Ania Jastreboff: Treating Obesity Without Shame

Transcript

Harlan Krumholz: Welcome to this special bonus episode of Health & Veritas. I’m Harlan Krumholz.

Howard Forman: And I’m Howie Forman. We’re physicians and professors at Yale University. We’re trying to get close to the truth about health and healthcare. What do we got in this bonus episode, Harlan?

Harlan Krumholz: Well, you and I talked about sometimes we have friends who put out a book that deserves attention.

Howard Forman: Absolutely.

Harlan Krumholz: And we thought, “Why not use this platform to do it?” And we’re lucky enough to have friends who, when we ask, they say yes.

Howard Forman: So far, so good.

Harlan Krumholz: So far, so good. So today, we have Ania Jastreboff. And let me just bring people up to speed. She’s one of the leading international experts in obesity science and treatment. She’s a physician-scientist at Yale School of Medicine and the founding director of the Yale Obesity Research Center, known as Y-Weight. She’s led many landmark clinical trials that have transformed how we understand and treat obesity, including pivotal trials of dual- and triple-hormone receptor agonists published in none other than The New England Journal of Medicine.

She’s both a scientist shaping the field, and honestly, she is one of the most extraordinary clinicians, who cares for patients deeply, and she brings a deep understanding of obesity biology together with a strong commitment to improving their lives. She’s here with us today, because she’s coauthor with—

Howard Forman: Oprah.

Harlan Krumholz: ... Oprah Winfrey of the book Enough: Your Health, Your Weight, and What It’s Like to Be Free. Ania, it’s spectacular to have you here with us today.

Ania Jastreboff: Thank you for having me.

Harlan Krumholz: So let me just jump off, and then I’ll let Howie go. But I wonder if you could just tell us a little bit about the story of this book. How did it start? What was it like to write it? How was it working with Oprah? Come on, give us some of the insider dibs here.

Ania Jastreboff: So Oprah and I had recorded two podcasts for her channel.

Harlan Krumholz: She just had reached out to you and said—

Ania Jastreboff: We had met previously on a special that she had had as well as on a panel, and then the next time that we had met was specifically for these two podcast recordings. And we were meant to record for 90 minutes, 90 minutes of content, so two podcasts, and we ended up recording for over four hours. There was just so much to say and so much to share. And afterwards, we were eating, and Oprah was sitting just to the left of me. I was with my husband, who’s also an endocrinologist, and we were—

Harlan Krumholz: A fantastic endocrinologist.

Ania Jastreboff: A fantastic endocrinologist and a beautiful human being. And we were all sitting together, and she turned to me, and she said, “You should write a book, and I will help you.”

Harlan Krumholz: Oh my gosh.

Ania Jastreboff: And in that moment, you think, “This is going to help thousands, if not millions of people.”

Harlan Krumholz: Millions. Millions.

Howard Forman: Right.

Harlan Krumholz: Yeah.

Ania Jastreboff: And so, the answer was clear, and that was less than a year ago. Well, now, it’ll be a year ago.

Harlan Krumholz: Did you have any idea what you’re in for when you said yes?

Ania Jastreboff: No. All I had written to that date was scientific articles, and it’s very different, right? You have data, tables, figures. You write your methods, your results.

Howard Forman: That’s a very fast turnaround for a book also.

Ania Jastreboff: Yes. It was very fast.

Howard Forman: I don’t know if anyone has written a book that fast.

Ania Jastreboff: Yes. It was very fast. So, very different type of writing than I’d ever done before in my life. I did not want a ghostwriter. I wanted to write it myself, but the goal was, how can we quickly and effectively help people with obesity? And with that goal and that mission in mind, that’s what I kept on thinking about. I think that’s what both of us kept on thinking about, and I had to do this.

Howard Forman: The preface is written by Oprah and by you—two separate prefaces, if that’s the plural, and she tells her story about obesity, and you tell your story. We’ll let our listeners read her story, but I’d love you to just summarize what is it that motivated you, because it’s so poignant about what motivated you to get involved in this field and to become the leader that you’ve become.

