Medications to Reduce Lipoprotein(a); Genome Models and CVD Risk

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include genetic testing of couples planning pregnancy, use of two medications in people who’ve had a heart attack, genome-wide association models and risk for cardiovascular disease, and two medicines to reduce lipoprotein(a).

Program notes:

0:40 Reducing lipoprotein(a)

1:40 Oral medicine prevents two components from binding

2:40 What proportion have this issue?

2:54 Polygenic risk scores and heart disease risk

3:54 Ended up with 46 scores

4:54 40-50% of risks involved with genes

5:56 Two medicines after heart attack

6:56 No benefit in all comers with heart attack

7:50 Nationwide genetic carrier screening

8:50 9107 couples completed

9:50 Wide number of diseases screened

10:50 Genetic counselor for those with increased risk

12:18 End

Transcript:

Elizabeth: Are polygenic risk scores of any utility at all in predicting cardiovascular disease?

Rick: Two new studies of people that have had an acute heart attack.

Elizabeth: Nationwide genetic screening of folks planning to conceive.

Rick: And two different strategies that reduce lipoprotein(a) levels.

Elizabeth: That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso, where I’m also dean of the Paul L. Foster School of Medicine.

Elizabeth: Let’s note it is the American Heart Association (AHA) meeting and therefore 3 out of the 4 studies we’re talking about this week are from that meeting. And I’m going to toss the ball right to you. Let’s talk about reducing lipoprotein (a), something that you foreshadowed last week.

Rick: Last week, we reported on how important it was to assess it at some time. Not only does LDL cholesterol predict who is going to have coronary heart disease, but lipoprotein(a) levels do as well. We’ve got statins to lower LDL levels, but we really haven’t developed anything until recently that can lower lipoprotein(a) levels. I’m going to report on two studies that were reported in JAMA this week.

One of them is an oral medication and the other is an injectable. Lipoprotein(a) is composed of an apolipoprotein B-containing, LDL-like particle — wow — that is bound to an apolipoprotein A molecule. Now, those two things have to combine together to make lipoprotein(a). The oral medication prevents those two things from combining.

The injectable medicine is a small interfering RNA that targets the gene. This small interfering RNA is called zerlasiran and the oral medication is called muvalaplin. Both were effective at lowering lipoprotein(a) by about 80% to 90% with no significant side effects. Elizabeth, this is great news. Does it lower the risk of heart attack or stroke?

Elizabeth: I’ll just remind everybody that we have seen smoking guns ostensibly before and so we really don’t know the answer about lowering lipoprotein(a).

Rick: No, but this is pretty exciting. We’ll test the hypothesis. But because lipoprotein(a) really can’t be modified by diet — it really is genetically determined — those that have high levels, we know it increases the risk, and hopefully lowering it will reduce the risk.

Elizabeth: Do we know what proportion of folks who ultimately develop cardiovascular disease have high lipoprotein(a)?

Rick: Elizabeth, I don’t know that answer. Perhaps that will be a topic of a future podcast.

Elizabeth: Okay. Let’s remain in JAMA and let’s continue to talk about this issue of heart disease. This is a study that’s looking at polygenic risk scores and their ability to predict coronary heart disease in individuals.

The first thing I’d like to do is just remind everybody — because this was a really useful definition for me — that polygenic risk scores are built from the results of genome-wide association studies, which identify genomic variants that are statistically associated with the disease of interest, whatever that disease is. There are a bunch of these out there and some of them are actually commercial.

In this study, they looked at a cross-sectional snapshot of participants from the All of Us Research Program, the Penn Medicine BioBank, the University of California, Los Angeles ATLAS Precision Health Biobank, and they got data clearly from their electronic health record and their genotyping. They originally had a total of 48 of these polygenic risk scores that they assessed. They ultimately reduced that to 46 of these.

They looked at these — lots of statistical analyses, clearly the area under the curve — and what does it really tell us. The really disappointing news is that while these things are capable of pointing to issues at a population level, there was very high variability when it came to predicting an individual’s level of risk and in point of fact they had 20% of participants who had at least one score in both the top and the bottom 5% of risk, so were predicted to be outliers when you took a look at this curve — a single person. Gosh, that says to me, “Polygenic risk scores are not ready for prime time.”

Rick: By the way, that’s absolutely right. Elizabeth, we’re trying to provide what’s called precision medicine. It appears that somewhere between 40% or 50% of the risk may be related to genes somehow. There are probably multiple genes involved and there is interaction. There is interaction with the environment. Secondly is, even though we developed these polygenic risk scores, the precision and accuracy for the individual just isn’t there yet. Why that’s important is there are a lot of clinical labs right now that are proposing they’re going to measure your genes and they’re going to tell you something. Well, it really doesn’t tell you anything. We’re not ready yet to assess whether your particular genetic makeup influences your risk.

Elizabeth: A question that I would pose to you is how much more risk information do we really need after we employ all of the clinical ones that are currently employed? We’re already pretty good at predicting people’s risk.

