More on Wegovy (semaglutide), Covid-19 outcomes, and a deeper dive with BBC radio.

Getty Images, Manuel Breva Colmeiro.

On Friday, I wrote about the results of an amazing new study showing that Wegovy (semaglutide) lowered Covid-19 mortality. As expected, there was a lot of interest in this, and journalists I spoke with had some of the same questions many of you asked. Take a look:

• New York Times (by Gina Kolata).

• Boston Globe (by Adam Piore).

• The Hill (by Lauren Irwin).

• MedPage Today (by Nicole Lou).

I also did an interview with BBC Radio over the weekend. I confess that I expected a 5-10 minute “quick and easy” segment in which we would cover the basics of what I’d already written or said elsewhere. Instead, I found myself in the hot seat for over 22 minutes. I would say that the host occasionally straddled the line between “friendly if inquisitive” and “vaguely menacing.” But, as the kids say, I was here for it!

What I realized late in the interview was that, for Stephen Nolan, the BBC host firing questions at me, this was all personal. At some point, he mentioned that he has obesity and that he has been unable to lose weight. Given that, he was understandably skeptical—not wanting to cling to any unrealistic hopes of a miracle cure for a long-standing issue.

It ended up being a very substantive interview, which I enjoyed, precisely because I was forced to defend my views on the data directly and quite specifically. Even though the presenter was rather suspicious of the hype around these drugs—which I admire in a journalist—he never crossed into hostile territory. Even the way he asked whether I have any financial conflicts of interest related to these drugs (which I do not) was respectful.

Here’s that interview in its entirety (courtesy of BBC Radio 5 Live), and a transcript of the conversation. It answers many of the questions people have about the amazing class of drugs (glucagon-like peptide 1 receptor agonists, or GLP1s) that power semaglutide (i.e., Wegovy and Ozempic).

BBC News (Stephen Nolan) (00:00):

It's hailed as the Fountain of Youth. I'll read from the Daily Telegraph. Ozempic could offer the Fountain of Youth and turn back the clock. And a host of diseases scientists have found in an unprecedented development. Eleven studies published in one day found that the new class of semaglutide medications have far reaching benefits beyond what was ever imagined. The findings will put pressure in the NHS to roll the drugs out more widely. Like statins. Currently only patients who are obese or of type two diabetes can access these drugs on the health service. The injections are marketed as Ozempic for type two diabetes and as Wegovy for weight loss, let's talk to a man who will not just know how to pronounce it, but can tell us all about it. Dr. Jeremy Samuel Faust is from Harvard Medical School. Jeremy, good morning.

Jeremy Faust (JF):

Hello.

BBC News (01:00):

Did I pronounce this? First of all?

JF (01:03):

Well, Ozempic and Wegovy are two brand names for semaglutide, these molecules that mimic hormones that we have in our body already.

BBC News (01:13):

So tell us what we know about what's new here. What are we learning about what they can achieve?

JF (01:20):

Well, what we learned last year was that for people with heart disease, that these drugs can actually decrease mortality from all causes cardiovascular disease. And then the surprise was that even there were fewer deaths in patients who received these drugs from other causes, non-cardiovascular diseases. And that led investigators to look into whether some of these deaths had been Covid deaths. And it turned out that patients who'd been on semaglutide for a couple of years when the Covid pandemic started, actually when they went on to get COVID-19, died about a third less of the time than the people who'd been on placebo during that time.

BBC News (02:03):

What is a semaglutide?

JF (02:06):

Well, semaglutide is the actual act of compound in these drugs, and that's just the scientific, that's the generic name for the compound itself. And the compound itself is called the glucagon-like receptor agonist, meaning glucagon is a hormone we have on our bodies. And semaglutide is basically a synthetic version of a similar molecule that our body recognizes as essentially an appetite suppressant.

BBC News (02:39):

So that's what it does. Does it go to the brain and suppress appetite or what does it do?

JF (02:44):

Well, there are these GLP1s, the glucagon-like receptor peptides. There are receptors for these molecules all over the body, and they're in the GI, the gastrointestinal tract. They're in the brain as well. But I think that we don't know where and how these molecules are interacting, but we do know that it has some pretty important clinical effects. The big one I think is appetite suppression. It slows down the rate of the stomach, kind of pushing things forward into the small intestine and forward. And that just makes people want to eat less. And when they eat less, their metabolic demands really change. And over time, that has tremendous health benefits.

BBC News (03:28):

Their metabolic demands is that fancy talk for hunger?

