An Inspiring Nobel Win and Other News

Harlan Krumholz: Welcome to Health & Veritas. I’m Harlan Krumholz.

Howard Forman: And I’m Howie Forman. We’re physicians-professors at Yale University. We’re trying to get closer to the truth about health and healthcare. We thought we would take this week without a guest to talk about the many health and healthcare topics that we think are not getting nearly enough attention but assuredly are very important. And one of those topics is a Nobel Prize in Medicine and Physiology. This is always newsworthy, but I don’t think that the audience—or me, quite frankly—understand all the layers to this story. And I wanted to ask you about this, Harlan. To start off, what should we all know that isn’t really being covered about this? And maybe start off by just telling us about this Nobel.

Harlan Krumholz: Well, I’m not sure if this qualifies as something that hasn’t gotten enough attention, but I can’t stop talking about it. Let me just say it starts with nice people can win. Nice people can win it.

Howard Forman: It’s a good story.

Harlan Krumholz: It’s a good story. My God, by all accounts, these are just two remarkable people. I’ll start with Drew Weissman, because I want to spend more time with Kati Karikó. So Drew Weissman, by all accounts, is this extraordinarily nice person, generous in the lab. One of his mentees wrote a really nice piece for WBUR a while ago when he was getting some attention, and just talking about how this was someone who welcomed people into the lab, was extremely collaborative. Anyway, it warmed my heart to think that this is the kind of person who wins. But even more than that, his partner is someone who, again, just was someone enthralled by science who wouldn’t quit.

Howard Forman: Never quit.

Harlan Krumholz: Just kept going, overcame so many obstacles, encountered the headwinds of academia when she couldn’t get a grant because her ideas maybe were just too novel, too good, and had trouble publishing and was sort of washed away, in a way. And yet in the end, they contribute so importantly to saving so many lives. I want to put that first. I mean, it’s not that “They won the Nobel,” but it’s “What did they do to win the Nobel?” They contributed to the saving of so many lives. So I think... well, go ahead, Howie.

Howard Forman: No, and I was going to say, I think a lot of people, when they first see this, are thinking Covid vaccines, but the Covid vaccines didn’t get developed in just 10 months. The work they’ve done go on for decades.

Harlan Krumholz: So there’s this amazing story. She comes over, she has a lab in Hungary, and they run out of money. And she and her husband decide they’re going to come with their two-year-old daughter to the United States. And it’s not easy then. And actually, Hungary doesn’t want you to take money out, so they’ve got to sort of smuggle money. I mean, there was a piece on The Daily that Gina Kolata was sort of part of where this was being described, and talk about stuffing money into teddy bears so they can come over with some cash. And they’ve almost got nothing, and she tries like heck to find some position. She gets a position at Penn. She says her first position, she’s being paid $17,000 as a researcher. I mean, we should pause on that. It was 1990s....

Howard Forman: Right. Put it in perspective, I was an intern... I was a first-year resident at that time being paid more than twice that amount. That was considered a low wage at the time. So that’s a tiny wage.

Harlan Krumholz: Well, but she’s making $17,000. She doesn’t have any sense of bitterness about it. I mean, more like, “We made it, we pushed, we progressed.” She meets Weissman, famously, it said, at a photocopier. It’s a chance encounter. By the way, it should make us think about remote work versus in-person work.

Howard Forman: Yes.

Harlan Krumholz: They meet, they start talking. She’s got this idea that mRNA, which is really the blueprint for proteins. It takes the code from the DNA, and it’s sort of enabling the blueprint to be made that ultimately transfer code—

Howard Forman: It’s sort of like the input to the factory of the cell to make proteins.

Harlan Krumholz: That’s right.

Howard Forman: So you can’t make proteins until you get to that point.