Ania Jastreboff: So my brother was teased as a child for his weight, and his nickname was Spanky from The Little Rascals, who’s a highly intelligent, beautiful, amazing human being that I looked up to from a very young age and still do. And to this day, I think he thinks of himself or he sees himself as Spanky, even though he actually joined the swim team and did all these things, and his life transformed in other ways. But somehow that stayed with him, and it stayed with me to see him being teased at that young age, and that sparked, I think, for me, all of this.

And then really, it was my father. So when I was a young adult or, I would say, high school and then college, my father began to gain weight and eventually developed obesity, and then he developed diabetes. And I saw how both obesity and diabetes impacted his health and his life, his well-being, how he felt guilty every time he ate food. He knew it would cause his blood sugars to go up, and he really enjoyed food. He loved food. And for him, the amount of food wasn’t enough. He wanted to eat more, and I knew that it wasn’t a choice.

Harlan Krumholz: Right.

Ania Jastreboff: It was something else that was compelling him, and it was biology that was compelling him, and it was really that. So I think seeing that early on in life, I never thought it was my father’s choice.

Harlan Krumholz: Right.

Ania Jastreboff: It was never his choice. And so, people ask me, “Well, how do you not blame patients?” Well, how can we blame patients? It’s not their choice. Having obesity is not a choice. It’s a disease. It’s driven by biology.

Harlan Krumholz: There are so many special things about you. You’re such a caring physician. You’re a great communicator, and people should also know you’re an exceptional scientist. I mean, you really have been leading these trials that have transformed the way that we think about it. You’ve got the deep expertise in actually the biology of obesity and the clinical science and what’s come around.

I wanted to just ask you, since we have you here, the field of obesity science is moving so fast. What do you think we can expect to see this year? What’s going to happen around the corner that people should stay alert to? Because I hear there are 50 or 100 drugs in the pipeline. There are so many things going on. What are you looking toward this next year? What do you think we’ll see?

Ania Jastreboff: Yeah. There are hundreds of drugs in the pipeline, well over a hundred, and they’re not only nutrient-stimulated hormone-based therapy, so not only medications that are similar to semaglutide or tirzepatide, but many other mechanisms being explored.

To answer your question, what’s coming in the next year, the next wave that we’re going to see are oral medications. So there are two that are currently under FDA review for the treatment of obesity. One is oral semaglutide, which is a peptide. There’s lower doses of oral semaglutide that are already FDA-approved for the treatment of diabetes. But because peptides are—

Harlan Krumholz: This is Wegovy or Ozempic. People might have heard the trade names.

Ania Jastreboff: Yes. And Rybelsus is the oral version of semaglutide, which is both Ozempic and Wegovy. So oral semaglutide is a peptide. All of them are the same molecule, and peptides are chewed up by our digestive enzymes. So you need higher doses in order to have a certain effect, because they’re chewed up. So the dose that’s under FDA review is higher than what we have for diabetes.

Now, there’s another oral GLP-1 receptor agonist that is under FDA review, and that’s called orforglipron, and that is the first small-molecule GLP-1 receptor agonist. And the benefit of the small molecule is they’re not chewed up by our digestive enzymes. So it can be taken anytime with or without food, water, anything. There’s no restrictions.

Any peptide like oral semaglutide, there are food restrictions. So you have to take it a half hour before eating. So those are the two. And with both of them, what you see is not only weight reduction. You also see improvements in blood pressure, in blood sugars, in all of these other health measures that are so key for our patients with obesity.

Harlan Krumholz: Yeah. And as a cardiologist, I’ve been focusing saying, “Actually, I don’t care about the weight loss. This is cardiometabolic health that we’re seeing improve.” So do you think these will be approved this year and you’ll start using them in your patients?

Ania Jastreboff: In 2026.

Harlan Krumholz: In 2026?

Ania Jastreboff: Yeah. I mean, again, we have to wait and see when the FDA is done with their review, but they have the data to review to make those decisions. So it’ll be oral semaglutide and orforglipron. And then in terms of—

Harlan Krumholz: And how will you decide what you will recommend to your patients when you’ve got now the option of the old-line injections versus the new oral drugs?

Ania Jastreboff: I think it’s a discussion with the patient. What are their goals? What are they anticipating in terms of their health? What do they think that they could adhere to?

