A (9:09)

Neil John, I think this is one of the most exciting things going on right now in medicine. So over the last few years we've seen a number of observational trials that show that the GLP1s decrease the risk of dementia. But those are observational trials. This is a meta analysis of randomized trials showing essentially the same thing with about the same risk reduction. So almost a 50% risk reduction in the development of dementia. We know that this is a good group to look at because people with diabetes, as we've talked about many times on this podcast, have a high, higher risk of dementia than the population at large. And Here we see GLP1s having a significant effect. Why might it have that effect? There's a number of potential reasons. One, adverse effects of glucose on the production of beta amyloid. So lowering glucose. Obviously the GLP ones do that well, but so do the other diabetes agents. So it's not just that there are other anti inflammation inflammatory effects of the GLP1s that are different than the other agents. So maybe that's what's going on. Whatever the mechanism, the data here is strong enough that there are right now two large clinical trials that are looking at semaglutide, the Evoke trial and the Evoke plus trial that are randomized, double blinded, placebo controlled trials with a specific primary endpoint of dementia. And if they show a positive effect, it will likely lead to an FDA submission and approval for treatment of mild cognitive impairment, which is one of the inclusion groups in the Evoke trials for mild cognitive impairment and mild dementia, which are really some of the scariest things that any of us face as we grow older. For our article this month we are going to talk about an article published in the New England Journal of Medicine that is titled A Randomized Trial of Automated Insulin delivery in type 2 diabetes. Joining us to discuss the article and its clinical implications is one of the authors, Davida Kruger, who is a nurse practitioner and director of Clinical research for the Division of Endocrinology at Henry Ford Health System in Detroit, Michigan. She is a past chair of the American Diabetes Association's Research foundation and is also a past present health care and education of the Ada DaVita. Welcome back to our podcast.

C (12:02)

Well, thank you for having me back. It's very exciting to be here, especially given the topic. I'm really excited, as I tell my kids, is that I may not know what to do with my cell phone and I may not know what to do with my computer, but I do know what to do with AIDS and anything related to diabetes.

A (12:21)

You sure do, because so often when I read an article on aids, I notice that you're one of the authors. Can you give us some background on the importance of this article and why you all undertook looking at AIDS and type 2 diabetes?

C (12:41)

I think you and I both agree that diabetes has expanded. Like when we. When I first started, and I've been in the field for 43 years, we didn't have anything for diabetes that was type 2 diabetes. We had sulfonylureas, we had mixed beef pork insulin. We had nothing to offer and we did not think it was a serious disease. We now know it is a serious disease and we need to be doing better. And so to be able to offer insulin pumps to those individuals who have type 2 diabetes, and there's no reason not to offer it for those individuals. That was the excitement about this study, is to say, how can we do better at what we do for people with type 2 diabetes?

A (13:22)

That's right. And we know that automated insulin delivery has made a huge difference for people with type 1. How did you go about looking at this for people with type 2?

C (13:32)

First of all, in the studies, and I think this is really important, in the studies, we really took people where they were. We didn't say that you had. We want everybody to see a diabetes educator. We want them to have mnt, we want all that to occur. But the reality is everyone doesn't have it. And that should not be a reason for an individual to not be on a sensor and for them to be offered an aid. And in this study, we didn't do a lot of pre education. We took people where they were and we said, hey, if you're taking a set bolus, we'll take you. If you're not yet taking boluses, we'll take you. If your carb counting, we'll take you. And I think that's the important thing to understand is that we met people everywhere they were and included them and they did very well.

A (14:16)

And I love that because when we have research trials that allow us to generalize the people that are seen to, the people we see in our practice, that gives more legitimacy to the results. So this was a randomized trial. Who were the people included in the trial?

C (14:34)

You had to have type 2 diabetes. You had to have diabetes for been on insulin for stable doses for three months. You had to have. If you were on STLT2 inhibitors and GLP1s, which we hope everybody is on, you had to be on Stable doses of those as well. And I believe it was 18 to 75 years. And what was really exciting about all of the studies that I've worked on in type 2 diabetes is that we made sure we included people from all races, which we don't always do. And I think that was also very important. All socioeconomic status, all educational levels. It doesn't take a college degree to use an insulin pump.

A (15:16)

Okay. And these were people on multi dose insulin.

C (15:20)

It could have been on just basal insulin too.

A (15:23)

Okay. And so they were enrolled in the study, they got some training. But I love the fact that it wasn't unbelievable amounts of training. What did the studies show?