JF (03:34):

Well, metabolic demand, well, no, not exactly. Hunger is what drives us just to eat. And if we eat too much, our body has to process that. And so our metabolic rate changes to process all the calories coming into our body. And so over time, if we overeat the metabolic demand, meaning the activities of our body to process that energy into fat tissue or into energy, that goes up over time. But in exchange for that, if we overeat, that leads to buildup of all kinds of inflammation, which can cause heart disease, can cause kidney disease, can cause diabetes. And so these drugs do the opposite. They say, look, we're full. We don't need more. We need less. And so therefore over time how much energy we are burning, how much we're taking in goes down. And as a result of that, these inflammatory pathways that can cause all these various diseases seems to dramatically--is reduced dramatically.

BBC News (04:35):

There are risks with most drugs. What are the side effects? Every time I go to America and you see an ad for any medication, they take about 10 minutes telling you how you're going to die in multiple different ways from how you might die or get serious disease. It's unbelievable. What are the side effects possibly of these drugs?

JF (04:56):

Yeah, so we have a strange system here in the United States where these drug companies are permitted to directly market them their products to consumers. But in exchange for that, they've got list off all these umpteen things that could happen to them, whether or not they're common or rare. And so in this case, well first of all, I'll say, as you say, with any drug, there are benefits and there are possible side effects, and you always want to balance those. And with these compounds, I will say I'm unusually encouraged because we keep seeing that the benefits are incredibly important ones. Decreased heart attacks, decreased mortality, now even covid mortality reduced, these are incredible benefits. Now, as you say, nothing comes without a risk. We have from these trials, and we have also from observational data afterwards that the most common side effect is nausea, gastrointestinal kind of discomfort mostly during the early phases so people can get inflammation of the pancreas. This is not pancreatic cancer, it's just a pancreatitis inflammation that seems to have been a little higher in people who took this drug. Although I will say in this big trial, there was no difference between placebo and semaglutide, same rates of that condition. And sometimes people will have other conditions like their intestines kind of temporarily stop pushing things through. That's called an obstruction or the medical term would be an ileus. But again, these are self-limited. We haven't seen any major side effects that would really be much cause for alarm when on the other side of the ledger is a decrease in heart attacks, is a decrease in mortality.

BBC News (06:36):

Although have they been around long enough for us to be confident or do we not know yet? In terms of the dangers? Look, it's highly tempting. I'm not asking for a friend, I'm asking for me, I'm 19 stone, I can't lose weight. It sounds too good to be true. Dr. Faust, do we know enough about these drugs to be sure?

JF (07:04):

First of all, I will say as a clinician, I work in emergency departments and I very frequently started to notice at a couple of years ago that we'd see these patients, we'd see their vital signs and we'd see their weight, and I would say that patient does not weigh what they say they weigh. They weigh a lot less. And then I would look and lo and behold, they'd be on one of these drugs. It really has been amazing, and we're seeing lower rates of heart attacks. I think that, as you say, with any drug, we want to see long-term follow up. What we have so far is quite a bit more than usual for a quote-unquote blockbuster because these drugs have been around in earlier generations for diabetes. So we've been seeing for over a decade now, these patients do quite well. Now who's to say that 30 years from now something might not crop up? I mean, that's definitely something we're going to watch. But what's so unusual here is that right now the benefit is not some decrease in something like a cholesterol level and who knows what that means? Or your blood pressure level, which you'd like it to be lower, but who knows what that adds to your daily risk? The benefits we're seeing in certain patients is life or death. They don't die as much. And so if 30 years from now it turns out that there's some increase in something that we don't like, we don't want to hear about, that'll have a very steep climb to overcome all the benefits today. So I'm unusually optimistic, but that doesn't mean that something's not going to crop up. And the caveat of course is that if there are patients who wouldn't benefit from this in the same way, they won't have that mortality benefit because they're already fairly healthy, then what you're doing is you're putting those people at risk because as you say, who's to say 20 years from now, what will happen to people who take it? And if their lives weren't saved, what did they get? So that's a very important thing that we're watching

BBC News (08:47):

This, then if it turns out to be as much of a wonder drug as some people are suggesting, this puts health systems around sophisticated societies under intense pressure because there are lots of fat people, there are lots of obese people, and they will want this on the public health services. How do you think the NHS and the UK, your health service, how will these be afforded?

