“These drugs, when taken by patients with clinical cardiovascular disease, reduces the risk of heart attack, stroke, and cardiovascular death. And, for patients with chronic kidney disease, it reduces the progression of kidney disease over time.”
-Dr. John Buse describing benefits of SGLT2 inhibitors
Ron Falk, MD: Hello, and welcome to the Chair’s Corner from the Department of Medicine at the University of North Carolina.
This is our series on new treatments, and today we will discuss new treatments available for people who have diabetes.
We welcome Dr. John Buse, the Verne S. Caviness Distinguished Professor of Medicine and Chief of our Division of Endocrinology. He directs the UNC Diabetes Center and the North Carolina Translational and Clinical Sciences Institute – NC TraCS. Welcome, John Buse.
John Buse, MD, PhD: Thank you very much.
Benefits of SGLT2 inhibitors
Falk: Let’s start by discussing a series of medicines for type two diabetes, specifically the new SGLT2 inhibitors—which, you’ll have to tell us what that means in a moment. Patients may recognize the names “Jardiance,” “Invokana,” and “Farxiga.” Please tell us what SGLT2 really stands for, and what is exciting about these new drugs.
Buse: SGLT2 stands for sodium glucose co-transporter 2, and these drugs are inhibitors, so they block that molecule. You’re going to love this—this involves the kidney. The way the kidney works (endocrinologists view) is that the juice in the blood space is squeezed into the urine space through the glomerulus, and then all of the good stuff is reabsorbed back into the blood space. One of the “good stuff” that is reabsorbed is glucose. These SGLT2 inhibitor blocks the reabsorption of glucose, so you pee sugar. By peeing sugar, you reduce the blood sugar in the setting of diabetes, you lose calories—so it actually promotes weight loss, and you also lose a little bit of salt with that sugar. As a result of that, it also reduces blood pressure.
What’s really exciting is that over the last three years—and most recently just in October—we have additional data that these drugs, when taken by patients with clinical cardiovascular disease—people who have had strokes or bypass surgery, or have angina kind of symptoms— it reduces the risk of heart attack, stroke, and cardiovascular death. And, for patients with chronic kidney disease, it reduces the progression of kidney disease over time. This is one of the first classes of drugs in diabetes to really show that it changes basically how things turn out for people with diabetes, more so than just changing blood sugar.
Falk: It’s an exciting development, and it’s exciting that there are three versions of drugs that inhibit the same receptor.
Buse: Right, and we’re just beginning to understand the kidney disease part. There are additional big trials that are going to be released in the next few months that promise even more impressive outcomes with regards to kidney disease.
Falk: In terms of preventing the progression of chronic kidney disease to end stage, or dialysis-dependent kidney disease.
What are the differences between those three new drugs?
Buse: As far as their blood sugar effects, not much. There is a concern with Invokana, that perhaps it increases the risk of amputations—primarily losing toes. That needs to be taken in the context of saving lives, preventing heart attacks and strokes. In general, if there really is a problem with increased risk of amputations, it’s a much smaller problem than the benefit of reducing the risk of heart attacks and strokes.
Falk: Is that only true for Invokana, or is it also true for Jardiance and Farxiga?
Buse: To date, we have not seen the signal with the other two, but there is a little bit of debate about whether the studies have been done exactly the same way. To date, Invokana has the problem of amputations, and they also seem to have a problem with a bit of an excess in bone fractures. Again, we don’t see that with the other two, and how important that difference is, is really under debate.
Falk: In other words, it’s a statistical difference, it’s not clear whether it’s clinically applicable to an individual who is already on that drug and doing well.
Buse: Exactly, and the risk of amputations is mostly in people who have already had an amputation or they have severe neuropathy or nerve damage. Their feet have very advanced vascular disease. People who are already concerned about their feet might stay away from Invokana, but the other two—Jardiance and Farxiga seem to be fair game.
SGLT2 inhibitor side effects & weight loss
Falk: Are there side effects from these new drugs?
Buse: Remarkably, very little. The major issue is yeast infections—vaginal yeast infections in women. It’s about one in ten women will have a vaginal yeast infection on these drugs, generally in the first couple of months, and about one in ten of those will have a second episode, and about one in ten of those—now we’re talking about one in a thousand will have recurrent episodes. In the grand scheme of things, not a lot of trouble.
