The Story Behind the ‘Miracle’ of GLP-1 Medications: Dr. John Buse, Chief of Endocrinology at University of North Carolina School of Medicine

Lindsey Smith

Hi, I'm Lindsey Smith, welcoming you to Raise the Line with Osmosis for Elsevier, an ongoing exploration about how to improve health and healthcare.

One of the biggest stories in medicine over the past few years has been the arrival of GLP-1 receptor agonist medications such as Ozempic, which have proven to be effective in treating type two diabetes, promoting significant weight loss, and reducing cardiovascular risk.

Today we will learn from Dr. John Buse, a world renowned diabetes researcher, about how these drugs came to be and the difference they're making for patients as he's played a key role in ushering in this new era of diabetes care. Dr. Buse is a distinguished professor at the University of North Carolina School of Medicine where he's also chief of the Division of Endocrinology and director of the Diabetes Care Center.

As a physician scientist for the last three decades at UNC, Dr. Buse has led or participated in over two hundred clinical studies spanning early stage drug development to large scale outcomes trials, has authored more than five hundred publications, and has maintained a clinical practice as well.

Thank you so much for joining us today, Dr. Buse.

Dr. John Buse

It's a pleasure.

Lindsey 

I'd like to start by learning more about you and what first got you interested in medicine, particularly endocrinology.

Dr. Buse

That's a long and sordid tale. My parents actually met during an endocrine fellowship. So I was kind of born into the role. But as many children do, I decided that I to move in a path away from medicine and actually thought I would do something like the State Department. Jimmy Carter was elected president and I thought the world was safe for democracy. And I struggled mightily as a government and comparative literature major. So I ended up doing a biochemistry degree and decided to pursue medicine.

I started in the MD-PhD path also almost by happenstance but I knew that I didn't want to do endocrinology because my parents were endocrinologists and they would quickly sniff out my weaknesses and that I wasn't nearly as good a student as they thought I was. But I was doing research on immunology as a preparation for going into cancer as my field and was working with a rat model of autoimmune type one diabetes and just fell in love with diabetes.

Primarily because these rats would develop type one diabetes and I'd come in in the morning and they'd be laying on their side panting with sort of glazed over eyes and matted fur, you know, soaked with urine, sticky, you know, they were just a mess. And I'd give them a shot of insulin and come back three hours later and they were bright eyed, bushy tailed, they looked like a million bucks. I mean, it was a miracle, the miracle of insulin. And so that's what really hooked me in endocrinology was being a rat doctor.

Lindsey

Yeah, well that's a really great story. I appreciate you sharing that with us. I'm always interested by how those early experiences can really kind of shape anyone's path into medicine. And as a follow-up question, when did you know you wanted to pursue an academic and research path in medicine? And secondly, how do you balance it all, being a clinician, educator, and researcher today?

Dr. Buse

Yeah, another sordid tale. So I had done a fair amount of research going all the way back to high school actually and loved being in the lab with people that were focused on a question. I liked a lot of the mechanics, you know, being meticulous in your washing of glassware, being meticulous in the way you conducted the experiments. You know, it's like being a chef or being a violinist that there's sort of precision to what you can do. It was just a really interesting place to be.

So I was a bit hooked on research. And as I went through my career as a basic scientist, I had a little detour where I was asked to be a chief resident, which is where you are sort of the head clinician for all the residents. You hear about all the great cases. You're actively involved in teaching medical students and residents and I fell in love with that as well, the idea of being a master clinician.

I recognized that it was hard to be a master clinician and be a master basic scientist and I thought it would be easier to just focus on clinical research and throw down the middle of the lane and, you know, that worked out for me. It's a lot easier to do experiments with rats than with people.

Lindsey

Right, right. Well, that's really impressive. And it sounds like a lot of your roles kind of feed into each other. I know the big hot topic for today is GLP-1 drugs. Before we get into it, I wanted to see if you can give us some background on how diabetes care looked before these newer drugs were introduced and how you describe their overall impact on the field.

