GLP-1s

John: If they decide to take these drugs for weight loss, they really should be reasonably committed to doing it for the rest of their life. And then there are specific pharmaceuticals being developed with an eye to using GLP-1 to get your 50 pounds of weight loss, but then finding a better way of keeping the 50 pounds off.

Brent: Welcome to Death Clock. I'm your host, Brent Franson. Today we speak with Doctor John Buse about GLP-1 agonists like Ozempic and Wegovy. Doctor Buse is a professor of medicine at the University of North Carolina, chief of the Division of Endocrinology, executive associate dean for clinical research at the UNC School of Medicine, and has been extensively involved with the FDA, including advisory committee service.

Brent: He's a published author on more than 500 peer-reviewed papers and the recipient of many honors, including the American Diabetes Association Outstanding Achievement in Clinical Diabetes Research Award. He's a really good guest. He stood up to Big Pharma about 20 years ago and was pulled in front of the Senate Finance Committee. He's also a user of these drugs himself.

Brent: He struggled with being overweight and credits these drugs, GLP-1s and semaglutide, for his weight loss. We talk a lot about its use in obesity, but also in the context of longevity and general health. It's a really wonderful conversation. He's an awesome guest, and we're lucky to have him. Hope you enjoy.

Brent: Doctor John Buse, welcome to the show.

John: It's a pleasure to be here.

Brent: Today we're going to talk about GLP-1 agonists—Wegovy and Ozempic—the drugs where we've had a pretty substantial breakthrough in weight loss, but that are increasingly being used in the context of longevity by people who are not struggling with obesity. So I'm very interested to get your perspective on that.

Brent: Before we do, can you give us a quick sense of your background?

John: Yeah, I am a diabetes care provider and a scientist. I did a PhD in the immunology of type 1 diabetes, but starting in my 30s, I switched over to clinical trials. For approximately the last 35 years, I have been heavily involved in the research that led to the current marketplace of diabetes drugs and guidelines.

Brent: Will you give us the basics in the context of obesity and diabetes first? When we hear the term GLP-1 or GLP-1 agonist, what is that? What does it mean? What is it doing to the body?

John: It's a great question, and there are all kinds of layers to it. The first is to understand that overweight and obesity is probably the major driver of diabetes, but also of many other disabling and life-shortening illnesses—from cancer to cognitive impairment, depression, liver disease, kidney disease, and heart disease. The GLP-1 molecule in the human body and across animal species all the way down to fish is produced by cells in the intestine in response to food intake.

John: And it may really be driven by taste receptors. Receptors inside your intestine detect bitter and sweet much like those in our mouth, leading to the secretion of hormones like GLP-1. GLP-1 acts all over the body to do all kinds of interesting things.

John: It's a short-lived molecule because enzymes throughout the body chew it up in the bloodstream and on the lining of blood vessels. Almost as soon as it gets into the body, it disappears. But it is active in promoting insulin secretion, which is the major mechanism to lower blood sugar after a meal.

John: It works in the brain to improve satiety—that sense of feeling full or satisfied after eating. It works in other tissues to potentially reduce inflammation and basic atherosclerotic processes. The pharmaceutical story started in the late 1990s with a peptide found in the saliva of a lizard in Arizona called the Gila monster.

John: It was demonstrated that this peptide would lower blood sugar without promoting weight gain, and it was developed into a human drug. The earliest studies showed that it flattened blood sugar spikes after meals. Eventually, we had Byetta, and since then, we've developed easier and stronger medications that today are characterized as the most effective blood sugar lowering and weight loss drugs on the planet.

John: The major mechanisms for lowering glucose and weight are separate, and the mechanism for improving outcomes like cardiovascular disease is likewise not entirely a weight and glucose story, but tied to other activities of GLP-1. It's really been a miraculous journey over the last 27 years.

Brent: Okay, so these drugs mimic the GLP-1 hormone that we produce naturally. They help us control blood sugar after meals and help us feel full, which makes them really helpful for weight loss.

