AIMS: Familial Hypercholesterolemia (FH) is a frequent genetic cause of early coronary artery disease, and is still under-diagnosed and under-treated. With the advent of PCSK9 inhibitors as adjunctive therapy to maximal lipid-lowering therapy, a significant reduction in cholesterol levels of low-density lipoprotein (LDL-C) and cardiovascular events was observed, while maintaining a good safety and tolerance profile. Ultrasonography (US) detects Achilles tendon (AT) xanthomas in patients (pts) with FH. Given the recent introduction of new therapies, there are no studies in the literature that evaluate the efficacy and safety of this therapy over a period of more than 3 years.
We analysed the potential associations between FH genotype, clinical phenotype and ultrasonographic AT findings, evaluating the contribution of AT US to identify individuals with an FH-causing mutation. We also analysed the long-term efficacy and safety of additional therapy with PCSK9 inhibitors, comparing treatment with evolocumab and that with alirocumab.
SUBJECTS AND METHODS: Genetic screening, clinical and biochemical parameters in 194 pts with possible, probable or definite clinical diagnosis of FH according to the Dutch Lipid Clinic Network Score (DLCNS); 71 pts underwent bilateral AT US.
RESULTS: 43 pts carriers of null allele (NA) and 62 of defective (DEF) allele for LDL receptor while 33 pts with no known mutations (NM) for FH. Presence of xanthomas and gerontoxon, total and LDL-cholesterol (NA vs DEF vs NM: 326.5+97.7 mg/dl, 316.9+93.9 mg/dl, 211.1+76.3mg/dl, p<0.000) at diagnosis were significantly higher in NA pts than other subgroups. AT thickness was significantly different among the three groups (p< 0,005) and 78.2%, 72.4% and 31.6% had USX in NA, DEF and NM carriers respectively (p=0.002).
Among the 52 pts positive for FH-causing mutations, 16 pts had a clinical diagnosis either possible or probable and in nine pts the presence of USX was clinically undetected and thereby not considered for DLCNS calculation. Tendon ultrasound was able to show a prevalence of 51% of tendon xanthomas in comparison to the prevalence of alterations detected only by physical examination, which was 10,2%.
Following the addition of treatment with PCSK9 inhibitors, a mean reduction in LDL-C levels from 169 ± 30 mg / dl to 46 ± 16 was obtained, compared to the traditional maximal lipid-lowering treatment, ie in percentage terms a reduction of 72.4%. Compared to baseline LDL-C levels, this corresponds to an average reduction of 86.9%. There were no statistically significant differences between treatment with evolocumab and that with alirocumab in terms of reduction of LDL-C levels. In the course of traditional maximal lipid-lowering therapy, the goal of LDL cholesterol was obtained based on the personal level of cardiovascular risk in 0% of cases, while with the addition of PCSK9 inhibitors, 100% of subjects achieved therapeutic goal. No statistically significant differences were found following the introduction of PCSK9 inhibitor treatment with regard to CPK and transaminase levels. Over the years we have observed that LDL-C levels remained substantially stable.
CONCLUSIONS: Genotypic functional characterization is associated with different phenotypic clinical features, AT thickness and presence of US xanthomas. AT ultrasonography may help reclassifying as definite FH, patients with DLCN score of possible/probable FH. Achilles tendon ultrasound has a greater sensibility than standard physical exam. It discloses a noticeable higher prevalence of tendon xanthomas (51%) in comparison to clinical evaluation (10,2%). This exam allows to look in a more integrated way at the cardiovascular and tendon complications in everyeach patient. It also suggests, when xanthomas are found, the necessity to adopt a stronger lipid-lowering therapy.
In our study, in subjects with FH, it emerged that PCSK9 inhibitor therapy (evolocumab or alirocumab), in addition to maximal lipid-lowering therapy, results in a significant reduction of LDL-C levels, allowing the totality of patients to achieve the therapeutic goal of LDL-C related to its cardiovascular risk. Further studies are needed to confirm mainly the persistence of long-term efficacy and safety of PCSK9 inhibitor therapy and to evaluate on a larger scale whether there are differences between evolocumab and alirocumab in terms of efficacy in reducing LDL-C and cardiovascular risk
