1/20 Saturday Morning Class #16 Lp(a) and PCSK9i
Apologies for delay. We had a tragedy this week- our 2 kids' dear cats Captain Jack and Leonardo, who have graced these pages, were taken by a bobcat and her 3 kittens. Good bye dear friends, we will miss you and never forget you
Apologies for delay. We had a tragedy this week- our 2 kids' dear cats Captain Jack and Leonardo, who have graced these pages, were taken by a bobcat and her 3 kittens. Good bye dear friends, we will miss you and never forget you
2/20 First some definitions- what is a PCSK9 protein (Proprotein convertase subtilisin/kexin type 9 (PCSK9). As the name implies, it cleaves other proteins to convert them to an active form. The one of interest to lipid metabolism is type 9.
3/20 It is secreted by the liver, and binds to lipoproteins (LDL, HDL and Lp(a)) in plasma. It then comes back to the liver on LDL/Lp(a) that bind to the LDL receptor. The LDLR/PCSK9 gets internalized and the LDLR is destroyed, resulting in less LDLR in liver cell surface
4/20 This prevents more LDL uptake and the LDL-C is increased. This process can be reversed by PCSK9i “inhibitors”, which results in more LDLR and more LDL uptake and a reduction in LDL-C.
5/20 Nabil Seidah and Catherine Boileau labs co-discovered PCSK9 in 2003 and Helen Hobbs and Jonathan Cohen found that loss of function mutations are associated with lower LDL-C and lower CVD and gave it clinical relevance. There is likely a Nobel in the making here.
6/20 The first PCSK9i to lower LDL-C were antibodies that lower LDL-C ~60%, then siRNA inclisiran ~50%, and latest is @ionispharma (AZD8233 with AZ) antisense that lowers LDL-C 70%. Inclisiran and AZD8233 are not approved yet in US.
7/20 The first report on PCSK9i lowering Lp(a) was by Stein et al with alirocumab in 201- ncbi.nlm.nih.gov/pubmed/22435370
8/20
Take home messages:
1-PCSK9i lower Lp(a) 15-30%. Unfortunately, in people with high Lp(a) it is typical to get 15% only, so people that need it the most get the least benefit. There are outliers. ncbi.nlm.nih.gov/pubmed/30561610
Take home messages:
1-PCSK9i lower Lp(a) 15-30%. Unfortunately, in people with high Lp(a) it is typical to get 15% only, so people that need it the most get the least benefit. There are outliers. ncbi.nlm.nih.gov/pubmed/30561610
9/20 2-In hierarchy of Lp(a) lowering best to worst it would be ASO/siRNA>apheresis>niacin>estrogen=PCSK9i. I don’t include others that have not been validated by well designed trials
3-Statins, low fat diets, garlic, tend to raise Lp(a) 10-25%- ncbi.nlm.nih.gov/pubmed/31111151
3-Statins, low fat diets, garlic, tend to raise Lp(a) 10-25%- ncbi.nlm.nih.gov/pubmed/31111151
10/20 4-PCSK9 is carried by LDL, but with assays we developed and with collaboration with Fazio and Mayr, have shown most of PCSK9 in plasma is present on either HDL or Lp(a).
11/20 This was previously missed since the isolation of LDL spins down these non-covalently bound interactions. ncbi.nlm.nih.gov/pubmed/32216920, ncbi.nlm.nih.gov/pubmed/27121620
12/20 5-Mechanism of Lp(a) lowering not fully established yet. Some is clearance via LDLR, controversial but likely very little. ncbi.nlm.nih.gov/pubmed/28750079
6-Other studies suggest PCSK9 protein prevents apo(a) secretion basictranslational.onlinejacc.org/content/1/6/41…
6-Other studies suggest PCSK9 protein prevents apo(a) secretion basictranslational.onlinejacc.org/content/1/6/41…
13/20 7-In FOURIER and Odyssey Outcomes, the highest quartile of Lp(a) was associated with highest risk in both studies
8-Alirocumab in OO reduced Lp(a)-mediated risk, accounting for nearly 1/3rd of the benefit noted in that study ncbi.nlm.nih.gov/pubmed/31948641
8-Alirocumab in OO reduced Lp(a)-mediated risk, accounting for nearly 1/3rd of the benefit noted in that study ncbi.nlm.nih.gov/pubmed/31948641
14/20 Patient implications-
1-If both LDL-C and Lp(a) are elevated despite statin and CVD is present, a PCSK9i is a good choice
2-PCSK9i can get approved by insurance for high Lp(a) if CAD is present
1-If both LDL-C and Lp(a) are elevated despite statin and CVD is present, a PCSK9i is a good choice
2-PCSK9i can get approved by insurance for high Lp(a) if CAD is present
15/20 3-Its nearly impossible to get PCSK9i approved by insurance for high Lp(a) if one does not have CVD. I have several pts that pay the $5-6K out of pocket.
4-Its not known if all PCSK9i will lower Lp(a) the same. Data from the most potent PCSK9i, Ionis/AZ8233 will tell us
4-Its not known if all PCSK9i will lower Lp(a) the same. Data from the most potent PCSK9i, Ionis/AZ8233 will tell us
16/20 The difference between antibodies and ASO, is ASO works in hepatocyte, so if intracellular PCSK9 mediates apo(a) metabolism, it should be more potent in lowering Lp(a) than antibodies. If intracellular PCSK9 does not affect apo(a), then it will be same as antibodies.
17/20 5-Niacin is more potent than PCSK9i in lowering Lp(a), but no study in high Lp(a) pts has been done to see if 30% lowering makes a difference in outcomes.
18/21 6-Bottom line- PCSK9i are great drugs, if you have high Lp(a), get on them if you can to see if they lower Lp(a) more than 15%. But at this point, its not clear how much benefit one get from the LDL-C vs the Lp(a) lowering. We really do need the ASO/siRNA therapies.
19/20 Quiz- 5 points
Chose the incorrect answer:
1-PCSK9 is an enzyme
2-PCSK9i can be antibodies
3-PCSK9i work through the LRP receptor
4-PCSK9i lower Lp(a) less than niacin
Chose the incorrect answer:
1-PCSK9 is an enzyme
2-PCSK9i can be antibodies
3-PCSK9i work through the LRP receptor
4-PCSK9i lower Lp(a) less than niacin
20/20 Bonus- 1 point - true or false
PCSK9i are approved to lower Lp(a)
1-True
2-False
PCSK9i are approved to lower Lp(a)
1-True
2-False
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