JF (09:17):

Yeah, I mean that's a really important question. And for every single kind of patient population, these systems think in terms of something called willingness to pay. And a very simple example of this would be if I told you that there's a cure for a certain kind of cancer, but it would cost a trillion pounds per dose, we can't afford to do that, right? No matter how great of a treatment. So there are certainly already populations that have been studied for this compound or these compounds where the usual economic analysis, in my view has been met, meaning it's worth it. There's some argument as to where that line is. If it's just for obesity, maybe not. But if it's for obesity and history of a stroke or heart attack, then yes. And so the question is really going to be for whom is it cost effective and can we afford it at what point? And I think that obviously a few things can help with that. One is for the price to come down, which I think will happen inevitably. And two is for us to continue to understand the benefits. So if we understand that these are lifesaving for 50-year-old people, well that adds economic benefits. We might someday find out that these drugs lead to fewer knee replacements, which would be cost saving. So you have to take these things into account. And I think the sort of second and third order effects are things that we're going to be studying. But yeah, I think there are some patients for whom already, and there are probably some for whom it wouldn't be economically wise just to help 'em lose a few extra pounds.

BBC News (10:49):

And then we have in the front pages of some of our newspapers today, Dr. Faust, not just the journalistic focus on what this can do for obesity. There are reports that, well, I'll read from this newspaper. The mind blowing results showed the drugs appear to slow down standard markers for aging in a way no other medication has achieved. Is that true?

JF (11:17):

Well, it depends on what you mean by aging. I mean, I hear terms Fountain of Youth, and I think people imagine waking up one day and looking like they're about ready to go to university again. And I think what they mean by that is that you might be someone who is 50, 60, 70 years old and suddenly you have the risks of someone 10 years younger than that age or that if you go back to having risks you had when you were 30, when you're 40, I think that's what is how I would think about this fountain of youth or markers of aging. But yes, I mean, look, people's cholesterol goes up as they age. There's a diabetes diagnostic blood test called Hemoglobin A1C that rises with age and is how we diagnose diabetes. These drugs have been absolutely incredible in lowering those numbers where other drugs have quite frankly failed. And that is why I'm, like I say, like I mentioned, unusually optimistic about this because it's not like we haven't tried other things and I had to see it to believe it. Again, when I look at these studies, I look at the methods, I look at the data, and these drugs just continue to surprise me.

BBC News (12:31):

So you're seeing this in hospitals, in real patients, the real results from this, are you?

JF (12:37):

Well, look, it's hard for me to say who would and would not have had a heart attack, but when I see a patient who it says that they weigh 140 kilos and I walk in and they don't look anything like that, I have to imagine that the downstream impact of that is pretty impressive. And these studies show that. These studies show that when people lose 10, 20% of their body weight, along with it comes these reductions in these major cardiac events like heart attacks. And I ask patients, how do you feel? And they just say they feel great. I mean, look, there are some who have side effects. And I have seen patients, by the way, who while they were just starting the drug, had those side effects and said, I'm not sure this drug is for me, or I asked to change the dose, and they talk about it with their doctors or refer them back to their GPs, their general practitioners. But yes, I have really been amazed by, I've been noticing this, seeing how they feel and noting what a difference these drugs are making for people. And again, if it can be afforded.

BBC News (13:46):

How much is it?

JF (13:48):

Well, United States, I guess it depends. I think it is over $10,000 a year in the United States right now. But that's not what patients are paying out of pocket. Of course. And then there's also, of course there, there's different formulations and there's going to be government intervention in terms of lowering the price. But yeah, I mean at the moment it's quite expensive.

BBC News (14:11):

And if someone is on it, does it help when you're talking about it's making people feel full, as soon as they stop taking it, do they feel like they need to overeat again or does this retrain the body over time, retrain the mind?

JF (14:30):

So I think it's a little bit of both. And that's an area where I think the research is beginning to look into, for example, these studies go out three, four years, which is pretty good, but how do they do five, six years later? And who among them stops? I've seen data that says maybe that. Basically, I think once people stop taking these drugs, they do start to, not overnight, but they start to, their body eventually might pendulum back a bit, but about one third of patients don't. So those people might just get off the drugs and maybe they'll be able to stay off of them forever. We don't know that. But there's at least a reasonably sized group who that's very optimistic. Then people do gain back some of the weight and with it, their markers that we mentioned could actually get worse. Again, the question is over what period of time and to what extent? And the analogy I would use is if you sort of start on the top of a ladder on the 10th rung and it brings you down to the third rung and you stop taking them, and then over a year or two you're up fourth, you're on the fourth or fifth or sixth rung, well, maybe after a couple of years of that, it's time to maybe go back on it and get down to the third rung again. And so I think that this is an area that's wide open. There is a dogma in the field that says, oh, people should be on these things forever. And I think that that's really untested. I think that's something that yes, we know that some people might have to be on them for long-term or might have to resume them.

BBC News (15:57):

Do children take it?