Brent: What are the side effects? Whenever we artificially put something into the body, we need to thoroughly research it and make sure the juice is worth the squeeze.

Brent: We can characterize these as big breakthroughs in obesity, but what's the downside? What side effects are we worried about with these drugs?

John: The most common side effects are nausea, vomiting, constipation, and diarrhea. About half the people who take these drugs experience nausea in a 6 to 12 month study. To put that in perspective, 20 to 30% of people on a placebo also report an episode of nausea.

John: About 95% of people can tolerate it. The most important thing about microdosing or gradual titration is that starting with a low dose, increasing slowly, and eating smaller, more frequent meals can minimize nausea and vomiting.

John: The vast majority of people can reach a clinically effective dose. Beyond common side effects, there are less common ones like an increased risk of gallbladder disease, gallstones, and gallbladder attacks, sometimes requiring removal.

John: There is a 50 to 100% increased risk for gallbladder events, representing a few cases per thousand. Then there are rare concerns where it's hard to definitively attribute causation to the drug.

John: There have been reported visual disturbances and rare occurrences of suicidal ideation. Animal studies raised concerns about medullary thyroid cancer, and while clinical trials haven't shown pancreatitis issues, it remains listed on the drug label.

John: I would characterize these as unproven potential side effects to keep in mind. These drugs provide major benefits for high-risk individuals, but because some people may be harmed, you must ensure the juice is worth the squeeze.

John: And the rest of the potential side effects carry less certainty.

Brent: Perhaps that's why these drugs are such a breakthrough in obesity—most side effects involve manageable discomfort like temporary nausea or diarrhea, rather than life-threatening events.

Brent: When weighed against the benefit of treating obesity after previous methods failed, there's an outstanding return on investment.

John: The big excitement is that most people can lose substantial weight on these drugs. Aside from bariatric surgery, few drugs or lifestyle interventions consistently produce these results for most people.

John: They work really well in some people. But these drugs work really well in most people.

Brent: What about bone density degradation or muscle loss? Are there concerns in those areas?

John: Any rapid weight loss can lead to muscle and bone loss. That is an adaptive response: carrying less weight reduces the body's need for dense muscle and bone structure.

John: Excessive muscle loss is largely dependent on the rate of weight loss, dietary quality, and physical activity levels.

John: Muscle loss can be mitigated by ensuring adequate protein intake—at least 0.5 grams per pound of body weight daily—along with regular resistance training to preserve lean tissue.

Brent: Isn't there circular logic there? Strict adherence to diet and exercise is difficult. If someone starts GLP-1s because lifestyle changes were hard, but still needs strict diet and exercise to prevent muscle loss, does that create a tricky paradox?

Brent: Is there a is there a tricky circular logic there?

John: That's simply the reality of health. Proper nutrition and physical activity are essential for everyone. GLP-1s help manage appetite so these lifestyle adjustments become far more manageable.

John: Physicians should monitor patients to prevent overly rapid weight loss that leads to severe fatigue or nausea. In early trial protocols, doses were increased rapidly regardless of symptoms, but today we prefer slower titration aiming for 1 to 2 pounds of weight loss per week.

John: the way the clinical trials did it. So we would ramp up every four weeks. Damn the torpedoes. You know, I don't care how much nausea, vomiting you have. If you're willing to take it, I'll increase the dose. And now we tend to be much slower in our titration, looking for 1 to 2 pounds of weight loss per week maximum.

John: We emphasize protein consumption. Relying solely on carbs and vegetables during weight loss will result in unwanted muscle loss.

Brent: Hitting 0.5 grams of protein per pound is harder than it sounds. At 195 pounds, getting 100 grams of protein daily takes conscious effort.

John: Because GLP-1s reduce appetite rapidly, if you don't start your meal with protein, you may feel too full to finish it.

John: It requires mindfulness. Fortunately, many products now make getting 20 to 40 grams of protein per meal much easier.