Some people, because they do have to pee more as a result of losing the sugar through the urine, are bothered by having to get up at night more than they did before. If you’re getting up twice a night, you might find getting up three times a night, to be really annoying. In general, most people tolerate it very well.
Falk: How much weight on average do people lose once they start taking these drugs?
Buse: It varies, but in general, I tell people three to five pounds on average. Some people lose twenty or thirty pounds. The amount of sugar that you lose in the urine is in part dependent on how high your blood sugar is, but also on how good your kidney function is. Younger, healthier patients in general may lose a bit more weight than older people with more advanced kidney disease.
Falk: How low does the blood pressure drop? Is it a significant drop in blood pressure?
Buse: In most people, it’s pretty modest—three to five millimeters of mercury.
Falk: Osmotic diuresis is what’s occurring here.
Benefits of GLP-1 receptor agonists
Falk: There is another class of drugs used in people with type 2 diabetes, these are called GLP-1 receptor agonists. Patients will be familiar with the names such as “Victoza” or “Ozempic.”
Buse: There’s also one called “Bydureon” and “Trulicity”. There’s a bunch of these.
Falk: What are GLP-1 receptor agonists, and how do they help, and do they also reduce cardiovascular risk—heart disease risk— and help in preventing the progression of kidney disease?
Buse: GLP-1 stands for glucagon-like peptide 1. It’s a hormone, like insulin, but different. It’s made from the intestine in response to meals. What it does is it stimulates the body’s own production of insulin. In diabetes, there are two problems: insulin doesn’t work very well, and we don’t make enough of it. This helps you make enough of it. It also has some effects on the brain to promote what we call satiety—it makes you feel more full when you eat a meal. As a result of that, you also get weight loss.
Falk: How much weight loss do you get with this class of drugs?
Buse: A little bit more—more like five plus pounds. Some people will lose fifty pounds. Actually, a high dose of Victoza is marketed under the trade name Saxenda is probably the most effective weight loss drug in America. That’s more like ten to fifteen pounds of weight loss on average. In any case, these drugs lower blood sugar, arguably they’re as powerful as insulin in the glucose-lowering department, but they don’t cause hypoglycemia or low blood sugar. It promotes weight loss, and also has a small effect on blood pressure.
Once again, these drugs have been shown to reduce the risk of heart attack, stroke, cardiovascular disease, and reduce the rate of progression of kidney disease.
That said, the GLP-1 receptor agonists seem to be particularly good at modifying the process of atherosclerosis—the process by which we develop heart attacks and strokes, blockages in arteries. Whereas the other drugs we talked about, the SGLT2 inhibitors seem to be particularly good for heart failure and for kidney disease. They’re both good for both. But in general, the GLP-1 receptor agonists are better for atherosclerosis, and the SGLT2 inhibitors are better for heart failure and kidney disease.
Treating a new diabetes diagnosis
Falk: When you see a person with diabetes for the first time, are you going to start these drugs—one or the other—before other kinds of therapy?
Buse: Well, right now, we don’t have any evidence that for people who don’t have any problems with their heart or their kidneys, or blockages in their arteries, for people who are clean in that regard, we don’t have any evidence that there’s extra benefit from these drugs. Now that said, these are the only two drug classes for diabetes that really provide substantial weight loss. They’re great blood sugar-lowering drugs, and they lower blood pressure, so they have a lot to recommend them. If you haven’t had problems with your heart, and you don’t have problems with your kidney, there’s probably not an extra-special benefit of these drugs.
Falk: If there is an extra special benefit—you have had kidney disease, you know you’ve had problems with your heart, are these now first-line drugs?
Buse: We generally say not first-line. The first-line drug is still Metformin, just because it’s so cheap, so effective, and it has its cardiovascular benefits of its own. Certainly, there is what we call a compelling indication, meaning that there’s very good reason to use these GLP-1 receptor agonists or SGLT2 inhibitors if you have chronic kidney disease or heart disease.
Falk: Where is the use of insulin in this thinking process?
Buse: That’s a great question. Recently, on October 5, we published new guidelines with the American Diabetes Association, and the European Association for the Study of Diabetes, and we talked about SGLT2 inhibitors and GLP-1 receptor agonists being used specifically in people with heart disease and kidney disease as a compelling indication, and we also downgraded the use of insulin. We said, if you need the additional power, the additional effectiveness of a blood sugar-lowering drug that you get from these injected agents, that’s the GLP-1 receptor agonists and insulin, you really should use the GLP-1 receptor agonists.They’re equally effective, maybe even more effective than insulin at blood sugar lowering, but they provide weight loss instead of weight gain, and they don’t increase the risk of hypoglycemia, or low blood sugar reactions like insulin does.
