Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. A significantly greater proportion of patients receiving 2-3 lipid lowering medications achieved LDL-cholesterol targets compared to those receiving monotherapy.

2. Median age at diagnosis was 44.4 years of age and only 2% were diagnosed before 18 years of age.

Evidence Rating Level: 2 (Good)

Study Rundown:

Familial hypercholesterolemia is a common genetic disorder in which LDL cholesterol (“bad cholesterol”) is elevated. An increased concentration of LDL-C is correlated with an increased risk of atherosclerosis and cardiovascular events, such as myocardial infarction and stroke. This study analyzed patient data from an international registry of individuals with heterozygous familial hypercholesterolemia on numerous outcomes. Findings from the 42 167 eligible patients showed that median age of diagnosis for this genetic condition was 44.4 years and it was rarely detected before the age of 18. Another major finding from this study showed that there are significant sex differences between men and women. For example, women were more likely to be diagnosed with coronary artery disease at an older age compared to men. Furthermore, women were more likely to have higher LDL-C concentrations than comparable male counterparts, yet they were on lower dosages of cholesterol-lowering medication. In terms of treatment, combination therapy was found to be significantly more effective than single-pill therapy at reaching target LDL-C concentrations. This study also showed that being screened for familial hypercholesterolemia due to a known family history was a positive factor in lowering LDL-C concentrations, even untreated by medications. This suggests the clinical importance of having patients learn of their diagnosis at an earlier age which may allow for appropriate lifestyle changes. An interesting outlier in this study was the cohort of patients from the Netherlands, as the Dutch had implemented a national screening program which identified many cases which would have otherwise gone undetected. Nevertheless, this study was able to use this cohort to analyze the potential merits of this type of screening program.

In-Depth [cross-sectional study]:

The European Atherosclerosis Society Familial Hypercholesterolemia Studies Collaboration (FHSC) is a global registry for patients with genetic hypercholesterolemia. Patients included in this study were from this registry, ≥18 years old and had suspected or confirmed heterozygous familial hypercholesterolemia. 42 167 patients (53.6% women, median age 46.2 years old) were included in this study, mostly (84.2%) from Europe. Most patients were diagnosed by the Dutch Lipid Clinic Network criteria (75.4%). The median age at diagnosis was 44.4 years with only 2.1% being diagnosed before age 18. The prevalence of co-morbid cardiovascular risk factors increased with age (e.g., diabetes, hypertension, obesity).

Analysis was done on cardiovascular disease rates in these patients. The most common was found to be coronary artery disease (CAD), which was deemed premature CAD (<55 years in males and <60 years in females) in 11.3% and directly correlated with LDL-C concentrations (p<0.0001). After adjusting for risk factors, men were twice as likely as men to be diagnosed with CAD (p<0.0001). Other vascular diseases, such as peripheral artery disease and stroke, did not increase in likelihood with LDL-C concentrations.

The effects of medications were also studied in which 59.5% of patients were found to be on lipid-lowering medications. Of those patients, most were on statins (81.1%) and only 21.2% of these patients were on combination therapy with two or three of statins, ezetimibe, or PCSK9 inhibitors. Men were more likely to be on combination therapy and higher dosages of statins. When looking at LDL-C concentrations, only 2.7% of patients on cholesterol-lowering medications (statins, ezetimibe, PCSK9 inhibitors) were at the target LDL-C of <1.8 mmol/L. LDL-C concentrations were on average higher for women then men, even when stratified by risk factors and medications. Combination therapy increased likelihood of having an LDL-C <1.8 (p<0.0001).

Index cases (those who were the first of their family diagnosed) versus non-index (those who were screened due to known family history) was also an important distinction between patients. Non-index cases, who were younger at diagnosis and had less risk factors (except more smokers), had lower LDL-C even if untreated with medication (p<0.0001). Cardiovascular disease was also significantly lower in non-index cases, except for stroke.

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