Brent: That's a helpful strategy. People often recommend eating vegetables first when hungry to ensure they get consumed, but here the priority is prioritizing protein.

Brent: And then you could, you know, and then you eat less of that pasta or whatever is remaining in the meal. But you're saying, you're saying, hey, get the protein in first.

John: During rapid weight loss, prioritizing protein is critical. I used to weigh 220 pounds and now weigh 155 pounds. Early on, I lost weight too quickly without paying enough attention to protein intake.

John: And shame on me. But, you know, I started a long time ago.

Brent: How are these drugs being used for longevity? There is discussion around reducing inflammation, improving heart and metabolic health, reducing type 2 diabetes risk, and even potential cognitive benefits for Alzheimer's, often via microdosing.

Brent: How do your recommendations change for someone using them for general health and longevity rather than obesity?

John: The best evidence for long-term clinical benefits comes from cardiovascular outcome trials, which follow high-risk individuals over several years.

John: Those trials demonstrated reductions in heart attack, stroke, and cardiovascular death, but not in cognitive impairment or cancer. Higher therapeutic doses consistently yielded better cardiovascular protection than lower doses.

John: There is currently no strong clinical evidence that microdosing extends longevity in healthy individuals. Regarding cognitive health, results from trials evaluating semaglutide in mild cognitive impairment should be available soon.

John: And that's going to be really important, the level of evidence that that's going to work is small. It's really exciting. But it either is going to work or it won't. And it's been hard to develop drugs that reduce the rate, you know, cognitive decline in people with mild cognitive impairment.

Brent: Given the safety profile established in obesity studies, why can't we extrapolate those findings to general metabolic health?

Brent: If someone has elevated A1C levels approaching pre-diabetes, why shouldn't low doses be considered low-risk with potential upside?

John: It's a reasonable hypothesis, but treating healthy, normal-weight individuals with low doses for years is unlikely to show measurable differences in major outcomes over a decade.

John: Young, healthy individuals rarely experience cardiovascular events in that timeframe, and stopping the medication typically reverses its effects within a year or two.

John: However, for individuals with a BMI over 27 (or lower thresholds in specific populations) combined with weight-related comorbidities like hypertension, high triglycerides, or pre-diabetes, the benefits are clear.

John: Trials consistently show benefits across cardiovascular disease, osteoarthritis, liver disease, kidney disease, and sleep apnea for individuals with existing metabolic risk factors.

John: But if you have no problems, it may not provide you the benefit that you hope it will.

Brent: So for someone who isn't classified as obese but is pre-diabetic, it makes sense to discuss options with their doctor.

Brent: If someone has an HbA1c around 6.0%, treatment could be worth exploring.

John: Absolutely. BMI is an imprecise metric. Recent publications emphasize evaluating cardiometabolic health, central fat distribution, triglycerides, and blood pressure rather than weight alone.

John: Addressing underlying metabolic drivers with a single medication often makes more clinical sense than taking separate prescriptions for blood pressure, lipids, and blood sugar.

John: And I, I do think the more of these problems you have, even if it's mild hypertension and a little bit of triglycerides and maybe your liver enzymes are a little bit high, you know, all kind of mild and maybe not something that you would specifically worry about. But once you have 2 or 3 different things, you know, taking care of the root cause, dealing with the whatever level of overweight you have makes it a lot more sense than taking one medicine for pre-diabetes, and one medicine for high triglycerides and one medicine for, a little bit of hypertension.

John: In my case, I had several of those mild risk factors, and they resolved after treatment.

Brent: Do you attribute your weight loss primarily to GLP-1 agonists?

John: Yes. While I was mindful of diet, I had previously gone through 20 cycles of losing 10 to 15 pounds only to regain it.

Brent: So GLP-1s helped break the cycle of weight regain?

John: Yes. Despite my professional knowledge, long-term weight maintenance was extremely difficult until I started semaglutide (Wegovy).

John: It normalized my relationship with food, making weight maintenance straightforward.