The downside to the GLP-1 receptor agonist, though, is that they’re more expensive. The retail price—and nobody pays retail anymore—but the retail price is on the order of twenty to thirty dollars a day, as opposed to insulin which is more on the order of three to five dollars a day.
Injections vs pills
Falk: But again, you don’t have those episodes of hypoglycemia, or those other kinds of side effects. Now the SGLT2 inhibitors, those are oral drugs.
Buse: The SGLT2 inhibitors are pills, yes.
Falk: And the GLP-1 drugs are injectable.
Buse: Today, they’re injectable. We’re doing trials now with the same chemical, semaglutide, that’s in Ozempic, arguably the most powerful of the GLP-1 receptor agonists, in an oral formulation. It’s a capsule that you take first thing in the morning with a small swallow of water, and the capsule settles in the stomach and it has some material that allows these proteins to get into the bloodstream through the stomach. At least so far—it’s not yet FDA-approved—but the clinical trial program is largely complete, it seems to be just as effective as the injected Ozempic. So, we’ll soon have a pill form of GLP-1. Today, it’s injected.
And, just to make things a little bit easier, the Ozempic and Trulicity and Bydureon are a once a week injection. It’s not the every-day injection with other agents from the class, or like with insulin you’re often taking multiple injections in a day.
New international recommendations & what’s missing
Falk: You referenced an international meeting that re-thought the recommendations for diabetes, not just in the United States, but also in Europe. What was left out of those recommendations? What type of condition was not fully considered?
Buse: The meetings were actually held over a period of a year. It was such a controversial area to change the guidance in diabetes from one where we’re really just targeting levels of blood sugar to one of preventing complications and getting away from insulin, that we weren’t able to do everything. The areas that we specifically left out were: What about kids with diabetes? You may know now that in children, maybe a third to half of diabetes is not Type 1 diabetes, but the same type 2 diabetes that fifty-year-old overweight men get.
And we left out pregnancy: how we should treat diabetes in pregnancy. In general, what we’ve talked about today is not approved in pregnancy or in children. It may not be a bad idea in children, but we need to do the studies.
Then the big thing that was left out was the pre-diabetes issue. There are thirty million people in the United States with diabetes—that’s about one in ten adults. There’s another eighty million people with pre-diabetes, which means blood sugar is higher than normal, but not high enough to say that you have diabetes, and those people have about a one in three chance of developing diabetes in the next five to ten years.
We haven’t endorsed using these newer agents to prevent the progression of diabetes—they probably would work really, really well. Still, the news there is that everybody in America that’s overweight should be screened for pre-diabetes. If they have pre-diabetes, they really need to work to lose five to ten to fifteen pounds to try to prevent the progression of diabetes. That weight loss can reduce the risk of developing diabetes by fifty percent.
Recommendations for diet and weight loss
Falk: Which brings into focus: what about diet? It used to be the emphasis was almost exclusively for pre-diabetics as well as diabetic patients, to try to lose weight. What kind of recommendations do you now make about dietary control?
Buse: Now you’re getting into sort of the deep, dark secrets of medical care. We have always said that diet is the most important thing in diabetes, but we’ve kind of known that we talk to our patients about: you need to lose five to ten pounds, you need to cut back on your carbohydrates. Some people will boil it down to, don’t eat any white foods. There’s all kinds of quick and dirty messages that physicians have been providing to patients around diet management. The impression has been that it doesn’t really work. The reason it doesn’t really work is that we haven’t been doing it very well.
One of the most exciting things that’s come out over the last couple of years, are these studies that show that for people who want to lose weight, using techniques like powdered meal replacements, can result in big weight loss, on the order of twenty pounds. Something like sixty percent of patients actually having their diabetes go away—going from diabetes that’s not very well controlled on medication, to having no diabetes.
Falk: With weight loss?