Rick: We are, but Elizabeth, you and I both know the occasional individual that just out of the clear blue has a heart attack and doesn’t have risk factors. Let’s talk about Jim Fixx, the gentleman that put running on the map, who died of a heart attack at age 41 with extensive coronary disease and nobody saw that coming. But it’s the individuals that otherwise seem to be low-risk.

Elizabeth: Let’s move to the New England Journal of Medicine.

Rick: We talked about not ready for prime time. We’re going to talk about two different strategies that were tested in people with an acute heart attack. This was the use of colchicine, which is an anti-inflammatory medication, and spironolactone, which is a mineralocorticoid receptor antagonist.

Now, they’re currently both used. Spironolactone — if you’ve had a heart attack and you have heart failure, studies have convincingly shown that spironolactone is beneficial. If you have stable coronary artery disease and evidence of inflammation, studies have shown that colchicine can be helpful in preventing subsequent heart attacks or strokes. Well, they’re helpful in those particular subgroups, but should we be just giving them to everybody that has a heart attack instead of waiting?

That’s what these two studies did. They enrolled over 7,000 patients at 104 centers in 14 different countries. Individuals got either a placebo or spironolactone, or colchicine, or both together, 2 × 2. What they found is, unfortunately, that if you just routinely gave it to everybody with a heart attack there was no benefit. It didn’t reduce the risk of death from cardiovascular cause, the risk of new or worsening heart failure, the risk of stroke, or another heart attack. Some side effects — with colchicine, it causes diarrhea. Well, if it doesn’t help you at all and it causes diarrhea, it’s not going to be beneficial at all.

Elizabeth: One of the things clearly that has been observed before is this idea that just because some medicine is useful in one sub-category of patients doesn’t mean it’s going to be useful in everybody, and the underpinnings that get people to the clinical manifestation of an MI are different for every individual.

Rick: They are. I think whenever you use a particular medication and you’re doing it — what’s called evidence-based medicine — you just say, “Which population was it proven to be beneficial in?” Those are the people that should receive it.

Elizabeth: Okay. Remaining, then, in the New England Journal of Medicine, our non-heart study for this week entitled “Nationwide, Couple-Based Genetic Carrier Screening.”

This is kind of a hot-button issue and before we started to record we talked about how it’s a little uncomfortable-feeling because it feels like almost an eugenics kind of an intervention.

They did this in Australia. They wanted to look at, in the general population, what is a couple’s risk of having a child with either an autosomal recessive or an X-linked genetic condition — common ones. They were able to get results obtained from testing at least 1,281 genes. They obtained samples from persons either before pregnancy or early in pregnancy. What’s your risk of having a child who might have one of these types of genetic conditions?

They had 10,038 reproductive couples enrolled in this study; a total of 9,107 completed the screening. Of that number, 175, or 1.9%, were newly identified as having an increased chance of having a child with a genetic condition for which they screened. Clearly, there are some that they don’t screen for. These conditions involved pathogenic variations in 90 different genes. Almost 75% of the conditions were autosomal recessive.

The outcome after these screenings was that just shy of 77% of the couples with a newly identified increased chance had used or planned to use reproductive interventions to avoid having an affected child. They had greater anxiety, also, than those who were identified with a low chance. They also asked these folks afterwards, “What was your level of regret?” and that was very low, with almost 99% of the participants identifying screening as acceptable.

Rick: A wide number of different diseases were screened and the ones they focused on were those that either resulted in a serious condition or one that with an early intervention they could alter the course. In most individuals, screening was obtained prior to the woman becoming pregnant, but in about 20% of the time it was after the woman became pregnant.

If it was done prior to the woman becoming pregnant, they offered them one cycle of in vitro fertilization with preimplantation genetic testing. That was offered free. If the condition was discovered after the woman was pregnant, they were offered genetic testing for the baby and then they could terminate the pregnancy at that point.

Less than 2% ended up with what would be considered to be high risk. All of the testing was done for free. The in vitro fertilization was offered for free. The question is, is this something that can actually be rolled out across the United States or to a larger population? Because it’s not inexpensive. All couples that were found to have an increased risk were contacted by a genetic counselor. The average time they spent with a genetic counselor was over an hour.

Elizabeth: I also would note that while those folks who were identified as having an increased risk did have a session with a genetic counselor, those who did not were notified by electronic means. I’m not sure that I feel that would allay all of their fears.

Rick: Yeah. It’s interesting. They originally offered this study to 19,000 reproductive couples, of whom only about 46% decided that they wanted to be involved. The people that were more likely to be interested were those that had a higher educational level, higher socioeconomic status, and less likely to have had children previously.

Elizabeth: It kind of makes you wonder, is avoidance of having these children the primary goal? What’s the goal of doing it?

Rick: And you’re right. What they told individuals is, they said, “It puts you at a higher risk, but it doesn’t necessarily mean that your child will have that condition.” Now that these individuals have made these reproductive choices, it’s going to take years to find out how that has altered things, if it has at all.

Elizabeth: On that note then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.

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