ABSTRACT
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an autosomal dominant disease that leads to cardiovascular (CV) disease. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) demonstrated efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and in prevention of CV events. The aim of our study is to evaluate the relationship between LDL receptor (LDLR) mutations and response to PCSK9-I therapy. METHODS AND RESULTS: We evaluated total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in consecutive patients with FH before PCSK9-I treatment and after 12 (T12w) and 36 (T36w) weeks of treatment. We evaluated LDL-C target achievement according to different mutations in LDLR. Eighty FH subjects (mean age:54 ± 13.3 years), 39 heterozygous (He) with defective LDLR gene mutations, 30 He with null mutations and 11 compound-He or homozygous (Ho) were recruited. At baseline, 69 subjects were under maximal lipid lowering therapy (MLLT) and 11 subjects had statin-intolerance. From baseline to T36w we observed an overall 51% reduction in LDL-C. We found no difference in LDL-C changes between subjects with He-defective mutation and He-null mutations both at T12w (p = 1.00) and T36w (p = 0.538). At T36w, LDL-C target was achieved in 59% of He-defective mutations subjects and in 36% of He-null mutations subgroup (p = 0.069), whereas none of compound-He/Ho-FH achieved LDL-C target. CONCLUSIONS: After 36 weeks there were no differences in response to PCSK9-I therapy between different groups of He-FH subjects. Response to PCSK9-I was significantly lower in carriers of compound-He/Ho mutations. Registration number for clinical trials: NCT04313270 extension.
Subject(s)
Hyperlipoproteinemia Type II , Proprotein Convertase 9 , Adult , Aged , Humans , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/drug therapy , Hyperlipoproteinemia Type II/genetics , Middle Aged , Mutation , PCSK9 Inhibitors , Proprotein Convertase 9/genetics , Proprotein Convertase 9/therapeutic use , Receptors, LDL/geneticsABSTRACT
BACKGROUND AND AIM: Protein convertase subtilisin kexin type 9 (PCSK-9) inhibitors demonstrated efficacy in cholesterol reduction and in the prevention of cardiovascular events. We evaluated changes in lipid profile and carotid stiffness in patients with familial hypercholesterolemia during 12 weeks of treatment with a PCSK-9 inhibitor, Evolocumab®. METHODS AND RESULTS: Patients with familial hypercholesterolemia starting a treatment with Evolocumab® were included. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), small dense LDL (assessed by LDL score) and carotid stiffness were evaluated before starting treatment with Evolocumab® and during 12 weeks of treatment. Twenty-five subjects were enrolled (52% males, mean age 51.5 years). TC and LDL-C were reduced of 38% and 52%, respectively during treatment, with LDL score reduced of 46.1%. In parallel, carotid stiffness changed from 8.8 (IQR: 7.0-10.4) m/sec to 6.6 (IQR: 5.4-7.5) m/sec, corresponding to a median change of 21.4% (p < 0.001), with a significant increase in carotid distensibility (from 12.1, IQR: 8.73-19.3 kPA-1 × 10-3 at T0 to 21.8, IQR: 16.6-31.8 kPA-1 × 10-3 at T12w) corresponding to a median change of 62.8% (p < 0.001). A multivariate analysis showed that changes in LDL score were independently associated with changes in carotid stiffness (ß = 0.429, p = 0.041). CONCLUSION: Small dense LDL reduction, as assessed by LDL score, is associated with changes in carotid stiffness in patients with familial hypercholesterolemia treated with Evolocumab®.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Anticholesteremic Agents/therapeutic use , Carotid Artery Diseases/drug therapy , Carotid Artery, Common/drug effects , Cholesterol, LDL/blood , Hyperlipoproteinemia Type II/drug therapy , Vascular Stiffness/drug effects , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Anticholesteremic Agents/adverse effects , Biomarkers/blood , Carotid Artery Diseases/diagnostic imaging , Carotid Artery Diseases/etiology , Carotid Artery Diseases/physiopathology , Carotid Artery, Common/diagnostic imaging , Carotid Artery, Common/physiopathology , Down-Regulation , Female , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/complications , Hyperlipoproteinemia Type II/diagnosis , Male , Middle Aged , Prospective Studies , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND AND OBJECTIVE: Arterial stiffness (AS) is an independent cardiovascular risk factor. A number of studies have reported a beneficial role of statins on AS albeit with controversial results, in addition to their effects on lipid profile. Therefore, we carried out a meta-analysis of the available randomized controlled trials assessing the effects of statin therapy on AS, in the attempt to reach more definitive conclusions. METHODS: A systematic search of the on-line databases available up to March 2017 was conducted, including intervention studies reporting AS expressed by carotid-femoral pulse wave velocity (PWV), as difference between the effects of treatment with or without statins. For each study, mean difference (MD) and 95% confidence intervals (CI) were pooled using a random effect model. RESULTS: Eleven studies met the pre-defined inclusion criteria, for a total of 573 participants and 2-144 weeks' intervention time. In the pooled analysis, statin therapy was associated with a -6.8% (95% C.I.: -11.7 to -1.8) reduction in PWV. There was significant heterogeneity among studies (I2 = 96%); none of the study characteristics seems to have influenced the effect of statin use on PWV. CONCLUSIONS: The results of this meta-analysis suggest that statin therapy reduces AS. This effect appears to be at least in part independent of the changes in blood pressure and lipid profile.