Buse: With weight loss. This is not, “Bubba, you’re too fat. Eat less and exercise more.”This is a serious engagement with health care professionals who are focused on weight management. But the impact is huge for the people who really want to do it. I think the good news is we now know that weight loss does work. It’s just a matter of really putting your heart and soul into it, both the patient and the provider. It’s not something we can sort of short shrift, or no one would have a problem with being overweight. Almost everybody who is heavy would like to lose weight, but it’s not easy to do.
Falk: You pointed out earlier that one of the GLP-1 inhibitors, has, with a different name, is being marketed as a weight loss medication. Is it a weight loss medication that works, and is it a weight loss medication that doesn’t lower the blood sugar?
Buse: That’s one of the great things about the SGLT2 inhibitors and the GLP-1 receptor agonists—neither one of them will make your blood sugar too low.
Falk: Even in a person who has no problems with their blood sugar to start with?
Buse: Right. You can take someone who has no problems with their blood sugar, or even someone who is a little bit low. You might have heard of this reactive hypoglycemia. Some people who are overweight will get these low blood sugar spells after they eat cereal for breakfast. Even in those people, if anything, these lower the risk of hypoglycemia. These drugs are moderately effective for weight loss.
The very intensive lifestyle programs involving powdered meal replacement, very frequent follow-up with health care providers who specialize in obesity management, are frankly more effective on average than the drugs, so we do a tiered thing where we try our very best with whatever lifestyle program we can come up with, and then depending on how people respond, consider these drugs. If that doesn’t work, we can’t forget about the power of bariatric surgery.
We hate to advocate for surgically correcting problems that at least, theoretically, are underpinned by behavioral issues, but I think all is fair in love and war. For people who are very heavy, or have medical consequences of being heavy, bariatric surgery is likewise extremely effective. There, you see weight loss on the order of fifty percent of the excess weight, and you see reversals of diabetes in more than seventy percent, even in some patients who are already on insulin.
Glucose monitoring & insulin pumps
Falk: If these two classes of drugs don’t lower blood sugar, what’s the role now of glucose monitoring?
Buse: That’s another great question. The blood sugar monitoring we studied here at UNC in a very important trial called MONITOR, that’s been very controversial, because we showed that patients who weren’t on insulin, if they’re not on insulin where we’re doing glucose monitoring really for safety, to catch low blood sugars before people get into trouble, that if patients aren’t on insulin, it’s unclear that there’s benefit for glucose monitoring in general.
For patients on insulin, there’s some very nice new advances—we have these Flash glucose monitors which is basically like having a thumbtack with a head on it about the size of a quarter, that goes into the skin on your upper arm—
Falk: It actually doesn’t hurt..
Buse: Barely does it hurt. It’s a little bit like getting your blood drawn, the initial prick but then you’re fine. It stays in place for two weeks and you just move this wand next to it anytime you want to know your blood sugar. So, you don’t have to prick your finger, you don’t have to do all that stuff anymore. That’s a big deal in type 1 diabetes—that’s a different disease than type 2 diabetes, what we were talking about before—but in type 1 diabetes, these advances really help a lot with avoiding low blood sugars and improving control.
Falk: We haven’t talked about insulin pumps. Where now do those fit in your armamentarium of therapies?
Buse: An insulin pump fundamentally is like a very, very fancy insulin syringe. In the setting of type 1 diabetes where the problem is the body just has quit making insulin for the most part. It allows the patient to very precisely administer insulin to match their activity level, their food intake, and their stress, and it allows for very precise control over blood sugar.
Now we have these continuous glucose monitors that can be linked to the insulin pump in a closed loop fashion, so basically the patient just has to provide some advice to the pump and the pump takes care of a lot of the details. This is evolving very rapidly. I suspect, in the next five years, the life of patients with diabetes treated with insulin will be dramatically enhanced by these kinds of technologies. The technology we have today is so much better than two years ago. It still needs perfecting, but management of insulin in the setting of diabetes is getting much better, much faster.
Type 1 diabetes
Falk: You’ve mentioned type 1 and type 2 diabetes. For reference, what are the differences?
Buse: For type 1 diabetes, the process by which you develop diabetes is that the cells in the body that make insulin have been destroyed by a selective autoimmune attack—a little bit like rheumatoid arthritis destroys the joints. In type 1 diabetes, you destroy your beta-cells that make insulin. The only problem is insulin. You have to precisely administer insulin to match activity and diet.
Falk: There’s no insulin?
