Effect of PCSK9 inhibition with evolocumab on lipoprotein subfractions in familial dysbetalipoproteinemia (type III hyperlipidemia).

BACKGROUND AND AIMS: Familial dysbetalipoproteinemia (FDBL) is a rare inborn lipid disorder characterized by the formation of abnormal triglyceride- and cholesterol-rich lipoproteins (remnant particles). Patients with FDBL have a high risk for atherosclerotic disease. The effect of PCSK9 inhibition on lipoproteins and its subfractions has not been evaluated in FDBL. METHODS: Three patients (65±7 years, 23±3 kg/m2, 2 females) with FDBL (diagnosed by isoelectrofocusing) and atherosclerosis (coronary and/or cerebro-vascular and/or peripheral arterial disease) resistant or intolerant to statin and fibrate therapy received evolocumab (140mg every 14 days). In addition to a fasting lipid profile (preparative ultracentrifugation), apoB and cholesterol concentrations were determined in 15 lipoprotein-subfractions (density gradient ultracentrifugation; d 1.006-1.21g/ml) before and after 12 weeks of evolocumab treatment. Patients with LDL-hypercholesterolemia (n = 8, 56±8 years, 31±7 kg/m2) and mixed hyperlipidemia (n = 5, 68±12 years, 30±1 kg/m2) also receiving evolocumab for 12 weeks were used for comparison. RESULTS: All patients tolerated PCSK9 inhibition well. PCSK9 inhibitors reduced cholesterol (29-37%), non-HDL-cholesterol (36-50%) and apoB (40-52%) in all patient groups including FDBL. In FDBL, PCSK9 inhibition reduced VLDL-cholesterol and the concentration of apoB containing lipoproteins throughout the whole density spectrum (VLDL, IDL, remnants, LDL). Lipoprotein(a) was decreased in all patient groups to a similar extent. CONCLUSIONS: This indicates that the dominant fraction of apoB-containing lipoproteins is reduced with PCSK9 inhibition, i.e. LDL in hypercholesterolemia and mixed hyperlipidemia, and cholesterol-rich VLDL, remnants and LDL in FDBL. PCSK9 inhibition may be a treatment option in patients with FDBL resistant or intolerant to statin and/or fibrate therapy.

Protease inhibitor related type III hyperlipoproteinaemia is common and not associated with apolipoprotein-E E2/E2 phenotype.

OBJECTIVE: To determine the prevalence of type III hyperlipoproteinaemia in a cohort of HIV infected patients taking protease inhibitors and its correlation with the apolipoprotein-E2 isoform. DESIGN: Cross sectional study of 57 consecutive HIV infected subjects taking protease inhibitor therapy for a median of 12.5 (1-29) months, seen in an outpatient HIV clinic. Controls were 17 patients on non-nucleoside reverse transcriptor inhibitor therapy (NNRTI) for 9 (1-19) months and 50 antiviral naive patients. METHODS: Fasting cholesterol, triglyceride, HDL cholesterol, lipoprotein (a), and glucose were measured. Lipoprotein electrophoresis was performed on patients with a cholesterol >6.5 mmol/l and a triglyceride concentration of >4.5 mmol/l. Apolipoprotein-E phenotype was determined in serum. RESULTS: Dyslipidaemia was found in 43 (75%) PI treated patients-37 with triglyceride >2.3 mmol/l, 30 with cholesterol >6.5 mmol/l, and nine with HDL cholesterol <0.9 mmol/l. 38% had a lipoprotein (a) >300 mg/l. 11 patients (19.3%) had a type III hyperlipoproteinaemia pattern. Only one was homozygous for the E2 phenotype and none had clinical diabetes. An additional patient had a serum lipid profile compatible with type III hyperlipoproteinaemia and an E3/E2 phenotype in whom electrophoresis was not carried out before treatment. Six (35%) of the NNRTI and 16 (32%) of the antiviral naive patients had dyslipidaemia. 18 (31.6%) of the PI and none of the control patients had a cholesterol and/or triglyceride >8 mmol/l. CONCLUSION: Type III hyperlipoproteinaemia is common in this group of patients and need not be associated with the apolipoprotein-E2/E2 isoform. HIV protease inhibitors may interfere with lipoprotein receptor related protein.

Metabolic effects of oral contraceptives containing 30 micrograms and 50 micrograms of oestrogen.

In Study A, biochemical data from 17 women who were not taking oral contraceptives were compared with those from women taking preparations which contained either 30 microgram of ethinyl oestradiol and 150 microgram of D-norgestrel (18 women) or 50 microgram of ethinyl oestradiol and 250 microgram of D-norgestrel (nine women). In Study B, biochemical data were collected from eight women before and during the first three or four months therapy with preparations containing 30 microgram of ethinyl oestradiol and 150 microgram of D-norgestrel. The two oral contraceptive dosage forms studied produced qualitatively and quantitatively similar metabolic changes. Both caused an increase in serum concentration of triglycerides (30% to 33%), beta-lipoproteins (27% to 29%) and ceruloplasmin (75% to 90%), and a decrease in serum levels of antithrombin III (22% to 29%) and ascorbic acid (30% to 42%). Serum cholesterol and phospholipid concentrations were unchanged. However, the proportion of serum cholesterol carried by alpha-lipoproteins (high density lipoproteins) decreased, while that carried by beta-lipoproteins (low density and very low density lipoproteins) increased. The former change is in the same direction, but much smaller than that observed in coronary heart disease.

PIP: 2 studies, A and B, were conducted to determine the metabolic effects of oral contraceptives (OCs). The subjects were healthy nonsmokers (17 to 27 years old, 1.52 m. to 1.75 m. in height, and 50 kg. to 60 kg. in weight) who were not undergoing any therapy. Controls did not have any previous history of hormonal therapy. In Study A, biochemical data from 17 women who were not on OCs were compared with those of women taking pills containing either 30 ug of ethinyl estradiol (EE) and 150 ug of D. norgestrel (18 women) or 50 ug. of EE and 250 ug. of D. norgestrel (9 women). In Study B, 8 women were studied before and during 3 to 4 cycles of low-dosed OC therapy (30 ug. of EE and 150 ug. of D. norgestrel). In both studies, the 2 oral contraceptive dosage forms had similar metabolic quantitative and qualitative changes: both resulted in an increase in serum concentration of triglycerides (30 to 33%), B-lipoproteins (27 to 29%), and ceruloplasmin (75 to 90%), and a decrease in serum levels of antithrombin 3 (22 to 29%) and ascorbic acid (30 to 42%). Serum cholesterol and phospholipid concentration did not change. The proportion of serum cholesterol carried by a-lipoproteins (high density lipoproteins) did decrease (the change is much smaller than that seen in coronary heart disease) while that carried by B-lipoproteins (or low density and very low density lipoproteins) increased. A significant negative correlation was observed between serum concentrations of ascorbic acid and cholesterol; this is interesting as clinical and experimental evidence suggests that latent ascorbic acid deficiency leads to hypercholesteroleamia, while ascorbic acid supplements reduce plasma cholesterol levels. As 500 mg. daily of ascorbic acid supplements supposedly help maintain normal ascorbic acid levels in blood during OC use, they should perhaps be prescribed to pill users in this study.