Pradeep is a brilliant geneticist and Director of Preventive Cardiology, holds the Paul & Phyllis Fireman Endowed Chair in Vascular Medicine at Mass General Hospital and on faculty at Harvard Medical School and the Broad Institute. His prolific research has been illuminating for the field of improving our approach to reduce the risk of heart disease. That’s especially important because heart disease is the global (and US) #1 killer and is on the increase. We didn’t get into lifestyle factors here since there was so much ground to cover on new tests. drugs, and strategies.

A video snippet of our conversation on ApoB. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.

Transcript with links to key publications and audio

Eric Topol (00:06 ):

Well, welcome to Ground Truths. I'm Eric Topol and with me is Pradeep Natarajan from Harvard. He's Director of Preventative Cardiology at the Mass General Brigham Health System and he has been lighting it up on the field of cardiovascular. We're going to get to lots of different parts of that story and so, Pradeep welcome.

Pradeep Natarajan (00:31 ):

Thanks Eric, really delighted and honored to be with you and have this discussion.

Eric Topol (00:36 ):

Well, for years I've been admiring your work and it's just accelerating and so there's so many things to get to. I thought maybe what we'd start off with is you recently wrote a New England Journal piece about two trials, two different drugs that could change the landscape of cardiovascular prevention in the future. I mean, that's one of the themes we're going to get to today is all these different markers and drugs that will change cardiology as we know it now. So maybe you could just give us a skinny on that New England Journal piece.

Two New Lipid Targets With RNA Drugs

Pradeep Natarajan (01:16 ):

Yeah, yeah, so these two agents, the trials were published at the same time. These phase two clinical trials for plozasiran, which is an siRNA against APOC3 and zodasiran, which is an siRNA against ANGPTL3. The reason why we have medicines against those targets are based on human genetics observations, that individuals with loss of function mutations and either of those genes have reduced lipids. For APOC3, it's reduced triglycerides for ANGPTL3 reduced LDL cholesterol and reduced triglycerides and also individuals that have those loss of function mutations also have lower risk for coronary artery disease. Now that's a very similar parallel to PCSK9. We have successful medicines that treat that target because people have found that carriers of loss of function mutations in PCSK9 lead to lower LDL cholesterol and lower coronary artery disease.

(02:11 ):

Now that suggests that therapeutic manipulation without significant side effects from the agents themselves for APOC3 and ANGPTL3 would be anticipated to also lower coronary artery disease risk potentially in complementary pathways to PCSK9. The interesting thing with those observations is that they all came from rare loss of function mutations that are enriched in populations of individuals. However, at least for PCSK9, has been demonstrated to have efficacy in large groups of individuals across different communities. So the theme of that piece was really just the need to study diverse populations because those insights are not always predictable about which communities are going to have those loss of function mutations and when you find them, they often have profound insights across much larger groups of individuals.

Eric Topol (03:02 ):

Well, there's a lot there that we can unpack a bit of it. One of them is the use of small interfering RNAs (siRNA) as drugs. We saw in the field of PCSK9, as you mentioned. First there were monoclonal antibodies directed against this target and then more recently, there’s inclisiran which isn't an RNA play if you will, where you only have to take it twice a year and supposedly it's less expensive and I’m still having trouble in my practice getting patients covered on their insurance even though it's cheaper and much more convenient. But nonetheless, now we're seeing these RNA drugs and maybe you could comment about that part and then also the surprise that perhaps is unexplained is the glucose elevation.

Pradeep Natarajan (03:53 ):

Yeah, so for medicines and targets that have been discovered through human genetics, those I think are attractive for genetic-based therapies and longer interval dosing for the therapies, which is what siRNAs allow you to do because the individuals that have these perturbations, basically the naturally occurring loss of function mutations, they have these lifelong, so basically have had a one-time therapy and have lived, and so far, at least for these targets, have not had untoward side effects or untoward phenotypic consequences and only reduce lipids and reduce coronary artery disease. And so, instead of taking a pill daily, if we have conviction that that long amount of suppression may be beneficial, then longer interval dosing and not worrying about the pill burden is very attractive specifically for those specific therapeutics. And as you know, people continue to innovate on further prolonging as it relates to PCSK9.

(04:57 ):

Separately, some folks are also developing pills because many people do feel that there's still a market and comfort for daily pills. Now interestingly for the siRNA for zodasiran at the highest dose, actually for both of them at the highest doses, but particularly for zodasiran, there was an increase in insulin resistance parameters actually as it relates to hyperglycemia and less so as it relates to insulin resistance, that is not predicted based on the human genetics. Individuals with loss of function mutations do not have increased risks in hyperglycemia or type 2 diabetes, so that isolates it related to that specific platform or that specific technology. Now inclisiran, as you'd mentioned, Eric is out there. That's an siRNA against PCSK9 that's made by a different manufacturer. So far, the clinical trials have not shown hyperglycemia or type 2 diabetes as it relates inclisiran, so it may be related to the specific siRNAs that are used for those targets. That does merit further consideration. Now, the doses that the manufacturers do plan to use in the phase three clinical trials are at lower doses where there was not an increase in hyperglycemia, but that does merit further investigation to really understand why that's the case. Is that an expected generalized effect for siRNAs? Is it related to siRNAs for this specific target or is it just related to the platform used for these two agents which are made by the same manufacturer?

Eric Topol (06:27 ):

Right, and I think the fact that it's a mystery is intriguing at the least, and it may not come up at the doses that are used in the trials, but the fact that it did crop up at high doses is unexpected. Now that is part of a much bigger story is that up until now our armamentarium has been statins and ezetimibe to treat lipids, but it's rapidly expanding Lp(a), which for decades as a cardiologist we had nothing to offer. There may even be drugs to be able to lower people who are at high risk with high Lp(a). Maybe you could discuss that.

What About Lp(a)?

Pradeep Natarajan (07:13 ):

Yeah, I mean, Eric, as you know, Lp(a) has been described as a cardiovascular disease risk factors for quite so many years and there are assays to detect lipoprotein(a) elevation and have been in widespread clinical practice increasing widespread clinical practice, but we don't yet have approved therapies. Ho