C (15:34)

Basically the study showed that no matter how you took your mealtime insulin, and people were taking mealtime insulin, whether it was just carb counting or whether it was just a set dose, the A1Cs came down between 0.7 and 0.9. And remember, it's only a three month study. So that's a very significant. But here's the other thing is there was greater time and range and without Hypoglycemia. So better A1Cs, better time and range without hypoglycemia and less diabetes distress, which I know is very important for. And we, I think we minimize how much distress diabetes causes people. But because this enhance their lifestyle, they had less distress.

A (16:19)

Yeah, it's so important. And for those of our listeners who care about P values, I read this study again this morning and that was a P value of less than 0.001. So if there's any question here, this was real, there was some real improvement in the people who had aids. And David, I love the point about diabetes distress because diabetes, it's 24, 7 every day of the year and it's a lot of work. And so that's an important endpoint. So what do you see as the clinical implications of this trial?

C (17:01)

I think the clinical implications of this trial is that those individuals who have type 2 diabetes, as I believe everybody, should be on a sensor. That's a right, not a privilege. But after we put them on a sensor, we should be offering people with type 2 diabetes an insulin pump. Of the other things we saw was even those individuals who had done very well on GLP1, their A1C came down the same as those individuals who were not on GLP1. Which reminds us that our job is not done just because we use incretins and SGLT2 inhibitors. So I think that was the other important thing that came out of that study. If you have type 2 diabetes, you should be on or be offered the opportunity to use a pump. So my feeling is once I'm starting to think insulin, it's the vehicle I use to deliver the insulin and why shouldn't it be an insulin pump?

A (17:55)

David I always love talking to you. You're always pushing the edges of technology and science and we all grow from that. Davita Kruger thank you so much for joining us.

C (18:08)

Thank you for having me.

B (18:09)

This next article is from Diabetes Care and it looked at screening for metabolic dysfunction associated steatotic liver disease related advanced fibrosis in diabetology. This was a prospective multi center study. The researchers conducted a planned interim analysis of a prospective multicenter study including participants who had type 2 diabetes and or obesity and metabolic dysfunction associated steatotic liver disease MASLD with comprehensive liver assessment comprising blood based noninvasive testing, vibration controlled transient elastography and two dimensional shear wave elastography. The risk stratification for advanced fibrosis was determined by a composite criteria of liver biopsy, MRI elasticity or VCT depending on availability. Of the 654 patients, 87% had type 2 diabetes, 56% were male, 74% had obesity, 17.6% had intermediate or high risk of advanced fibrosis and 9.3 had a high risk of advanced fibrosis. The area under the empirical receiver operating characteristic curves of non invasive testing for detection of high risk were as follows. So the fibrosis or fib 4 score 0.78, the fibro meter 0.74, the fibro test 0.78, enhanced liver fibrosis or ELF test 0.82 and the SWE 0.84. And then they looked at algorithms with the FIB score VCT that showed good diagnostic performance for referral of patients at intermediate high risk of advanced fibrosis to specialty care and hepatology. An alternate of using the FIB score with the ELF test strategy showed a high negative predictive value 88 to 89% and a lower positive predictive value 39 to 46% at threshold. The Fib4Score2D SWE strategy had a negative predictive value of 91% and a positive predictive value of 58 to 62%. The age adapted Fibs4 scored threshold resulted in lower negative predictive value and positive predictive value in all algorithms.

A (20:38)

