The effect of achieving LDL-C <1.8 mmol/L to prevent the first atherosclerotic cardiovascular events in the primary prevention settings of severe heterozygous familial hypercholesterolemia

Abstract

Abstract Introduction The International Atherosclerosis Society (IAS) has proposed “severe familial hypercholesterolemia” (FH) as a phenotype with the highest cardiovascular risk. LDL-C <2.5 mmol/l is a recommended therapeutic goal for the primary prevention settings of severe FH. However, given that ESC guidelines recommends LDL-C <1.8 mmol/l in FH patients, this stricter goal may be better to prevent the first atherosclerotic cardiovascular disease (ASCVD) in severe FH patients. Purpose To determine whether achieving LDL-C<1.8 mg/dl is more beneficial to reduce the first ASCVD events. Methods A total of 148 severe FH subjects without any history of ASCVD were analyzed. Severe FH was defined as untreated LDL-C >10.3 mmol/l, LDL-C >8.0 mmol/l+ 1 high-risk feature, LDL-C >4.9 mmol/l + 2 high-risk features according to IAS proposed statement. The occurrence of ASCVD (all-cause death, CAD, ischemic stroke and lower extremity artery disease (LEAD)) were compared in those with on-treatment LDL-C < and ≥1.8 mmol/L. Results 10.1% (=15/148) of study subjects achieved on-treatment LDL-C <1.8 mmol/l. They were more likely to receive PCSK9 inhibitor (15.0 vs. 66.7%, p<0.01), whereas there was no significant difference in FH-related physical characteristics (tendon xanthomas: 72.2 vs. 93.3%, p=0.12) and causative genotypes (LDLR: 68.4 vs. 66.7%, p=1.00, PCSK9: 8.3 vs. 6.7%, p=1.00, LDLR/PCSK9: 3.8 vs. 6.7%, p=0.48), untreated LDL-C (7.3±1.7 vs. 7.9±1.8 mmol/l, p=0.22) and lipoprotein(a) (23 [11–42] vs. 25 [15–70] mg/dl, p=0.41) levels between two groups. During the observational period (median=7.0 years), severe FH achieving on-treatment LDL-C <1.8 mmol/l was associated with a lower likelihood of experiencing ASCVD events (Figure 1). Of note, any cardiovascular events did not occur in severe FH who achieved on-treatment LDL-C <1.8 mmol/l. In those with on-treatment LDL ≥1.8 mmol/L, CAD (76.5%=26/34) was more dominant component of ASCVD, followed by ischemic stroke (17.6%=6/34) and LEAD (5.9%=2/34). Conclusions A significantly lower frequency of ASCVD was observed in severe FH who achieved LDL-C <1.8 mmol/L in the primary prevention settings. Given that only 10.1% of severe FH patients achieved LDL-C <1.8 mmol/l, more actions are required to motivate physicians for further intensified management of LDL-C in severe FH patients in the primary prevention settings. Funding Acknowledgement Type of funding sources: None.