Thread by @nicknorwitz

1/ Wow!

Interesting study about HDL-raising & LDL-lowering medications, CETP & PCSK9 inhibitors, w 1 finding that caught me off guard

Will reveal later in thread 2encourage ppl 2read in context, bc study revealed both good and bad

#CVD #Alzheimers

nature.com/articles/s4146…

2/ Study used Mendelian randomization 2assess possible effects of SPECIFIC pharmacological CETP or PCSK9 lowering on risk

Useful for assessing whether the failures of CETP inhibitors are more likely due to off-target or on-target effects and for directing future development...

3/ Some positive things:
👉MR analysis suggests CEPT inhibition could be useful4reducing coronary hard disease risk (OR=0.95) risk & thus further drug development may be warranted

👉CEPTi anacetrapib&evacetrapib most closely
reflected the on-target association of lower CETP...

4/ 👉PCSK9 lowering in MR reduces CHD risk. The odds ratio is lower (OR 0.69, Fig 3) suggesting a stronger effect. This isn't anything new but supporting the conventional viewpoint that ApoB lowering with PCSK9 can reduce CHD risk. But what caught me off guard ...

5/ But what caught me off guard was the finding that lower PCSK9 was associated with much higher #Alzheimers risk (OR = 2.43). This was one of the strongest associations observed in the study. (see for yourself below)

AND what’s more…

6/ And I’ll here paraphrase the authors (so that I get myself in less trouble):

“The MVMR model… [indicated that]… the Alzheimer effect of PCSK9 was likely mediated by [lowering] LDL-C Figure 6).”

7/ Certainly, this does not indicate PCSK9 inhibitors should not be prescribed, nor that PCSK9 inhibitor-mediated lowering of LDL in an individual patient will increase risk of dementia. I also want to acknowledge out that I routinely point out I think MR studies have limitations

8/ with respect to what one can really conclude about causality in a real-world setting, since the exposure is due to genetics rather than a metabolic response (analogy would be high LDL in #LMHR vs. FH)

Nevertheless, I find it shocking...

9/ that the association between PSCK9 lowering and increase Alzheimer’s was so strong and that the MVMR pointed the finger at lowering LDL-C. IMHO...

10/ this does have implications for individual patient care, e.g. if someone is considering LDL lowering options and have a strong family history of #alzheimersdisease and/or #ApoE4 genetics