Background Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low density lipoprotein cholesterol (LDL-C) and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known if inhibition of PCSK9 has any effects on very low density lipoprotein (VLDL) or intermediate density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma Lp(a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors (LDLRs) in the clearance of Lp(a), is poorly defined, and there have been no mechanistic studies of the Lp(a) lowering by alirocumab in humans. Methods Eighteen (10F, 8M) participants completed a placebo-controlled, two-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCR) and production rates (PR) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides (TG) and apoB48 levels were measured. Results Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was due to an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was associated with a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of VLDL-apoB and VLDL-TG, or on postprandial plasma TG or apoB48 concentrations. Conclusions Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs, and decreasing LDL-apoB PR. These results are consistent with increases in LDLRs available to clear IDL and LDL from blood during PCSK9 inhibition. The possible increase in apo(a) FCR during alirocumab treatment suggests that increased LDLRs may also play a role in the reduction of plasma Lp(a). Clinical Trials Registration Clinical trials.gov # NCT01959971

Apolipoprotein E (APO-E) binds to the beta-amyloid peptide and is present in senile neuritic plaques in Alzheimer's disease (AD). The epsilon 4 isoform of APO-E has been associated with both sporadic and familial late-onset AD, implying a causal role. Among patients and control subjects similar in age, gender, and ethnic group from the New York City community of Washington Heights-Inwood, we found that the odds ratio (OR) for AD associated with homozygosity for APO-epsilon 4 was 17.9 (95% confidence interval [CI], 4.6-69.8) and that associated with heterozygosity for APO-epsilon 4 was 4.2 (95% CI, 1.8-9.5) compared with persons with other APO-E genotypes. The association was stronger among patients with sporadic disease (OR = 10.3; 95% CI, 3.4-31.1) than among those with a family history of dementia in a first-degree relative (OR = 0.9; 95% CI, 0.1-13.5). The association between APO-epsilon 4 and AD did not differ according to age at onset (< 65 vs > or = 65), but appeared to vary across the 3 ethnic groups investigated (black, Hispanic, and white). Our data confirm the association between AD and APO-epsilon 4 and support the hypothesis that the APO-epsilon 4 allele either confers genetic susceptibility to AD or may be in linkage disequilibrium with another susceptibility locus. Ethnic variability in the allelic frequency of APO-epsilon 4 in the elderly warrants further investigation.

Elevated plasma levels of VLDL triglycerides (TGs) are characteristic of patients with type 2 diabetes mellitus (T2DM) and are associated with increased production rates (PRs) of VLDL TGs and apoB. Lipoprotein lipase-mediated (LPL-mediated) lipolysis of VLDL TGs may also be reduced in T2DM if the level of LPL is decreased and/or the level of plasma apoC-III, an inhibitor of LPL-mediated lipolysis, is increased. We studied the effects of pioglitazone (Pio), a PPARgamma agonist that improves insulin sensitivity, on lipoprotein metabolism in patients with T2DM. Pio treatment reduced TG levels by increasing the fractional clearance rate (FCR) of VLDL TGs from the circulation, without changing direct removal of VLDL particles. This indicated increased lipolysis of VLDL TGs during Pio treatment, a mechanism supported by our finding of increased plasma LPL mass and decreased levels of plasma apoC-III. Lower apoC-III levels were due to reduced apoC-III PRs. We saw no effects of Pio on the PR of either VLDL TG or VLDL apoB. Thus, Pio, a PPARgamma agonist, reduced VLDL TG levels by increasing LPL mass and inhibiting apoC-III PR. These 2 changes were associated with an increased FCR of VLDL TGs, almost certainly due to increased LPL-mediated lipolysis.