The Role of CTP Inhibitors in Cardiovascular Outcomes

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In those days, we didn't understand that you really need to lower LDL cholesterol with a CTP inhibitor to see an effect on a CVD. And I think we would only go on afterwards to see two Mendelian randomizations. One looking at genes that raised HDL cholesterol and one looking at genes That lowered HDL cholesterol neither were found to be causally linked to ASCVD. So when I hear people tell me that their high HDL cholesterol is protecting them from coronary artery disease in the presence of high LDL cholesterol, I have to restrain myself in the context of C-type inhibitor failure.

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John Kastelein is a renowned expert in lipoprotein metabolism and atherosclerotic cardiovascular disease (ASCVD) research. In this discussion, John delves deep into familial hypercholesterolemia (FH), a genetic disorder characterized by high levels of LDL cholesterol in the blood that increases the risk of developing heart disease. He covers its definition, genetic underpinnings, and clinical identification. He then explores the therapeutic options available for the prevention and treatment of cardiovascular disease, including the captivating history of CETP inhibitors. He explains the past shortcomings of previous CETP inhibitors before underscoring the compelling potential of the latest iterations, not only for cardiovascular disease but also for conditions like Alzheimer's disease and type 2 diabetes. Moreover, he unveils the intricate role of APOE, shedding light on why the APOE4 isoform codes for a protein that significantly increases the risk of Alzheimer's disease and cardiovascular disease. Concluding the discussion, John shares a profound sense of optimism, envisioning the possibility of targeted therapeutic interventions for high-risk patients in the near future.

We discuss:

Familial hypercholesterolemia (FH): a genetic condition [4:30];
Differentiating between phenotype and genotype when it comes to FH [9:45];
The pathophysiology related to mutations of FH [15:30];
Clinical presentations, physical manifestations, and diagnosis of FH [22:00];
Why a small fraction of people with FH do not develop premature ASCVD [34:15];
Treatment and prevention for those with FH [39:45];
Addressing the assertion by some that elevated LDL is not casual in cardiovascular disease [52:45];
The history of CETP inhibitors, and the role of the CETP protein [55:45];
The thrifty gene hypothesis and why genes underlying FH may have been preserved [1:09:00];
The compelling potential of the latest CETP inhibitor (obicetrapib) [1:13:00];
Promising results from phase 3 trials exploring obicetrapib [1:27:45];
Why the APOE4 allele increases the risk of Alzheimer’s disease, and the connection to blood lipids [1:41:30];
The role of APOE in cardiovascular disease [1:51:45];
Takeaways and looking ahead [1:57:00]; and
More.