inclisiran is the first-in-class small interfering RNA (siRNA) proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor. In clinical trials inclisiran showed effective and sustained low-density lipoprotein cholesterol (LDL-C) reduction of ± 50 %. As data in clinical setting are scarce, we aim to investigate the efficacy and safety in clinical practice. METHODS: We describe a registry of consecutive patients who started with inclisiran at a lipid clinic of a university hospital. Patients were eligible if they fulfilled the reimbursement criteria in the Netherlands. Patients were included if they started with inclisiran as first line (group 1) or switched from PCSK9 monoclonal antibody (mAbs) to inclisiran (group 2). LDL-C levels were measured at 3 and 9 months after initiation of inclisiran. Median change of LDL-C levels was calculated on an individual and group level. RESULTS: We analysed 65 patients (36 women), median [25th percentile; 75th percentile] age of 63 [54; 68] years. Of these, 44 patients had both a 3 month and 9 month visit. At 3 months, patients who newly started inclisiran (group 1, n = 45) showed a LDL-C decrease of 38 [-49;-33] %. Patients who used statins as co-medication (n = 15) had a higher median LDL-C decrease compared to those without statin use (n=30; 45 % vs 38 %). However, patients who switched from mAbs to inclisiran (group 2, n = 20) had an increase in LDL-C of 38 [+4; +97] %. Adverse effects associated with inclisiran were mild and consisted of mild injection site reactions. Efficacy was slightly less whereas safety results were similar at 9 months. CONCLUSION: Our initial experience of inclisiran in a clinical setting showed less reduction in LDL-C levels compared to clinical trials but a similar safety profile. Moreover, patients who switched from PCSK9 mAbs to inclisiran generally showed an increase in LDL-C levels implying that inclisiran is less potent in LDL-C reduction compared to PCSK9 mAbs.

Sex differences in efficacy and safety of PCSK9 monoclonal antibodies: A real-world registry.

BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin 9 monoclonal antibodies (PCSK9 mAbs) reduce low-density lipoprotein (LDL-c) with a favourable safety profile. Available data from PCSK9 antibody trials suggest LDL-c reduction is lower in women compared to men. Data in real-world setting is scarce. The aim of this study was to assess sex differences in efficacy and safety of PCSK9 antibodies in clinical care. METHODS: All patients starting with evolocumab or alirocumab in our lipid clinic were included in a prospective registry. We collected clinical information, including baseline and follow-up mean LDL-C levels after initiation of PCSK9 mAbs treatment. In addition, side effects and PCSK9 mAbs discontinuation were recorded. RESULTS: We analysed 436 patients (209 women), mean age 58 ± 11 years. Women had higher baseline LDL-c levels compared to men (4.7 ± 1.6 mmol/L vs 4.1 ± 1.4 mmol/L, p < 0.01). PCSK9 mAbs resulted in less relative LDL-c reduction in women compared to men (50% vs 61% p<0.01), but equal absolute LDL-c reduction (respectively 2.3 ± 1.3 mmol/L vs 2.5 ± 1.1 mmol/L, p = 0.087). Women less often reached LDL-c target levels than men (50% vs 72%). No sex differences were observed in reporting of side effects (women 32% vs men 27% p = 0.26) or PCSK9 mAbs discontinuation (women 13% vs men 10%, p = 0.46). CONCLUSIONS: In clinical practice, PCSK9 mAbs are less effective in reducing LDL-c levels in women compared to men and equally safe, implying the importance of sex differences in PCSK9 metabolism.

Quality of life and coping in Dutch homozygous familial hypercholesterolemia patients: A qualitative study.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels leading to extremely premature atherosclerotic cardiovascular disease. Therefore, healthcare professionals consider HoFH to have major impact on patients' life. Remarkably, little is known on how patients deal with their condition. The aim of this study is to investigate how Dutch patients experience and cope with HoFH in daily life. METHODS: Adult patients with genetically confirmed HoFH, treated at the 3 specialized HoFH-centers in the Netherlands, were interviewed in-depth. Interview transcripts were analyzed according to grounded theory. Health-related quality of life (QoL) and coping were measured with the EuroQol (EQ)-5D-5L questionnaire and the Threatening Medical Situations Inventory (TMSI), respectively. RESULTS: 20 Dutch HoFH patients were interviewed: 50% women, median age 38 years, 60% with cardiovascular disease, 10% on apheresis. Coding of the transcripts resulted in a conceptual model, with disease perception as the central theme. Individual TMSI-results corresponded to the interviews, with most patients showing both monitoring (information-seeking behavior) and blunting (distractive strategies) coping styles. The median EQ-5D-5L health utility score (0.839) was only 5% below the Dutch population (0.887). Transient anxiety was reported when confronted with the consequences of HoFH in daily life. Patients reported high confidence in treatment by a dedicated HoFH center, which helped them cope with their disease. CONCLUSIONS: Dutch HoFH patients use a variety of effective coping mechanisms in such a way that their subjective QoL is only slightly affected. Healthcare professionals can use this knowledge to tailor their care to the specific needs of these patients.

Infection mimicking skin condition: pyoderma gangrenosum.

The a priori risk of infection is high when a patient presents with an ulcerative skin condition and elevated inflammatory parameters. If the ulceration is progressive despite adequate antibiotic therapy and tissue cultures are negative, pyoderma gangrenosum should be considered as the diagnosis. This rare infection mimicking skin condition can develop and worsen due to surgery. In this paper, we report two cases that illustrate the importance of making this clinical diagnosis in a timely manner in order to avoid unnecessary surgical interventions and worsening of the clinical picture.

The development and first results of a health-related outcomes set in familial hypercholesterolemia (FH) patients: Knowledge is health.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is the most common hereditary lipid disorder requiring life-long treatment to prevent cardiovascular disease. A recent concept in healthcare is not only to focus on outcomes defined by healthcare professionals, but also take Patient-Reported Outcomes Measures (PROMs) into account. The aim of this study is (1) to describe the development and first results of a health-related outcomes set including PROMs for FH patients and (2) investigate the influence of patient knowledge on health-related outcomes. METHODS: A multidisciplinary group of FH experts, in collaboration with a sounding board of FH patients (n = 166), developed a health-related outcomes set containing the domains: medication adherence (MARS-5), smoking, self-efficacy and self-management, quality of life (QOL) (EQ-5D-5L), reported adverse drug reactions, lipid outcome measures, and FH and cardiovascular risk factor knowledge. Knowledge scores ranged from 0 to 10. Two groups were created: Insufficient knowledge (INSUF) (<7.5), and Sufficient knowledge (SUF) (≥7.5). RESULTS: The response rate of the questionnaires was 81.4% (n = 429), implicating acceptance of PROMs. In general, FH patients showed good knowledge, high QOL and were adherent to medication. However, the INSUF group had higher triglycerides levels (1.0 vs 0.9, p < 0.05), lower QOL (0.89 [0.79, 1.00] vs 0.89 [0.85, 1.00], p < 0.05), were more often smokers (14% vs 7%, p < 0.05) and reported more adverse drug reactions (62% vs. 49%, p < 0.05). CONCLUSIONS: A health-related outcomes set for FH patients, including PROMs, has been developed, which shows that insufficient knowledge of FH is negatively related to health outcomes. Improving patients' knowledge of FH may lead to better health.