Dr. Buse

Yeah, I'll give you a long-term view. So this comes from my mother and father who started out in training in the 1950s. I remember my father telling me that in the nineteen fifties and sixties that people with diabetes were the most miserable folks in the hospital. They were often blind, they had amputations, they were dying of renal failure because there was no dialysis, they were, you know, having heart attacks and strokes and it’s just a terrible, terrible man-eating disease and the treatments were just hard to use -- primarily insulin or exclusively insulin until the mid to late nineteen fifties -- without glucose monitoring. So you can imagine how tricky that was to do.

By the time I went to medical school in the mid nineteen eighties, things hadn't changed much. There were plenty of people whose first presentation of diabetes was coming in with renal failure, ready to start dialysis, or coming in with a rotting foot that needed amputation, or coming in having acutely lost vision in one eye. We didn't screen for diabetes. We didn't recognize it early.

In the nineteen nineties, the DCCT trial was published and it showed that if you took patients with type one diabetes and treated them intensively with multiple daily injections or some patients even with insulin pumps as opposed to the way that diabetes was treated usually, which was one or two shots a day, not a lot of glucose monitoring. But anyway, the DCCT trial showed a dramatic reduction in the risk of complications over time and the ability to engage patients as being sort of the master of their disease.Before that, doctors told patients what to do and then fundamentally they didn't do it because the things that you are telling people to do, change your diet, change your activity, take this much insulin at this time of day, eat this way, that's just really hard for people to do twenty-four seven.

We evolved in the DCCT trial to giving people a lot of education and support and saying, this is how you might manage having a piece of cake at your birthday, this is how you might manage this, that and the other...giving people a lot of flexibility, teaching them adaptability. And that was the beginning of the modern journey, which has gone into overdrive since nineteen ninety-five when we started to develop new drugs for the treatment of primarily type two diabetes pretty much every year or two since then. So the pharmacology or the options in our toolbox have dramatically improved since nineteen ninety-five.

Lindsey

That's a really helpful overview. Thank you for setting the stage so well for us. So I want to shift our focus over to GLP-1 drugs. They're in the news a lot and they're generating a lot of buzz lately and notably your site was the first in the country to administer them. Can you explain how GLP-1s actually work inside the body?

Dr. Buse

Yeah, and just to clarify, GLP-1, the hormone, was studied in a number of labs across the world, but it was a professor, John Eng, in New York City, who first discovered a drug from the saliva of the Gila monster, a big lizard that lives in Arizona, that would last for hours after injection. The native GLP-1 drug is essentially instantly eliminated.

What was discovered about native GLP-1 and then exenatide — the first of the more stable GLP-1 analogs or GLP-1 receptor agonists — most importantly, they work in pancreatic islets to stimulate insulin secretion in a glucose dependent fashion. And that was magical because until then, all the drugs that stimulate insulin secretion do it in a glucose independent fashion. So if you give too much, you would end up with hypoglycemia. So that's the case for the sulfonylureas. This drug, if the glucose is high, it stimulates insulin secretion. If the glucose is low, it doesn't stimulate insulin secretion. So it doesn't cause hypoglycemia. 

Secondly, it suppresses glucagon. And it also does that in a glucose dependent fashion and hyperglucagonemia or too much glucagon is also a weird little quirk of type two diabetes and even type one diabetes in part because normally in the islet, insulin suppresses glucagon, but they have reduced insulin secretion. So they have reduced glucagon, increased glucagon. But anyway, so it also reduces glucagon.

And then more importantly today, at higher doses and with agents that are tweaked in a way that they can get into the central nervous system, they enhance satiety or that feeling of fullness after meals. Now sometimes that enhancement of satiety starts to spill over into just flat out reducing appetite, making people not hungry at all.

With the short acting agents there's a fourth effect to slow gastric emptying. And with the longer acting agents, that effect tends to be diminished over time through a process called tachyphylaxis. So that response tends to diminish with continued exposure beyond a couple of days.

Lindsey

Thank you for sharing that summary. So am I correct in thinking that the GLP-1 drug works by kind of mimicking that natural hormone that helps regulate the blood sugar, slows digestion, reduces appetite, which then in turn kind of leads to that improved glucose control and eventually weight loss?

Dr. Buse

Yeah, so the first one, exenatide from the Gila monster, that was a Gila monster protein. Interestingly, it's not even the Gila monster's GLP-1, but it has about fifty percent homology to human GLP-1. All the other drugs that we've developed are either GLP-1 analogs, so it's basic GLP-1 structure with a few substitutions to change some of the details of how it's metabolized, or a fusion peptide where they've taken GLP-1 and stuck it onto something else to prolong its half-life or change how it functions.

