Because there are no characteristic clinical or biochemical manifestations, the heterozygote state for lipoprotein lipase (LPL) deficiency has been difficult to detect. Measurements of postheparin plasma LPL activity and of LPL mass were performed In six families of probands with LPL deficiency to characterize the heterozygote state. LPL mass was measured in a sandwich enzyme-linked immunosorbent assay (EUSA) using a monoclonal antibody (5D2) that had been produced against bovine milk LPL Thirteen obligate heterozygotes from these families had reduced LPL activity and mass below the 95th percent confidence limits of 34 normal controls, while one obligate heterozygote had LPL activity and mass between the 90th and 95th percent confidence limits. Potential heterozygotes In these families were Identified as normal (n=8)
Aim To evaluate the effect of alirocumab on frequency of standard apheresis treatments [weekly or every 2 weeks (Q2W)] in heterozygous familial hypercholesterolaemia (HeFH). Methods and results ODYSSEY ESCAPE (NCT02326220) was a double-blind study in 62 HeFH patients undergoing regular weekly or Q2W lipoprotein apheresis. Patients were randomly assigned (2:1, respectively) to receive alirocumab 150 mg (n = 41) or placebo (n = 21) Q2W subcutaneously for 18 weeks. From day 1 to week 6, apheresis rate was fixed according to the patient’s established schedule; from weeks 7 to 18, apheresis rate was adjusted based on the patient’s low-density lipoprotein cholesterol (LDL-C) response in a blinded fashion. Apheresis was not performed when the LDL-C value was ≥30% lower than the baseline (pre-apheresis) value. The primary efficacy endpoint was the rate of apheresis treatments over 12 weeks (weeks 7–18), standardized to number of planned treatments. In the alirocumab group the least square (LS) mean ± SE (95% confidence interval [CI]) per cent change in pre-apheresis LDL-C from baseline at week 6 was −53.7 ± 2.3 (−58.2 to − 49.2) compared with 1.6 ± 3.1 (–4.7 to 7.9) in the placebo group. The primary efficacy endpoint showed statistically significant benefit in favour of alirocumab (Hodges–Lehmann median estimate of treatment difference: 0.75; 95% CI 0.67–0.83; P < 0.0001). Therefore, alirocumab-treated patients had a 0.75 (75%) additional reduction in the standardized rate of apheresis treatments vs. placebo-treated patients. During this period, 63.4% of patients on alirocumab avoided all and 92.7% avoided at least half of the apheresis treatments. Adverse event rates were similar (75.6% of patients on alirocumab vs. 76.2% on placebo). Conclusions Lipoprotein apheresis was discontinued in 63.4% of patients on alirocumab who were previously undergoing regular apheresis, and the rate was at least halved in 92.7% of patients. Alirocumab was generally safe and well tolerated.
A previous study reported that heterozygotes for lipoprotein lipase (LPL) deficiency have reduced LPL, the lipoprotein pattern classified as familial combined hyperlipidemia (FCHL), elevated apolipoprotein (apo) B levels, and reduced high density lipoprotein (HDL) levels. These findings suggest that subjects with reduced LPL may form one subset of the FCHL population. The purpose of the present study is to determine whether a subset of patients with FCHL have reduced LPL. Three patient populations with FCHL were studied: 1) subjects with the diagnosis of FCHL (n = 9) established by previous family studies, 2) clinic patients with a tentative diagnosis of FCHL (n = 14), and 3) subjects undergoing angiography who had coronary artery disease (CAD) and a diagnosis of FCHL by family study (n = 33). Two of nine subjects with the established diagnosis of FCHL, five of the 14 FCHL clinic patients, and 13 of the 33 CAD subjects with FCHL had reduced LPL activity in the same range as do individuals who are obligate heterozygotes for LPL deficiency. Subjects with FCHL and reduced LPL had higher plasma triglyceride (p < 0.01) and lower HDL cholesterol (p < 0.025) levels than did the subjects with FCHL and normal LPL levels (327 +/- 201 versus 210 +/- 122 mg/dl [mean +/- SD] and 36 +/- 7 versus 44 +/- 13 mg/dl, respectively). Thus, in all three groups of patients with apparent FCHL, 20 of 56 subjects (36%) had reduced LPL, suggesting that one subset of the FCHL population may be identified by an abnormality in LPL activity that is associated with lipoprotein abnormalities.
A monoclonal antibody to lipoprotein lipase (LPL) has been used in an enzyme-linked immunosorbent assay (ELISA) for LPL protein mass. Measurement of LPL immunoreactive mass in pre- and postheparin plasma distinguished three classes of abnormalities in patients with classical deficiency of lipoprotein lipase activity. The class I defect consisted of the absence of LPL immunoreactive homodimer in pre- and postheparin plasma compatible with a potential 'null allele'. Patients with a class II defect had almost no LPL immunoreactive mass in preheparin plasma but showed an increase in their LPL mass of 68 +/- 23 ng ml-1 (mean +/- SD) after heparin. Patients with the class III defect had considerable amounts of LPL immunoreactive material in preheparin plasma (159 +/- 190 ng ml-1). Heparin administration, however, caused very little additional release of LPL into the plasma (16 +/- 51 ng ml-1). Thus although both class II and class III patients had an LPL protein with abnormal catalytic activity, class III patients also appeared to have a defect in heparin binding of LPL. To test this hypothesis, postheparin plasma of classes II and III patients was analysed by heparin-Sepharose chromatography. In contrast to class II patients, the LPL immunoreactive mass of class III patients did not show affinity for the heparin and eluted in the column void volume, suggesting the class III defect is also associated with a defect in heparin binding.
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