Buse: Or very, very little. That is the disease that is more common among children. It still is five percent of new onset diabetes in adults, so one in twenty adults who is diagnosed with diabetes at the age of seventy-five actually has type 1 diabetes. But there, the game is really precisely administering insulin.
Type 2 diabetes, the more common form of the disease, is about ninety-five percent of the (diabetes) population, and there is a relative deficiency of insulin, meaning there’s less insulin than you need. But sometimes there is more insulin than you were born with. The real problem is insulin resistance, so insulin doesn’t work very well.
My dad was actually an endocrinologist, and he used to describe type 2 diabetes as when you have a Cadillac frame and a Ford pancreas. So, you just can’t get the car going like it should, because the pancreas is too small. But in any case, we have lots of drugs for type 2 diabetes, and the name of the game is mixing and matching them, and the lifestyle interventions that we talked about before.
Falk: Are there new treatments for type 1?
Buse: Well, the FDA is reviewing a class of drugs—the SGLT2 inhibitors that we talked about before that make you pee sugar, for use in type 1 diabetes. We have done a bunch of trials with this. It’s extremely effective—patients with type 1 diabetes seem to love it.
The problem is, about one in twenty-five patients—so, not everybody—but some patients will develop diabetic ketoacidosis, which is a life-threatening complication. The thing that makes it even more complicated, is because the SGLT2 inhibitors lower blood sugar, you can have diabetic ketoacidosis with a normal level of blood sugar. So, patients feel sick, but neither the patient, nor the doctor actually figures out what’s wrong with them because it never occurs to them that they could have diabetic ketoacidosis when their blood sugar is normal.
So, we’re working very hard to figure out how to minimize that risk and how to create educational programs that will make sure that patients and doctors never miss that DKA complication. I think we’ll work it out, but certainly not here today would advocate that everyone with type 1 diabetes should be on these drugs right now.
Parting thoughts for patients & physicians
Buse: I think the big message I would have for primary care doctors would be if you have a patient you have a difficult time getting their diabetes controlled now, there are so many new tools—certainly do feel free to call on your local diabetes specialist to help you out with those cases.
The main message I would have for patients with diabetes is, this isn’t your grandfather’s Oldsmobile. You know, it’s a new era. Back in the day, frankly, I was drawn to diabetes because it was so difficult to manage. You had to be sort of a faith healer and really motivate people to do things that they didn’t think they otherwise could do. The tools are so good now that no one has any business having long-term complications of diabetes. We really should be able to control diabetes in virtually everyone. Sometimes the treatments are pretty expensive, so with our healthcare system, there are issues in America with getting the right kind of care to the right people at the right time. But in general everybody with diabetes should do well, live out a full lifespan, without any disabling complications.
Faulk: Wonderful message—and for patients, if you know you have kidney disease, you know you have heart disease, these two classes of drugs are useful drugs to remember, so you can help your doc pick those drugs.
Buse: So, Ron, you’re a kidney specialist, we’ve had this conversation now—What did you hear as the real take-home message?
Falk: That patients who have kidney disease from diabetes should ask their nephrologist and ask their diabetes doctor whether this group of drugs, especially the SGLT2 inhibitors. If the trials come out definitively that this group of drugs really does decrease the progression of disease, they’re going to be first-line agents.
Buse: Yes— I spend most of my time doing clinical trials. We’ve done several hundred clinical research projects over the last twenty-five years here at UNC. I have to say the one disappointment I have in my professional career is not related to the lack of discoveries and lack of advances, it’s the lack of implementation of the things that we know work.
As an example, the message that we just talked about—reducing the risk of heart attacks—we’ve known that in some way, form or fashion for the last three or four years, and still only about ten or fifteen percent of people who have heart disease are taking either one of these drugs.
We need to do things like this to make sure that providers get this message, but also that patients are empowered to go to their doctor and say, “I listened to this podcast. I heard I should be taking these SGLT2 inhibitors. What do you know about that?”
Falk: And if you don’t know about it, please ask.
Buse: I remember a patient who called me out on something once, and I have really avoided being called out on that issue ever since, so it doesn’t take very many reminders from patients to change doctor behavior.
Falk: Thank you, Dr. Buse, for joining us today.
Buse: It’s a pleasure.
Falk: Thanks so much to our listeners for tuning in.Next time we will welcome Dr. Mike Cohen for a discussion on HIV medications.