Lindsey

Fascinating. So as I understand it, these drugs were originally developed to manage type two diabetes and the benefits of weight loss and cardiovascular risk were somewhat unexpected. Can you confirm if that's correct? And then from your perspective in doing all the research, is that how you would describe it?

Dr. Buse

Yeah, I'd say it was a little bit unexpected and I would say in the beginning it was more unexpected, but there were some people who figured it out quite early, certainly by the early 2000s. So with the native GLP-1, it was hard to create drug levels that were very high, but they did know about this gastric emptying effect, and they did know in animal models that it certainly didn't promote weight gain, which most of the diabetes drugs did, and that it was associated with somewhat lower weight, but they hadn't done really long-term studies.

I think the surprise was really how much weight loss could be produced by tweaking this molecule serially as we went from exenatide to liraglutide to now the super effective semaglutide and tirzepatide, and also the cardiovascular benefit. Some people had hypothesized that maybe for the first time a diabetes drug would provide a cardiovascular benefit. Till then, that had never been demonstrated because it lowered glucose, it lowered blood pressure, it improved lipids, it was associated with some weight loss in early studies. So it was kind of a dream, but certainly not an expectation.

Lindsey

So we've highlighted some of those benefits and now I want to see if you can walk us through potential risks, especially in terms of side effects and any safety concerns that we should be aware of.

Dr. Buse

Yeah, so the primary side effects are GI side effects. In about forty percent of patients with six months of therapy, they have at least one spell of nausea. So more than fifty percent have no spells of nausea. There's about five percent in very carefully treated patients to maybe ten percent that have vomiting as well, and enough vomiting or enough nausea and vomiting that they stop the drug. There are some patients that get into trouble as well with constipation. That tends to be a side effect that's less likely to go away with time. The nausea and vomiting almost always resolve relatively quickly once you're on a stable dose, but the constipation can be persistent. 

And a sort of newer, more emerging issue is that some people actually get to sort of more the obstipation phase where they are just plugged up and have had pretty serious problems that require medical intervention to deal with severe, severe constipation. Gallbladder disease is increased with GLP-1 receptor agonists, including the need for cholecystectomy or gallbladder removal. That's been reported with, I think, every weight loss strategy, probably due to a change in the way that bile acids are metabolized and handled. But anyway, that is one for sure side effect of the GLP-1 receptor agonists.

And then if you read the package insert of the drug or you pay a lot of attention to the medical literature, there's a lot of other stuff that isn't quite nailed down as to really how much of an increased risk there is or is there really an increased risk. But things that we think about all the time are pancreatitis, or inflammation of the pancreas, which can be a really serious, serious problem.

In the big studies, if you exclude people who already have pancreatitis in the patients that are enrolled in the trial, there was no increased risk of pancreatitis, but there's certainly lots of people with diabetes who develop pancreatitis on GLP-1 receptor agonists, but also lots of people with diabetes get pancreatitis anyway.

A more recently emerging area of concern includes eye problems, because these are the most powerful glucose-lowering drugs on the planet. You can go from really high blood sugars and hemoglobin A1C to flat out normal levels of glucose very quickly, and that's been reported with insulin to also be associated with accelerated retinopathy. So we are very careful now that we understand this to make sure people are having their annual indicated eye exams anyway, and then before you start the drug and if they have any abnormality that requires medical attention, to go ahead and do that first before you start a GLP-1 receptor agonist. Some weirder, more exotic eye diseases have also been reported. 

There are some concerns about suicidality, which is a little bit unclear whether there's an increased risk or not. Probably not, but now we tend to screen for advanced depression and suicidality before treating patients with diabetes. So there's a host of things that we worry about, but those things beyond the gallbladder disease, the nausea, and vomiting aren't exactly nailed down.

The thing that isn't really discussed much as a side effect is the idea that you can lose weight too fast and because of the way you lose weight, you may lose a lot more muscle than you would like. There are people who end up losing too much weight. They get to be sort of physically ill from weight loss. So careful management of patients and staying in touch with them, and aiming for a pound or at most two pounds per week of weight loss, going up slowly on the dose — those kinds of things can mitigate these problems.

