PCSK9 inhibition with alirocumab reduces lipoprotein(a) levels in nonhuman primates by lowering apolipoprotein(a) production rate

Croyal, Mikaël; Tran, Thi-Thu-Trang; Blanchard, Rose Hélène; Bail, Jean-Christophe Le; Villard, Elise F.; Poirier, Bruno; Aguesse, Audrey; Billon-Crossouard, Stéphanie; Ramin‐Mangata, Stéphane; Blanchard, Valentin; Nativel, Brice; Chemello, Kévin; Khantalin, Ilya; Thedrez, Aurélie; Janiak, Philip; Krempf, Michel; Boixel, Christophe; Lambert, Gilles; Guillot, Etienne

doi:10.1042/cs20180040

Cited by 41 publications

(18 citation statements)

References 24 publications

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“…A small kinetic study suggested that the reduction in plasma Lp(a) levels following alirocumab treatment was due to the increased clearance of Lp(a)‐apo(a), suggestive of a LDLR‐mediated clearance of Lp(a) from the circulation . A better powered human kinetic study and a kinetic study using non‐human primates, however, showed that the production rate but not the clearance of Lp(a)‐apo(a) was significantly reduced following evolocumab or alirocumab treatment, respectively . These data concur with the observation that statin treatment has no effect on Lp(a) levels despite a strongly up‐regulation of hepatic LDLR levels …”

Section: Efficacy Of Pcsk9 Inhibitors In T2dm Patientssupporting

confidence: 66%

Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia

Dijk

Cariou

2019

Diabetes Obesity Metabolism

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Diabetic dyslipidaemia, characterized by quantitative, qualitative and kinetic changes in all major circulating lipids, contributes to the increased cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). A promising therapeutic avenue is the inhibition of the proprotein convertase subtilisin kexin 9 (PCSK9) with human monoclonal antibodies (mAbs) that potently reduce plasma low‐density lipoprotein cholesterol (LDL‐C) levels on top of statin treatment. The aim of this review is to evaluate the efficacy of PCSK9 inhibitors to lower the residual cardiovascular risk of T2DM patients and to discuss the safety of PCSK9 inhibition in these patients. PCSK9 inhibitors potently lower plasma LDL‐C levels in T2DM patients and reduce risk for the development of cardiovascular disease. Anti‐PCSK9 mAbs are generally not more or less effective in T2DM patients compared to a general high‐risk population. Nevertheless, due to their higher cardiovascular risk, the absolute risk reduction of major cardiovascular events is more significant in T2DM patients. This suggests that treatment of T2DM patients with anti‐PCSK9 mAbs could be attractive from a cost‐effectiveness perspective. Treatment with anti‐PCSK9 mAbs did not result in significant treatment‐emergent adverse effects. While genetic studies suggest a potential link between PCSK9 inhibition and glucose homeostasis, anti‐PCSK9 mAbs did not worsen glycaemic control in T2DM patients, but their safety should be verified after a longer‐term follow‐up.

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Section: Efficacy Of Pcsk9 Inhibitors In T2dm Patientssupporting

confidence: 66%

Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia

Dijk

Cariou

2019

Diabetes Obesity Metabolism

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“…These results challenge the role for PCSK9 in Lp(a) catabolism, as observed previously with PCSK9 inhibitors in human hepatocytes in vitro 14 and in nonhuman primates or healthy volunteers in vivo. 16,18 However, Lp(a)-apo(a) APR did not correlate with plasma PCSK9 concentrations, likely due to the small number of subjects. Beyond Lp(a) levels, PCSK9 inhibitors also reduce plasma apoE concentrations.…”

Section: Discussionmentioning

confidence: 91%

“…15 In nonhuman primates, we reported that alirocumab strongly reduced the circulating Lp(a) concentration by acting on apo(a) production rate. 16 In humans, in vivo lipoprotein kinetics studies with PCSK9 monoclonal antibodies have also led to conflicting data. While alirocumab induced a nonsignificant increase in the Lp(a) FCR in one study, 17 evolocumab led to a significant decrease in the Lp(a) production rate in another one.…”