Harlan Krumholz: So we call it messenger RNA, is mRNA, and it’s got this blueprint. And then it combines with transfer RNA, which sort of brings in the amino acids. It helps construct these proteins. And she’s been enthralled by mRNA for a long time, and Drew Weissman is trying to develop a vaccine for HIV. And this is a guy who also had quite a remarkable history and had worked in Fauci’s lab at the NIH, ends up at Penn. He’s a successful academic, but this is his goal, is to make an HIV vaccine. And he meets her, and she’s got this idea that instead of injecting proteins into people where they would develop specific immunity to something, that what if you were able to get the blueprint into people and then let their own machinery create the proteins that the body would then develop a defense to?

And so what you’re doing is, in the case of a virus, if we can get the body to produce a small part of that, a fragment of that virus, that the body could then learn to recognize as foreign and attack and protect against, you could then put the person in a position of having a ready defense for when the real infection comes. And so this is all about getting people ready for the real infection or bolstering their infection, even if the infection takes hold. So I mean, one of the problems, though, was that if you inject mRNA into people, a foreign mRNA, the body attacks it as foreign. And so it never gets a chance to be the blueprint to create the protein.

Howard Forman: Right. Always sounds very simple until you actually understand it.

Harlan Krumholz: You actually do it. And then what you also have to do is you need to be able to find the right blueprint, but then you need to make sure you don’t have this effect. By the way, in mice, the mice got very sick. So it wasn’t even just that they destroyed the mRNA, but it was almost like they’d been infected by the mRNA. So by observing this transfer RNA, they come up with an idea about how you could sort of modify the mRNA in very minor ways, not to disrupt the blueprint, not to disrupt the instructions, but to enable the body to see it as “self,” not as “enemy.” And this turns out to be quite a feat that they do.

But the thing is so outlandish, I guess, within scientific circles that actually they can’t get it published in any of the top journals. And when they’re going for grants, no one’s recognizing this is pioneering work. They’re maybe seeing it as a little crazy. They get it published, finally, in Immunity, not to diminish that journal, but it’s not one of the top journals. And it kind of goes by without much notice. Actually, they try to get grants, they try to publish more papers, they have trouble. They actually built a company at that time, and no one would invest in it because they thought this was going nowhere. And by about 2013, she’s on the ladder faculty track because she’s having trouble. She’s actually demoted; she’s taken off of this track. And so she’s basically being told, “You’re not successful here, and we can’t promote you.” And then she’s giving a talk in 2013, and this guy who started that Bio...

Howard Forman: …intech. Biointech.

Harlan Krumholz: ... intech. He’s thinking about this kind of stuff, and he wants to build an mRNA vaccine for influenza. And so he, on the spot, offers her a job and says, “Leave academia. They don’t know what you’re worth. Come work with me.” And she joins the company, and then they work together on this influenza vaccine. And then when COVID comes, bingo, they’re primed, in a prime position to actually pivot and then work with Pfizer to then help create...

Howard Forman: But I mean, this is a few things that just strike me from this is, one, she’s an incredibly resilient person. I mean...

Harlan Krumholz: Oh, my goodness.

Howard Forman: ...just everything she’s done is defined by resilience, and she never gets negative. Every article you read about her, way before the Nobel, when they were still writing articles during the pandemic, always talked about her in a very positive way. And the other thing that strikes me at this point is, how many people talked about this vaccine having been rushed in 10 months? And the reality is 30 years of hard work went into this to get to the point where we could have a vaccine that is safe and effective, as we’ve seen.

Harlan Krumholz: Her daughter is an Olympian rower, and I sort of thought, “Must have gotten some of the persistence from her mom.”

Howard Forman: Yes, yes. Crazy.

Harlan Krumholz: But anyway, it’s a fascinating story of persistence, like you said, or resilience, persistence, and continued obstacles. Some of them imposed by the way in which our academic centers work.

Howard Forman: And it’s a nice story about the coordination between academic institutions and private companies, ultimately. Even though that might not be emphasized in the announcement of the Nobel, it clearly played a role.

Harlan Krumholz: I’ll tell you, she’s going to inspire me for a long time. I’ve rarely run into something like this. So what’s next, Howie? What’s on your mind? What do you want to flip to next? There’s lots of stuff out there.

