Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9.
Reducing circulating LDL-cholesterol (LDL-c) reduces the risk of cardiovascular disease in people with hypercholesterolemia. Current approaches to reduce circulating LDL-c include statins, which inhibit cholesterol synthesis, and ezetimibe, which blocks cholesterol absorption. Both elevate serum PCSK9 protein levels in patients, which could attenuate their efficacy by reducing the amount of cholesterol cleared from circulation. To determine whether PCSK9 inhibition could enhance LDL-c lowering of both statins and ezetimibe, we utilized small interfering RNAs (siRNAs) to knock down Pcsk9, together with ezetimibe, rosuvastatin, and an ezetimibe/rosuvastatin combination in a mouse model with a human-like lipid profile. We found that ezetimibe, rosuvastatin, and ezetimibe/rosuvastatin combined lower serum cholesterol but induce the expression of Pcsk9 as well as the Srebp-2 hepatic cholesterol biosynthesis pathway. Pcsk9 knockdown in combination with either treatment led to greater reductions in serum non-HDL with a near-uniform reduction of all LDL-c subfractions. In addition to reducing serum cholesterol, the combined rosuvastatin/ezetimibe/Pcsk9 siRNA treatment exhibited a significant reduction in serum APOB protein and triglyceride levels. Taken together, these data provide evidence that PCSK9 inhibitors, in combination with current therapies, have the potential to achieve greater reductions in both serum cholesterol and triglycerides.
Sirna Therapeutics/Merck & Co. Inc, San Francisco, CA 94158, USA. brandon_ason@merck.com
Brandon
B
Ason
Samnang
S
Tep
Harry R
HR
Davis
Yiming
Y
Xu
Glen
G
Tetzloff
Beverly
B
Galinski
Ferdie
F
Soriano
Natalya
N
Dubinina
Lei
L
Zhu
Alice
A
Stefanni
Kenny K
KK
Wong
Marija
M
Tadin-Strapps
Steven R
SR
Bartz
Brian
B
Hubbard
Mollie
M
Ranalletta
Alan B
AB
Sachs
W Michael
WM
Flanagan
Alison
A
Strack
Nelly A
NA
Kuklin
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000097:blood; D001384:Azetidines / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D000069438:Ezetimibe; D005464:Fluorobenzenes / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011743:Pyrimidines / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068718:Rosuvastatin Calcium; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D001384:Azetidines; D008078:Cholesterol, LDL; D005464:Fluorobenzenes; D011743:Pyrimidines; D034741:RNA, Small Interfering; D013449:Sulfonamides; D014280:Triglycerides; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000069438:Ezetimibe
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