Brent: Studies show that structured diet and exercise intervention programs often yield modest long-term increases in physical activity.

Brent: I'm probably screwing up the stat, but it's something that's like more depressing. Than than you would hope. Especially given that like perfect infrastructure. And in some of these studies.

John: Lifestyle modifications work well for some, but fail to maintain results for most people over time.

Brent: Does taking GLP-1s alter alcohol consumption habits or cravings?

John: In my experience, yes. I used to average two or three drinks during social events, but now I usually stop after one.

John: Now, if I go out, I'll generally have one drink and rarely two. And in the one drink that I have is mostly because everybody else is drinking. And I just, you know, and I like the taste. But anyways, yeah, I drink a lot less than I used to, and.

Brent: So the impulse subsides naturally without requiring strong willpower?

John: Exactly. It removes the constant mental struggle and cravings associated with caloric restriction.

John: Satiety signals take effect quickly, allowing you to easily stop eating mid-meal.

John: As weight stabilizes, appetite partially returns, settling into a healthy, manageable equilibrium.

John: I'm going to gain on my weight back. But eventually when you get to a new steady state, you have this sort of normal relationship with food where you I do mindfully have breakfast, I have lunch, I actually end up skipping dinner probably twice or three times a week. So I just don't have any appetite. And I've done a good job of getting my protein during the day.

John: It simplifies weight maintenance significantly without persistent nausea or discomfort.

Brent: If patients discontinue treatment, is there a high probability of regaining the lost weight?

John: Patients considering GLP-1s for weight loss should view it as a long-term commitment. Studies indicate over 50% of lost weight is typically regained within a year of stopping.

John: New therapies are currently being explored to help maintain weight loss after initial reduction with GLP-1s.

John: But then this might be a a better way of keeping the 50 pounds off.

Brent: Years ago, you publicly raised cardiovascular safety concerns about a drug, which led to significant pushback before your findings were validated by the Senate Finance Committee.

Brent: What is your current view of pharmaceutical industry practices regarding GLP-1 medications and high U.S. pricing?

Brent: And, you know, I wouldn't go there, but there is a role that pharma has in terms of money and the bottom line. And a lot of times that's great for us. They spend a lot of money on research and they develop these drugs and we benefit from these drugs. It does seem that there are cases where that goes wrong and the money, and the profit incentive end up being bad for people.

Brent: You know, that you've got to be a whistleblower. So so thank you for doing that. But what's your role, what's your sense of are the pharma companies playing well here as it relates to these drugs? The prices are really high. How is Big Pharma doing a good job here or how are they maybe contributing to pushing things in a way they shouldn't?

John: Primary developers like Novo Nordisk and Eli Lilly have operated ethically in this space. While U.S. pricing is excessively high due to systemic healthcare structure issues, international prices remain much lower.

John: They're they were pioneers in the development of insulin. You know, the critical drug going back to the 1920s, you know, my sense is they've acted very ethically. The price is way too high. But there's a whole scandal around drug pricing, particularly in America. The price is not way too high in the rest of the world. I actually once shopped overseas for a drug because I could get it, less than a third of the price.

John: As competition increases from dozens of compounds currently in development, market pressure will naturally drive down costs.

John: Given the global addressable market, sustainable high-volume, lower-margin models will emerge over time.

Brent: Yeah. Low margins, lots of scale. And you make, you know, you make a little bit of money per patient, but you just have a lot of patients. And so that adds up a.

John: Few billion patients. And you make $10 a year off of a few billion patients has serious money.

Brent: So your perspective is not on the high prices question. It's not that the executives at these companies are like cackling in their mansion in Aspen as they as they, you know, crank up the prices here. It's look, the U.S. system is a very complicated system that increases the prices of of drugs for a whole bunch of different reasons.

Brent: And that system and the complexity of that system is what's to blame for the high prices. But that competition is coming. There's so much demand for these, and competition is going to naturally drive down those prices. And so help is on the way. And if anything, Eli Lilly, Lilly and Novo Nordics look, they've been pioneers here. They've been pouring money into this.