Howard Forman: There is a lot of stuff. And about, I don’t know, I think six or seven months ago we reported on two separate lawsuits that were pending from the Department of Justice accusing Cigna of wrongdoing regarding Medicare Advantage plans. And Medicare Advantage plans are private health insurance plans that Medicare pays for. And right now, the majority of Medicare beneficiaries get their health insurance through these Medicare Advantage plans, not through Medicare itself anymore. So it was alleged that Cigna was essentially overbilling for Medicare Advantage patients by making them seem sicker than they might have actually been. And they did this two different ways. One, they had individuals reviewing charts to see if real diseases that patients had, that really, they really had but were not being coded for, could be coded for so they could get paid more money. That’s not a bad thing, that’s actually a reasonable thing to do for your business.

But during the same review, they also discovered that some people were being coded for diseases that they didn’t have. Right? You go in the chart, it says the patient has diabetes, and you go through the entire chart and you can’t find a single thing that would support having diabetes. So they corrected for the first error because it got them more money. But even though they identified the second error, they did not tell anybody about it because they would’ve lost money on that. And for what it’s worth, morbid obesity was one of the diseases that Cigna was coding for in patients that were not documented. In other words, patients were not morbidly obese but were being coded for morbid obesity. And then second, the second way Cigna did this is they sent healthcare providers into homes of patients to see if they could rapidly identify additional diseases or risk factors. Similar to the first part, but this time you’re sending people into people’s homes to talk to them, maybe even examine them.

It sounds well-meaning, but the investigators found that this was much more about increasing revenue than about improving health. So quick summary about this, Cigna settled for a whopping $172 million, and the whistleblower himself received $8 million from that settlement. So I want to first start with you, because a lot of your career has been about understanding how we risk-adjust populations and how we can use that to make sure that we properly pay for things. That if you give me two separate groups of a hundred people, that I might know that one group is going to be more expensive to treat than the other. But how do we do that? And I want to hear from you first about what is the state of the art in risk adjustment right now?

Harlan Krumholz: Well, first of all, let me just say one thing. We don’t say “morbid obesity” anymore. You know that?

Howard Forman: It was in the document, so I didn’t know that. What do we call it now?

Harlan Krumholz: Even the codes still maybe say “morbid obesity.”

Howard Forman: So what do we call it?

Harlan Krumholz: “Class III obesity.”

Howard Forman: Oh, interesting. I did not know that.

Harlan Krumholz: We’re trying to make them... because the idea is that it feels judgmental. But I agree with you. I think the codes still maintain these kind of...

Howard Forman: I mean, I use that term routinely. I mean, I always thought morbid obesity distinguishes it from nonclinical obesity.

Harlan Krumholz: Anyway, well, Ania Jastreboff keeps teaching me about this.

Howard Forman: Excellent.

Harlan Krumholz: Because I said the same thing. So, look, as an outcomes guy, I just want to look at the outcomes. And maybe you can give me a reality check about this. I thought the premise of Medicare Advantage was that if we take about the same amount of money that a group of people would be spending in traditional Medicare and gave it to you and then you managed their care, you promoted prevention, you did disease management. So when they needed nurses or they needed this or that, that you would be able to improve health and cut utilization because you were actively managing a population and you were at risk for that population. And then Medicare put a little sweetener in there, saying, “In order to do that, we’re going to make this a little more economically attractive because we’re trying to get people to want to do these plans and not to feel like they potentially are going to be at risk.” Is that true?

Howard Forman: It’s roughly true. So in the Clinton administration, they actually paid a little less than the average cost because they figured that these plans were going to attract healthier-than-average people. With the Bush administration, 2003, they did what you said. And the goal was, “Bring these people into the market. Let’s get a critical mass, let’s overpay for it for a while just to build it up. And then let’s get to competitive pricing.” But for our audience, competitive pricing is easier said than done because if I pick a million people at random, then maybe the pricing is easy. But when I get to sign people up, I might be particularly good at finding healthier-than-average people and then I don’t deserve the average payment for a million people.