Lindsey

I think it's really important to understand both the benefits and the risks, and you've given us such a balanced overview of both of those. So GLP-1 drugs have clearly made a big impact in diabetes and obesity care today. I want to know from your experience, how have patients responded to these medications, and what have their journeys looked like?

Dr. Buse

Yeah, I mean, it's kind of a miracle, frankly. You know, the one benefit of being an old guy that's been involved in the field for a long time is from my mom and dad's era in the nineteen fifties to when I really started out as a full-fledged endocrinologist faculty member, there hadn't been a lot of change in diabetes. Then we got metformin and the thiazolidinediones, which really made it a lot easier to treat diabetes. But nothing has impacted diabetes care like the GLP-1 receptor agonists and another sort of newer class of drugs called the SGLT2 inhibitors.

The real miracle there is that we're changing the natural history of the disease. So we have less heart failure, less kidney failure, people are having less knee pain related to their weight loss. People with obstructive sleep apnea find that it's going away. People with fatty liver disease have resolution of their fatty liver disease or slowing in progression. So these are disease-modifying drugs in the way that certain of the immunologic agents are disease-modifying drugs for rheumatoid arthritis or for inflammatory bowel disease, that sort of thing. So it's not just treating the disease, it's changing the trajectory of the disease.

I have lots of patients who were heavy and their diabetes was never well controlled and they had high blood pressure, which was tough to treat, and just a host of problems who on these highly effective GLP-1 drugs have lost twenty percent, thirty percent of their weight and basically all their metabolic problems are resolved or essentially resolved. And you know that’s just a miracle. 

Now that doesn't happen for everybody. Lots of people need additional therapy, not just the GLP-1 drug, but other things. But our ability to manage diabetes to the point where I don't think it's going to be a problem in their lives — meaning I don't think they're going to go blind, they're not going to have an amputation, they're not going to have an early death related to heart attacks or strokes, etcetera — I think we are at a place where diabetes is kind of on the ropes and we have the opportunity to just knock it out. It’s a problem that you’ve got to take care of, but not something that's going to leave you disabled or lead to an early demise.

Lindsey

It sounds like this has been a game changer for your patients. You mentioned something about additional therapies. Can you come back to that point and what that might include?

Dr. Buse

Yeah, so this is a huge debate now in diabetes. Historically in type two diabetes, metformin has been the sort of base therapy — lifestyle intervention, dietary counseling, increasing physical activity, and metformin. Now there's a real debate about what drugs should we really use first.

It's hard to fault using metformin as a first-line therapy because it's so inexpensive and it has a lot of good features to it. But these GLP-1 receptor agonists, because of their disease-modifying effect and the fact that essentially everybody with type two diabetes is at least overweight — not quite everybody, but the vast majority — and most are frankly obese, the advantages of GLP-1 receptor agonists kind of trump using metformin.

And the SGLT2 inhibitors also are disease-modifying therapies, particularly for the risk of kidney failure and heart failure in diabetes, which is very high. So there's an opportunity to also use those agents. I think more often now — often for cost reasons and insurance coverage — we start with metformin, but what we really want to get to is the GLP-1 receptor agonist and SGLT2 inhibitors.

You know, the one thing I didn't mention as far as side effects is the fact that these are expensive drugs and so many people can't afford them. There's great disparity in our use of these agents as a result of it. There are programs to help people who can't afford these drugs or don't have insurance coverage to be able to access them, but that takes time from doctors and healthcare systems and pharmacists to sort out. So we're working on making it more accessible, but that remains a problem.

Lindsey

I'm glad you touched on that accessibility piece and also just how far we've come and the different approach to treating diabetes. I want to talk a little bit about Osmosis, our company, and at Osmosis we love creating content that fills knowledge gaps. Is there a topic you think we should cover that's especially important or interesting to you?

Dr. Buse

You know, the question that I struggle with—I mean, there are many questions I struggle with—but the question that I think we need to come to a resolution on now is what should the target of obesity management be in diabetes and in general? Some people say it should be based on BMI. It's not a great measure. Should we make it based on fat mass? Or should we make it based on what metabolic problems occur? Like if you lose enough weight to where your diabetes and your liver disease and your osteoarthritis are well managed, is that enough? Should we be aiming for a BMI of twenty-five or twenty-three or twenty-seven or less than thirty?