JF (15:59):

No. Well, I think that children have, maybe--this is not an area where I'm familiar, I'm not a pediatrician. I think there are some children, teenagers who've been given it. But the studies that I've been reading are adult studies. So I wouldn't get ahead on the same benefits because again, I'm sure there are some who've been on it; but even for a morbidly obese teenager, the risks of having a fatal heart attack at the age of 20 is very low. It's really when they go on to be older when those risks crop up. So it's a different conversation.

BBC News (16:31):

Is there an age at which the risk sharply increases? Does that happen in, obviously it can happen at any time, but is there any graph to show? Does it happen on average in your thirties, your forties, your fifties, your sixties? What's the age at which you start to run out a chance?

JF (16:54):

Well, I think it really depends on the person. The studies that have been these big blockbuster studies have been very often middle aged and sort of early geriatric people in their forties and fifties and then some in their sixties and seventies. And that's where the studies have been done, just because quite frankly, in order to do a good study, you have to have enough bad events to prevent, right? If the risk of a heart attack, even in a very, very high risk 30-year-old might be one in a thousand, it's going to be very hard to reduce that in a study. You'd need a million patients. Whereas in a 60-year-old with a history of high cholesterol and diabetes and high blood pressure, maybe that one in a hundred of those people might have a heart attack in a year. And so it's easier to study the effect with that rate.

BBC News (17:44):

Let me double back to one of the basics, just a few more questions, and thank you, Jeremy, for your time. You mentioned in this interview a number of times about how obesity causes inflammation, and I don't actually understand inflammation in the body. I think I know what that means, but is that what is inflammation inside the body? What do you mean by that? What's happening if we're obese?

JF (18:12):

Yeah, that's sort of a catchall term, and it's a term that I understand is sort of understood to be vague, and that's actually kind of intentional. And the reason for that is that obesity and related syndromes, things that come from obesity, have so many prongs of potential risk associated with them that it's really impossible to say that to draw a line like A to B tp C, and this is how it works. It's really for every organ system, it's a little bit different. And for every person it's a little bit different. But a really good example might be that if you're, again, if you weigh a lot, if you weigh more than is healthy, your heart actually ends up having to really work harder, actually literally work harder. And it's sort of being stressed at every beat to push that blood to all the tissues of your body. And as a result of that, the arteries harden up. And so that's through an inflammatory pathway where there's literally a buildup of plaque and of damage to the vessels, and eventually that damage can lead to heart attacks. So that's one example of how being in this hypercaloric state, constantly more calories than the body really needs, can really damage the body. The term inflammation is a catchall for a number of these pathways that over time confer a ton of risk.

BBC News (19:42):

Have you ever been as excited, like you sound, and look, I'm not trying to be offensive, but if I can just say this bluntly, I'm minded to ask you, do you have any type of interest, financial or otherwise in this drug, or is this the most exciting drug you've come across in your career? You sound so effusive about it. I keep on thinking that it couldn't be this good.

JF (20:11):

Yeah. So, I take absolutely zero money from any pharmaceutical company. That is just a badge that I've chosen for myself. And it is really precisely so that in the very rare circumstance where something truly miraculous appears to be happening, that I can speak to these questions without that kind of conflict. And I think that, look, there are people who are experts who take money from these companies, and that doesn't necessarily negate their opinion, but I think it's impossible to know how much it influences their opinion.  

BBC News (20:43):

This the most exciting drug you've seen come up?

JF (20:45):

Yeah. I mean, look, I'm whatever, I've been a physician for a decade plus. I wasn't around when the retroviral combination therapy for HIV came on. I mean, that would've been another amazing moment in the 1990s where AIDS and HIV went from a sure death sentence to a manageable disease. That would've been a bigger moment probably because that was a certain death sentence for so many. But that's kind of like I think about it, when was the last time we had something this big? And I feel like that's one where we think about. Look, I was pretty impressed with the Covid vaccines. These were miracles in their own way. But most of the time when these pharmaceutical companies come out with some treatment and it makes a headline, maybe an Alzheimer's drug has been a really good example recently, and there've even been some other heart disease drugs in the past. It's been a lot of hype. And I think that I always find myself sort of squinting at the studies and finding things to complain about. And the reason that you're sensing my exuberance here is that I'm not seeing a lot of that. I'm seeing really just encouragement, encouraging news, just constantly. So yeah, I am unusually optimistic here.

BBC News (22:02):

Thank you so much for your time, Jeremy. Thanks for talking to us tonight. Really appreciate it.

JF (22:07):

I appreciate the interest. Thanks so much.

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Questions? Comments? Please add your thoughts!