Harlan Krumholz: So again, I’m going to get to the risk adjustment in a minute, but just before I get there, then I start seeing reports that come out, like this one from the USC Schaeffer Center for Health Policy and Economics, that said the Medicare Advantage overpayments may have exceeded $75 billion in 2023 due to this sort of favorable selection. So even before we get to risk adjustment, it seems like where I thought... by the way, more than half of Medicare enrollees are now in Medicare Advantage.

Howard Forman: Exactly.

Harlan Krumholz: I thought that were going to help us with costs. Actually, these reports are coming out that they’re saying that, “No, no, these people are costing a lot more.”

Howard Forman: So let me tell you that Humana and Cigna are probably two of the companies that are most dedicated to Medicare Advantage. They do a lot of other plans, but Medicare Advantage is disproportionately large for their business. Do you know that Humana is up 25-fold, 2400%, since the passage of the act we just talked about in 2003?

Harlan Krumholz: What do you mean, “they’re up 2400%”? What’s the...

Howard Forman: The stock, the stock.

Harlan Krumholz: The stock has gone up.

Howard Forman: 2400%, and Cigna is up 15-fold, or 1400%, in the same interval. Now, as a reference point, what is the average stock up in that point? 200%. So the companies in this business, as you just said, have become enormously profitable, probably mostly due to Medicare Advantage plans.

Harlan Krumholz: And so, to me, that suggests that the calculations we’re making in order to determine what represents fair payments are not exactly working. And it doesn’t surprise them because these are sort of antiquated formulas using crude descriptors of people based on billing data, largely. And there are many more sophisticated ways to assess risk if we wanted to employ them. Now, if I’m these companies, I’m probably going to hire a lot of lobbyists to try to maintain the status quo because it seems like in the status quo, it’s ending up to provide huge margins. And so this is what concerns me. I think actually our group, we should be digging into this a little bit more.

Howard Forman: I think this is a very important topic. Now, I will say, on a positive note, you had three separate district attorneys, one in Tennessee, one in Pennsylvania, and I think one in New York, that work collaboratively to both investigate and prosecute this and come to a settlement with Cigna. On the flip side of it, though, is there are many pending lawsuits on the same topic right now. And Medicare Advantage companies, including Kaiser, are suing the government saying that... “Keep your nose out of our books,” basically.

Harlan Krumholz: Well, let’s differentiate these two points. One is, playing by the game, does the game fairly compensate them for the people that they’re covering? So is there something wrong with the equations, not counting gaming the system? And then the second part of it is, are people gaming the system on top of the advantage that the equation’s giving them? And again, just to get back to this, the equation’s trying to say, “How sick are the people that you’re covering?” Your payments should be tagged to the severity of illness, the risks of the people that you’re covering. If it’s underestimating or overestimating the risk, you’re getting overpaid because it’s basically saying, “We expect you to be spending certain amount of money on these people,” and it doesn’t work out that way. And then on top of that, some of these companies... this is what the Cigna is. By the way, Howie, you say $170 million being a big deal. That’s chump change to them, given what their profits are.

Howard Forman: It is, but they got a settlement out of it and basically admitted it.

Harlan Krumholz: Cost of doing business.

Howard Forman: That’s how they’ll see it. I know.

Harlan Krumholz: I mean, just expense it out. And so if you’re allowed to... and this light hand slap on the billions of dollars that are moving, you’re paying $170 [million] and you’re mostly being able to upcode. And then I think they could fairly ask, “Well, we’re just more accurately characterizing our patients.” So there’s a back and forth about this, but I would say the system’s not working if largely we’re ending up paying a lot more for the people in Medicare. And I’ll say one last thing is, as more people have gone into Medicare Advantage, we have not seen life expectancy go up.

Howard Forman: No, exactly. No.

Harlan Krumholz: Right?

Howard Forman: There’s no evidence that I see right now that Medicare Advantage has been successful. Now, we pay more for it, and so there is great satisfaction among the patients. Satisfaction, not necessarily—

Harlan Krumholz: Well, because they get dental and gym.

Howard Forman: Exactly, exactly. That’s what it is.

Harlan Krumholz: They get extra benefit.

Howard Forman: Right.