Harlan Krumholz: Will the cost be about the thing?

Ania Jastreboff: Of course, and that was my next thing.

Harlan Krumholz: Oh, yeah.

Ania Jastreboff: And the next thing is, what will insurance cover? What will insurance pay for? And there are some inklings of hopefully cost coming down. And with any medicine that is new for any disease, we see high costs initially. I mean, this is not unique. The difference here is that so many people are affected by obesity. Nearly half of Americans already have obesity, and there’s been such a need and such a backlog.

And not everybody who has obesity will be seeking treatment, and that’s absolutely fine. It’s always the patient’s choice. It’s our job to inform them of the risks and benefits of treatment and the risks and benefits of not treatment. But there’s been such a need and such a backlog that that’s why we can’t wait. We can’t wait for costs to come down. They have to come down faster, and we need to improve access for our patients.

There’s other innovations coming down the pipeline. So I mentioned the orals. So CagriSema is combination of semaglutide with cagrilintide. So two molecules, but in one. Cagrilintide targets amylin. So it’s an amylin analog, and semaglutide is, of course, a GLP-1 receptor agonist. So that will be a weekly injection. It’s under FDA review, a weekly injection.

Harlan Krumholz: The advantage of amylin is?

Ania Jastreboff: Well, so each of these hormones, so GLP-1, GIP, amylin, they are each distinct and different. They’re all nutrient-stimulated hormones, but they target different receptors and therefore different pathways. We don’t know all the nuance and all the differences yet, but we do know that some people don’t respond to GLP-1 receptor agonists or GIP/GLP-1 receptor agonists, or they may have side effects even if we go up very slowly.

And so, giving patients different options is really key. So there’s CagriSema, which is the combo, and there are others that are in earlier stages of development. There’s a amylin analog that’s a monotherapy called eloralintide that Phase II just read out. So that’s not quite as far along in development. But all that to say is that our patients need more treatment options, because there’s different types of obesities, and everybody will not respond to the same types of treatments.

Howard Forman: In the last two years, we’ve seen supply chain problems and high prices, and the supply chain problems have mostly resolved, and the prices have come down a lot.

Ania Jastreboff: Yes.

Howard Forman: And yet in the last six or nine months, there’s been a number of private payers and Medicaid plans, including the state of Connecticut, that have basically reduced the access to these obesity drugs for patients. What is your experience as a clinician right now in terms of getting these drugs for patients who need it?

Ania Jastreboff: I think this is heartbreaking. I mean, imagine being a patient who’s lost 80 pounds. Their blood pressure has improved. Their blood sugars have normalized. Their knees have stopped aching. And now, they no longer have coverage. They no longer have access to something that was health- and life-transforming. It’s tragic.

Howard Forman: And this is common right now.

Ania Jastreboff: I mean, yes.

Howard Forman: Yeah.

Ania Jastreboff: A lot of patients do not have access, and I’m hopeful that this will change.

Howard Forman: Yeah.

Ania Jastreboff: I’m so hopeful that this will change. This past year, these past two years, and it actually started with the SELECT cardiovascular outcome trial, and there were other trials already, but trials that demonstrated clear health benefits, and there are direct effects of the medication in and of itself on those other obesity-related diseases. So there are effects to impact weight reduction, and there are effects in terms of disease-modifying effects on those—

Howard Forman: Right. Cardiometabolic.

Ania Jastreboff: ... downstream cardiometabolic diseases. So I think that if we think about long-term health, lifelong health, and the health of our nation and of the world, I mean—

Howard Forman: We’re not set up to think that way, though.

Ania Jastreboff: Well, we’re not, but maybe this is the disruption that we need.

Howard Forman: Yup.

Ania Jastreboff: Maybe this will be what propels us forward to understand that, because if we can treat obesity, this one disease, we can impact over 200 other obesity-related diseases, which means we can transform the health of our world by treating one disease, one person at a time.

Howard Forman: Yes. I mean, this is what we’re hoping for, but do you think we’re getting better or worse in the last two years at getting access? Well, the fact that you’re hesitating means it can’t be much better.