Brent: And this is this is an advancement that's very good for the world. And so no huge company is going to be perfect. But but, on balance, you know, they're they're doing the best they can.

John: As a disclosure, I consult and conduct clinical trials with these pharmaceutical companies. Systemic reform is needed in how the U.S. healthcare framework manages costs and preventive care.

John: You know, we do not have a health care system. It's purely about health care. And it's definitely not a system. It is a financial, you know, it is a huge business in the United States. It's nearly 20% of the gross domestic product of the United States.

Brent: But it's a sick care system. I mean, the only the only pushback I ever have on this point specifically is are we pretty good at reactive care? Like, would you rather get hit by a car and somewhere else in the world than you would here? Or would you rather get a really bad cancer diagnosis somewhere else in the world than you would here?

John: You know what I would say to that is, you know, those two examples, and I just don't know enough about cancer to say for sure. But yeah, if I were diagnosed with cancer today, I would much rather be diagnosed here in Chapel Hill, North Carolina, with our Lindberg Comprehensive Cancer Center. Than I would like to be diagnosed in Martinique.

John: While acute specialized care in major U.S. institutions is exceptional, population-level preventive health coverage remains fragmented and inequitable.

John: If you're willing and able to pay big money to get the best possible care, and fly yourself to the Mayo Clinic to kick it really good care in the United States. But that's not what we should aspire to as a country. We should aspire so that every citizen gets good care. And, you know, if you're a billionaire and you want to spend extra to get, you know, great care, so be it.

John: But we shouldn't have a system where basically a third of people get no care just because they don't have insurance or they don't, you know, they, they don't have access to, a health care provider in a rural area. You know, we could set up the system to be much more equitable and we could cut the costs that we spend for a GLP one receptor agonist by 30 to 90%.

John: I mean, the same drug that here. Now you can get it if you pay cash for $500, in Europe, you can get it for $100 a month. And the insurance companies are paying $1,000.

Brent: Yeah. I mean, totally agree. It. You know, the best way to treat a disease, it seems, is just to prevent it. We're terrible at preventative, care. We're riddled with chronic disease. And then I frankly think it's an awesome thing that people like you, whistleblowers, people who are willing to stand up to, you know, when when you see some bad behavior are also the ones who are, you know, they're coming to you and consulting with you and working with you.

Brent: I think that's that's great.

John: You know, I do think in many walks of life, but it is true that the best thing you can do is hold your critics close, listen to them, make sure that they're heard and that their, their issues are being addressed. And I, I do think the, the pharmaceutical industry, is pretty good that there's a lot of different voices, that are providing input, to the developers of these drugs as they move to the next generation agents about, you know, what is it that providers what what is it that patients want?

John: You know, what would be a clinically meaningful difference? How are you going to sell this drug if there's 40 different competitors? Why is this one going to be special? So they're getting a lot of input there. You know it it costs probably $2 billion to bring one of these drugs to market. And with 40 of them in the pipeline, you know, they are being extremely mindful about how to compete and provide value in the marketplace.

Brent: Thank you so much for your time. Thank you for your work. I found the story, I think, as I've said here, of you standing up for the cardiovascular issues to be really inspiring. Where can we find you or where would you point us in terms of, of a resource if we want to know more?

John: The American Diabetes Association, the Obesity Society, and the American College of Endocrinology offer reliable patient educational resources online.

John: There is a lot of garbage out there. Too. And, you know, I wish I, I wish I had thought about this more, and done a little bit of homework to find out where the best thing is. You know, I tend to use the sort of medical press, but they that's probably not appropriate for many of your listeners.

Brent: Thank you, Doctor John Buse. We appreciate your time and contributions.

John: It's a pleasure. It's been really a lovely chat.

Brent: Death Clock is recorded in Boulder, Colorado, and San Francisco, California. Produced by Patrick Gudino, music by Patrick Lee, and hosted by Brent Franson, founder and CEO of Death Clock.