Harlan Krumholz: But whether that’s translating into better health, lower utilization... and I know our friend, Jason Abaluck and others, I’m working... some with them. They’re digging into this. Maybe we’ll have him back on the show and we’ll talk to him soon.

Howard Forman: Great. That’d be great. So there was another paper that came out. I think it actually first got published a few weeks ago, but hit the press more recently. It’s in The New England Journal of Medicine now, I believe, on using a particular statin drug to treat patients with HIV in order to treat them for just cardiovascular risk factors. And I’m aware of the fact that HIV increases your risk of cardiovascular risk beyond what would be expected. And apparently there’s been some concern about some statins having some conflict with the HIV medications that they’re on. And so why is this paper important, and why is it sort of almost shockingly like, “So what?”

Harlan Krumholz: Well, look, first of all, anytime we come up with a medication that can reduce risk for a group in a very substantial way, 35% reduction in cardiovascular risk, we should applaud. My first emotion about a paper like this is just to reflect back when I was in residency when we had nothing to treat people with, and people were just dying terrible deaths. And it was just so tragic and sad, and that we fully converted this to a chronic condition.

Howard Forman: Seems that way.

Harlan Krumholz: And that now we’re talking about, “How do we manage the cardiovascular risk within a group of people who are living with HIV disease?” I know we know that, but it’s still remarkable to me about what kind of progress we’ve made. The issue about this study, to me, is this is a group of people.... They randomized 7,800 people with HIV infection and low to moderate risk of cardiovascular disease who were receiving antiretroviral therapy. And we’ve known for a long time that people who have this kind of therapy.... Actually, everything else considered, it elevates their cardiovascular risk. So basically, this is a worthy population to see whether we can lower their risk. Even if they don’t have all the traditional risk factors, they have higher risk. And some of that sought to be related to the inflammation; maybe some of it related to the treatments.

There’s lots of stuff here. But I think what’s interesting to me is I for a long time have felt that these statin drugs are not just about lowering cholesterol but about lowering risk. And you can give them to almost anyone, and you will lower their risk. I mean, if you look at all the studies, no matter what your starting cholesterol was, you can lower risk by about 20%. Maybe with high-intensity statins or more, you can lower maybe 30%, 35%, like what you saw in this study. And so this to me is validation of the idea that the statins are not necessarily about chasing a cholesterol level or getting to a target, but if you’ve got someone with elevated risk, you can give them a statin and you can cut that risk. And so the findings here weren’t surprising to me at all. I guess you could say the only thing that they wanted to check was that the principal mediator they thought might be inflammation.

And the question is for that kind of cardiovascular disease mechanism, would statins be affected. But so far I’ve seen, statins, any population you try them in, they lower risk. And so I like the study. It acknowledges the chronicity of HIV disease, which is a triumph. It’s a positive trial, which means we can help people even more avoid these cardiovascular complications. But I like it because it’s also a validation of this idea about thinking about cholesterol, not as a cholesterol-lowering drug. It does lower cholesterol, and that’s probably the principal mechanism by which it works, but it’s a risk reducer. So basically we should be finding everybody who’s got elevated risks should be on these drugs, not trying to find the right threshold of cholesterol or not trying to chase it to a certain level, but just recognizing these drugs’ risk reduce.

Howard Forman: It’s also a nice acknowledgment, I think, if we think back over a year when we had Amy Justice on the show, just about how you have these large groups of researchers that are doing mammoth studies on these populations and yielding real results. I thought, to me, this was a very intense effort by a lot of people to come up with a very important answer to a question that we hadn’t answered.

Harlan Krumholz: Yep.

Howard Forman: I heard you were in a meeting yesterday, Harlan. Tell me, Datavant, what is that?

Harlan Krumholz: I went down to DC. There’s a company called Datavant, which is actually helping to bring together data from different groups. Most of the meeting was about cognoscenti of the data universe in healthcare, people who are looking at this from various different angles. And then there were folks from the government there, Rob Califf came, commissioner of the FDA. People were there from various different segments of the healthcare universe. My take-home still is that there is progress being made, but my gosh, we still have this digital transformation where all of our data sits in digital, and we’re still not really able to exploit the digital nature of healthcare data in ways that are truly and fundamentally improving research and clinical care. And what was nice was, you had a bunch of people there who’ve been thinking hard about how you get to the promised land of really doing that, but it remains so interesting, Howie, between regulatory obstacles, privacy issues.