Harlan Krumholz: Well, I mean, I’ve seen some health systems pull back on coverage—

Howard Forman: That’s what I’m saying.

Harlan Krumholz: ... for these drugs. Small businesses are under stress.

Howard Forman: And Medicaid programs. Right. That’s what I’m saying.

Harlan Krumholz: They find it convenient to cut this even though that it’s been shown to be so highly effective and—

Ania Jastreboff: I think that there’s waves. And the other thing is that sometimes we hear about changes, and then they don’t occur or they occur in a different way, and we are truly right now in the messy middle of all of this. I mean, with any disease, any new therapy, they are always very expensive, even more expensive than this. It’s just that the need for this and the backlog has just been tremendous, because we didn’t have highly effective therapies that were safe. We didn’t have highly effective therapies, and now we do, and that’s the difference.

Harlan Krumholz: I want to go back to... Let me just ask you one other thing for... Maybe we can end focusing back on the book, because the book is so important, but I’ve noticed recently so many ads on microdosing, and I just wonder what your view is on this. This is the use of—

Howard Forman: Is there evidence?

Harlan Krumholz: ... what some people might consider even subtherapeutic levels of semaglutide, for example, being advertised, and there are many people taking it. Do you have any view on this?

Ania Jastreboff: So microdosing can mean different things. So taking small doses or mini doses, for example, when somebody is not tolerating a medicine for whatever reason, even starting dose, and doing clicks so that the tolerability can build up over time. So start low, go slow. Always starting with the lowest dose is one of the most important ways to help mitigate and prevent side effects, and the most common being nausea, diarrhea, constipation, vomiting.

And we don’t want to get to vomiting, which is why if somebody has nausea, we microdose. We give little tiny doses until their body gets used to it. So that’s one thing. In terms of what I think you’re asking is using small doses for people who may not have obesity.

Harlan Krumholz: That’s right.

Ania Jastreboff: That’s what you’re asking? Yeah. So there’s no data. We don’t have data. We don’t have data in people who do not have obesity in terms of the risk versus benefit.

Harlan Krumholz: Without obesity and without diabetes.

Ania Jastreboff: Without obesity or without being overweight or having overweight and an obesity-related disease such as hypertension, dyslipidemia, heart problems, diabetes.

Howard Forman: Which is what it is approved for.

Ania Jastreboff: Yes, diabetes. I mean, depending on the medication, there’s approvals for obesity, secondary cardiovascular event prevention. There’s approval for obstructive sleep apnea, specifically with tirzepatide. So there’s different approvals. Again, they’re all obesity-related diseases or obesity in and of itself. Most of these medications, well, actually all of them are also FDA-approved for diabetes, and that’s what these medicines were developed for 20 years ago. That’s why we have 20 years of data in terms of GLP-1 receptor agonists.

We do not have data in people who do not have obesity or are not overweight with an obesity-related disease. So anytime we’re prescribing a medicine for any disease for any patient, we think about risk versus benefit. There’s no medicine that does not have side effects for any disease, no medicine out there. So we always have to think about the risk versus benefit, and we don’t have the data to know the risk-versus-benefit ratio for patients, because they have not been studied.

Howard Forman: One of the themes of the book, and you talked about it in the preface, is stigma, and Oprah has literally dedicated her career to trying to destigmatize obesity. I mean, way, way back. Are you seeing progress made on that front? Do you think we finally turned the corner where the public understands that this is a disease, a central disease, and not a issue of somebody’s willpower or strength of character?

Ania Jastreboff: I think that this is a process. This is a process, and I think, hopefully, this book is part of that process, shifting from a culture of shame and blame for a disease that is not any patient’s fault to a culture and an understanding of compassion and care for our patients who have obesity. And I fully agree with you. Oprah—I am so grateful for what she has done and is doing. The fact that she took her own pain, she took her own struggle, her own struggle with shame and blame...

Howard Forman: Wholly shared it.

Ania Jastreboff: ... her global shame and blame for having a disease and turned that pain into a gift, a gift for patients, and giving patients with obesity a voice.