We don't have guidelines for that like we do for hypertension or diabetes or lipids, cholesterol, triglycerides. We have recommendations that you should achieve an LDL cholesterol of less than fifty if you have coronary artery disease and less than one hundred in general if you are fairly young and only have a risk factor. We have sophisticated guidelines for people with other problems, but with obesity, because we never really had very good drugs, all we say is you’d like to lose five to ten percent of your body weight, at least in the setting of diabetes.

But the truth is, if you start very, very heavy, you're definitely going to want to lose more than five to ten percent of your body weight. We need a more sophisticated way of targeting weight management in diabetes. There are great opinion leaders that you could talk to who might grapple with that question for you.

Lindsey

Absolutely, that's a great suggestion and we're always looking to spotlight areas that deserve a little more attention. I think that's a perfect one. At Osmosis, we have many students and early career professionals in our audience. I want to ask you what your advice is to them about meeting the challenges of this moment and approaching their career in healthcare.

Dr. Buse

Yeah, you know, I'll just tell you what happened with me. There were challenges in my career, in particular as I was starting to transition from being a fellow to being a faculty member. That was the time when the last big constriction in NIH funding occurred in the early nineteen-nineties.

I think the most important thing is to be open to the moment. Every major career decision I made, in retrospect, I feel glad that I made them. In retrospect, I always made the right decision for the wrong reason. Meaning that I thought one thing, but it turned out that wasn’t really what was important. I enjoyed doing what I was doing and just moved from opportunity to opportunity. Be engaged. If you decide to pursue an academic career, patients will give you so many ideas about things that could be done differently or questions like why do you do this or that. Those are great topics for focusing your research endeavors on. I wholly embrace the idea of physician-scientists—the idea that your patients will inform your science.

For PhD scientists, I think it’s great for them to have clinical collaborators they can engage with. If you don’t want to take a deep dive into research, at least hang out with people who are doing research and give them your great ideas. If nothing else, send them an email. Don’t be embarrassed. There’s no such thing as a bad question or a bad idea. There’s one that people may not pursue, but it will make your life more interesting in any case.

Lastly, with the current mayhem, keep your head down and keep doing what you do. We’ll work through it. In my circle of medical students, residents, fellows, and junior faculty I’ve worked with, I have never had a trainee who failed. I have had many who bailed—meaning that they decided this is too hard, or I’m not good enough. Just power through. You’re good enough. It’s not too hard. Sometimes you have to make difficult choices, but don’t stop doing something because you think you will fail. You will not fail.

Lindsey

So many good nuggets to pull out from that advice. A few that I captured just to play that back—be open to the moment, be engaged, remember patients can be the source of ideas, inspiration, and research, and keep doing what you’re doing. I really appreciate you sharing that with our audience today. Before we wrap up today’s episode, is there anything that we didn’t cover that maybe we should have?

Dr. Buse

Well, I was thinking as you were asking other questions that the one thing I didn’t put a fine enough point on is when you think about the adverse effects of GLP-1 receptor agonists, which get a lot of press now, we need to remember the benefits. So if there’s a one in a thousand or one in ten thousand chance that you’ll have this horrible eye disease, you need to be aware that’s a possibility.

If you’re at high cardiovascular risk, there’s a thirty percent chance of reducing your—or a twenty percent chance of reducing your—risk of heart attack, stroke, or cardiovascular death. You always need to think about things in balance. There is no free lunch. Everything has its costs. It’s just a matter of balancing those costs and benefits on an individual patient level and making sure that the patient is engaged in the decision-making as you move forward.

Lindsey

There is no free lunch. I like that to wrap up today’s episode. Thank you so much for being with us today, Dr. Buse.

Dr. Buse

It’s a pleasure.

Lindsey

That’s it for today’s episode. I want to thank Dr. John Buse for sharing his deep expertise and insights into the transformative impact of GLP-1 receptor agonists on diabetes care. It’s clear that we’re entering a new chapter in how we treat chronic conditions, and hearing from someone who’s helped shape that journey has been truly enlightening.

I’m Lindsey Smith. Thanks for checking out today’s show. Remember to do your part to raise the line and strengthen the healthcare system. We’re all in this together.