Howard Forman: So I’ve always felt like the privacy issues are a particularly big issue. Even when you can assure people that their data is their data, they control it and all that, I still feel like people are worried about health data in a way that they don’t worry about other things. How much do you think privacy does concern people?

Harlan Krumholz: Well, I think people have to comply with the federal guidance. But as I’ve talked to you about this before, a lot of these companies are moving around data that patients have no idea about. And so some of the solutions people are trying to come up with, this idea of tokenization where basically, what they’re saying, you’re sort of hashing or obscuring or it’s sort of encrypting the information about the individuals. The problem is, if I take away all of your identifiers but I’ve got your medical care history, most people could figure out who you are—

Howard Forman: Absolutely.

Harlan Krumholz: ...with a lot of other data. So it’s this idea of, how do we on one hand unlock the value of the data for society and patients and for companies and, on the other hand, ensure that we’re not releasing information that people would be shocked to find out that released. There’s another side of it where you actually and try to get overt consent from people. And like you said, Howie, some people get very concerned about giving that consent. But I’ve talked to you about this story of these pop-up COVID testing groups in New York City. If you got your test on that corner, then they were able to say that they were your caregiver and being able to go out and get your data.

Howard Forman: All your information. It’s horrible.

Harlan Krumholz: And then they could actually then commercialize that information, combination of your testing and the data. So it’s still, I think, a bit of a mess. But let me say there are a lot of people trying to work on this problem and from various different directions. So I left the meeting feeling optimistic that we will ultimately solve some of these problems but still concerned that we’re locked in an analog world in healthcare, largely. We’re not really able to use data in the ways that could ensure that the very next person that comes in is advantaged by all that we’ve learned by everyone before them. And that they were really capable of informing their choices in meaningful ways based on rapid agile analytics of real-world existing data.

Howard Forman: And to your credit, again, going back over 15 years, you’ve had conversations with me where you’ve talked about, “How do we get to a continuously learning healthcare system that is iterative, that takes account of the data that already exists to help inform future?” And I think back to that, when you said that to me, I knew it was ahead of the curve, but I did not think it was going to be decades before we saw that. And I’m not sure we’re getting there fast enough.

Harlan Krumholz: It’s still the promised land. Like I said, I remain optimistic, but medicine’s an information science now, and to fully assume that mantle and be able to achieve the promise of that, we’ve got to solve this issue about the data. We’ve got to solve it. You’ve been listening to Health & Veritas with Harlan Krumholz and Howie Forman.

Howard Forman: So how did we do? To give us your feedback or to keep the conversation going, I’m going to recommend that you reach out to us at health.veritas@yale.edu. That’s health.veritas@yale.edu. You can also find us on Twitter.

Harlan Krumholz: Or X or whatever it is. I’m @H-M-K-Y-A-L-E. I’m still there. @HMKYale.

Howard Forman: And I’m @thehowie, that’s @T-H-E-H-O-W-I-E. Aside from Twitter or X and our podcast, I’m fortunate to be the faculty director of the healthcare track and founder of the MBA for Executives program at the Yale School of Management. Feel free to reach out via the email I just left you for more information on our innovative programs, or you can check out our website at som.yale.edu/emba.

Harlan Krumholz: And we’re also increasingly using LinkedIn, and we’re thinking about Threads and we’re wondering about Instagram. And if you’ve got suggestions for us, let us know.

Howard Forman: We want to hear from you.

Harlan Krumholz: Health & Veritas was produced at the Yale School of Management, Yale School of Public Health. Thanks to our researchers, Inès Gilles and Sophia Stumpf, and to our producer, Miranda Shafer. They are great, and we’re lucky to have them. Talk to you soon, Howie.

Howard Forman: Thanks very much, Harlan. Talk to you soon.