Howard Forman: Yeah. No. When you watch the videos of you doing, I think, the podcast, talking to these patients, it is just heart-wrenching to hear these people, what their history is, and how much they are thankful, genuinely thankful to Oprah and to you now.

Harlan Krumholz: What are your hopes for the book? There are a lot of books on obesity. This one’s distinctive. What’s your special hope for this book?

Ania Jastreboff: I hope mainly that it helps a lot of people with obesity and also that it helps people who don’t have obesity to know or to feel what a patient with obesity may have experienced their whole life. It’s one thing to say to somebody, “Well, obesity is a disease.” It’s another thing to say, “Here’s why it’s a disease. Here’s the biology behind the disease.” And understanding that biology really can set patients free.

It’s the beginning of moving from self-shame and blame to compassion and care for yourself and, in so doing, hopefully for all of society. So I hope that the message of obesity biology, obesity as a disease, a treatable disease, really comes through in the book and helps us basically shift away from shame and blame to care and compassion.

Harlan Krumholz: I think that’s amazing. The idea of setting patients free and those who love and care about them help them have a greater understanding—

Ania Jastreboff: Absolutely.

Harlan Krumholz: ... of the struggles that they’ve had.

Ania Jastreboff: Absolutely. That’s so important, and there’s no one who’s not touched by obesity. Everybody has loved ones who have struggled with obesity. And if half of Americans already have obesity and two-thirds have obesity or are overweight, that’s most of us.

Harlan Krumholz: Yeah. That’s most of us.

Ania Jastreboff: Yeah. And in so doing, we have to continue to work on our obesogenic environment and make it a healthier one.

Howard Forman: Absolutely.

Harlan Krumholz: Right.

Ania Jastreboff: It’s everything. It’s both.

Harlan Krumholz: You also focus on exercise, diet, everything.

Ania Jastreboff: Yes. Yeah. Everything.

Harlan Krumholz: This isn’t just about medication.

Ania Jastreboff: Everything. It’s about health.

Harlan Krumholz: Health.

Ania Jastreboff: Treating obesity is about improving and optimizing health.

Harlan Krumholz: I think that’s a really important message, too, that people listening understand how deeply committed you are to saying, “When you’re not backing off of lifestyle, you’re not backing off of exercise.” This is just saying there are more tools.

Ania Jastreboff: It’s everything together. And if somebody comes to see you, Harlan, for hypertension, you say, “Here’s a medicine or medicines that will help you, and here is... I’d like you to talk to the dietitian about the DASH diet.”

Harlan Krumholz: And here are diets that can help you—

Ania Jastreboff: So it’s both. It’s together. It’s not one thing or another. It’s everything together, and that’s how we can optimize health.

Harlan Krumholz: That’s right.

Ania Jastreboff: Yup.

Howard Forman: Well, thank you so much.

Harlan Krumholz: Yeah. Yup.

Ania Jastreboff: Thanks for having me and for helping people with obesity.

Harlan Krumholz: Great to see you, Ania.

Howard Forman: Thank you.

Ania Jastreboff: Thank you.

Harlan Krumholz: Terrific interview by Ania. This has been a great bonus episode on top of the—

Howard Forman: She’s great.

Harlan Krumholz: ... other bonus episode we recently did with Zeke. It’s so great to do this with Ania. Just remind you, her book, Enough, that she wrote with Oprah Winfrey is now available. It’s a great read. We highly recommend it, and you’ve been listening to Health & Veritas with Harlan Krumholz and Howie Forman.

Howard Forman: So how did we do? Give us your feedback. Keep the conversation going. You can email us at health.veritas@yale.edu or anywhere on social media.

Harlan Krumholz: Yeah. And tell us why you like these bonus episodes. We really like to hear. And as usual, we’re sponsored by the Yale School of Public Health, Yale School of Management. We’re blessed with two superstar undergraduates, Gloria Beck and Tobias Liu, with a remarkable producer, Miranda Shafer, and I get to work with the best in the business, Howie Forman. Thanks, Howie.

Howard Forman: Right back at you, Harlan. We’ll be back at our usual time on Thursday each and every week.

Harlan Krumholz: Yup. Talk to you soon, Howie.

Howard Forman: Talk to you soon, Harlan.