mentioning

confidence: 99%

VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly

Croyal¹,

Blanchard

Ouguerram³

et al. 2020

ATVB

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To clarify the association between PCSK9 (proprotein convertase subtilisin/kexin type 9) and Lp(a) (Lipoprotein [a]), we studied Lp(a) kinetics in patients with loss-of-function and gain-of-function PCSK9 mutations and in patients in whom extended-release niacin reduced Lp(a) and PCSK9 concentrations.APPROACH AND RESULTS: Six healthy controls, 9 heterozygous patients with familial hypercholesterolemia (5 with low-density lipoprotein receptor [LDLR] mutations and 4 with PCSK9 gain-of-function mutations) and 3 patients with heterozygous dominant-negative PCSK9 loss-of-function mutations were included in the preliminary study. Eight patients were enrolled in a second study assessing the effects of 2 g/day extended-release niacin. Apolipoprotein kinetics in VLDL (very-lowdensity lipoprotein), LDL (low-density lipoprotein), and Lp(a) were studied using stable isotope techniques. Plasma Lp(a) concentrations were increased in PCSK9-gain-of-function and familial hypercholesterolemia-LDLR groups compared with controls and PCSK9-loss-of-function groups (14±12 versus 5±4 mg/dL; P=0.04), but no change was observed in Lp(a) fractional catabolic rate. Subjects with PCSK9-loss-of-function mutations displayed reduced apoE (apolipoprotein E) concentrations associated with a VLDL-apoE absolute production rate reduction. Lp(a) and VLDL-apoE absolute production rates were correlated (r=0.50; P<0.05). ApoE-to-apolipoprotein (a) molar ratios in Lp(a) increased with plasma Lp(a) (r=0.96; P<0.001) but not with PCSK9 levels. Extended-release niacin-induced reductions in Lp(a) and VLDL-apoE absolute production rate were correlated (r=0.83; P=0.015). In contrast, PCSK9 reduction (−35%; P=0.008) was only correlated with that of VLDL-apoE absolute production rate (r=0.79; P=0.028).CONCLUSIONS: VLDL-apoE production could determine Lp(a) production and/or assembly. As PCSK9 inhibitors reduce plasma apoE and Lp(a) concentrations, apoE could be the link between PCSK9 and Lp(a).

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“…However, data on the possible effect of PCSK9 on them is limited only by annexin A2 [ 24 ]. Furthermore, the results of recent studies with primates demonstrated the influence of PCSK9 inhibitors on Lp(a) production but not on catabolism [ 27 ]. An alternative mechanism might involve the elimination of circulating immune complexes formed by therapeutic MABs and PCSK9 associated with apoB100–containing lipoproteins and Lp(a), in particular [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Evolocumab on Lipoprotein(a) and PCSK9 in Healthy Individuals with Elevated Lipoprotein(a) Level

Afanasieva

Ezhov

Klesareva

et al. 2020

JCDD

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Background and aims: The aim of this study was to investigate the influence of a single injection of Evolocumab on the dynamics of Lp(a), fractions of apoB100-containing lipoproteins, PCSK9, and their complexes in healthy individuals with elevated Lp(a) levels. Methods: This open-label, 4-week clinical study involved 10 statin-naive volunteers with Lp(a) >30 mg/dL, LDL-C < 4.9 mmol/L, and a moderate risk of cardiovascular events. The concentrations of Lp(a), lipids, PCSK9, circulating immune complexes (CIC), and plasma complexes of PCSK9 with apoB100-containing lipoproteins (Lp(a)–PCSK9 and LDL–PCSK9) were measured before and each week after Evolocumab (MABs) administration. Results: After a single dose injection of 140 mg of MABs, the median concentration of PCSK9 in serum increased from 496 to 3944 ng/mL; however, the entire pool of circulating PCSK9 remained bound with MABs for 2–3 weeks. LDL-C level decreased significantly from 3.36 mmol/L to 2.27 mmol/L during the first two weeks after the injection. Lp(a) concentrations demonstrated multidirectional changes in different patients with the maximal decrease on the second week. There were no positive correlations between the changes in levels of Lp(a), LDL-C, and TC. The change in the amount of circulating complex of PCSK9–Lp(a) was significantly less than of PCSK9–apoB100 (−5% and −47% after 1 week, respectively). Conclusions: A single administration of monoclonal antibodies against PCSK9 (Evolocumab) in healthy individuals with hyperlipoproteinemia(a) resulted in a decrease of Lp(a) of 14%, a 5% decrease in PCSK9–Lp(a), a 36% reduction of LDL-C, a 47% decrease in PCSK9–apoB100 and a tenfold increase in total serum PCSK9 concentration.

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PCSK9 inhibition with alirocumab reduces lipoprotein(a) levels in nonhuman primates by lowering apolipoprotein(a) production rate

Cited by 41 publications

References 24 publications

Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia

Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia

VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly

Effect of Evolocumab on Lipoprotein(a) and PCSK9 in Healthy Individuals with Elevated Lipoprotein(a) Level

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