Neil John this has become a really vexing issue because if we look at MAFLD you have in total over 2/3 of people with diabetes who have whether we call it MAFLD or the old name fatty liver. So this occurs in a lot of people and a relatively small, but a large enough to be important number of them go on to develop mash. And remember the difference there is with mash you have inflammation, not just fat infiltration of the liver, but inflammation of liver leading to ballooning and pathologic changes, which in turn then leads to different degrees of fibrosis, F1 through F4, then cirrhosis. This is important because MASH has become the second most common. It's on its way to being the most common cause of end stage liver disease requiring transplant. The challenge, of course, when so many people have the early stages, is how to select which people move on to hepatologists without overwhelming the system with too many people being referred on. And this is important because there are now treatments for advanced fibrosis and there are more treatments that are on the way. So this study looked at different approaches and it's pretty clear that the entry is the fib four score. And I was surprised actually that a higher proportion over 50% of people had a low Fib 4 score than was my sense when I do it in the office. And that's great. So we, with a high degree of confidence can not send on or do any other tests in about half the people with diabetes who we put through a simple fib four score, right? It has age, it has liver function, AST, ALT and platelets. And we move 50% of people out of the algorithm. No other tests done with a very high negative predictive value. Then for people who have a cutoff, if they used above 1.3, those people go on to get a second level test. And those second level tests can either be a VTCE elastography, which I think most of us are pretty used to getting. And then with elastography using 8 Kpa as the cutoff, if it's less than that, high predictive value, high negative predictive value, that they don't have advanced fibrosis, they can be followed over time by us in primary care and endocrinology. If they have more than 8kpa, they go on to see the hepatologist. The test here that was looked at, and I think we're going to be seeing a lot more of this that many of us are not familiar with, is the ELF that stands for enhanced liver fibrosis testing. It's just a simple blood test and it uses a equation based on three biomarkers to give a prediction of the likelihood of fibrosis and the elf and they talk about different cutoffs and I'm not going to go into the different cutoffs right now using they decided the cutoff of 9.2 also had a very good negative predictive value. So if you're in a place where it's hard to get elastography or perhaps more conveniently a blood draw than a visit for a radiology test, an ELF can be used. So we have an algorithm that has a high degree of accuracy starting with fib and if needed, someone has a fib greater than 1.3 either getting elastography or an ELF in order to decide who we can follow over time or who needs to be sent on to one of the specialists. Our final article of this issue is from Diabetes Care entitled the Risk of Urogenital Infections in people with type 2 diabetes initiating SGLT2 inhibitors versus GLP1 receptor agonists in Routine Clinical Care. It is a Danish cohort study. The authors investigated whether initiation of SGLT2 inhibitors compared with GLP1s was associated with an increased risk of either UTI or what they abbreviated as GTI, genital urinary infections. Essentially that stood for mycotic infections. This cohort study emulated a target trial. They included all adult metformin users who initiated SGLT2s or GLP1s in Denmark from 2016 to 2021. As I say that it is just phenomenal how good the ability to access information is in Denmark and it's somewhat awe inspiring to think that you could include all adults who meet these certain categories in all of Denmark. And because of that ability to access that data, the study included an enormous number of people, over 50,000 SGLT2 inhibitors and 27,000 GLP1 initiators with a median follow up of 2.9 to 3.9 years. The estimated risks of UTI within the first year were nearly identical between GLP1s and SGLT2s, around 10%. For mycotic infections, though the one year risk was elevated with with the SGLT2s, it was 2% versus 0.7% with the GLP1s and that was a risk ratio of approximately 3. During the five years of follow up, the relative UTI risk remained constant, meaning there was no difference between the SGLT2s and the GLP1s and the mycotic infections, while they became less over time, still remained quite a bit higher in the SGLT2s.

B (27:05)

John, I think this is a fascinating thing. So in the 5th century some physicians in India called Diabetes urine, like honey, because it attracted ants. And it really wasn't until 1798, a Dr. Rollo, in kind of the Latin melodus, urine that is sweet. So diabetes insipidus, if you tasted the urine, which thankfully we have moved away from as a bedside point of care test, was sweet. So intuitively, if it attracts ants, 1700 years ago, we're going to say, wow, this is something that kind of makes intuitive sense. And you and I have been working together a long time, and I think when they first talked about these medicines coming out, we thought there would be a much higher rate of UTIs. And in fact, in 2015, the FDA kind of parked in the warning signs of this class of medicines that all our patients get about worrying about UTIs. So that's a bit of the background. Working in the hospital recently, a person with a bad pyelonephritis who also had diabetes. And the clinical question came up, does this person need to be off their SGLT2? And said, going through the literature year over year, patients with diabetes do have an increased rate of having UTIs, but it's not necessarily higher with this category of treatment versus the other. If you dive into the literature, it talks about emphysematous pyelonephritis on a patient who's on this category or at that category. But that rare radiologic finding happens more often our patients with diabetes. So our patients with diabetes with a suspected pyelonephritis need some imaging potentially to make sure they don't have this rare side effect. But what do we do now? Kind of baseline. We got a patient and we're treating their pyelonephritis, and. And we have them on an SGLT2, and we probably don't have them on an SGLT2 to make their diabetes appreciably better. The A1C response is always pretty modest, about 0.5, but we have it for all of these pleiotropic effects. And I think it really becomes difficult to say, you have diabetes, and I'm going to take away this thing that might protect you from a litany of other things, heart failure, heart disease, kidney, progression of kidney disease, etc. Because of this. But I think as clinicians, we also sit there and say, the package insert says X and what do I need to do? And probably there's enough literature that someone could hold up against their stance that these are okay. But I think there is enough evidence now that really would be nice for the FDA to change that or amend it in some way. So for the average clinician who takes care of the average person with diabetes, who gets a pilo, who gets a uti, what do I do? And this isn't talking about the mycotic infections and even that, that person who gets one candidal yeast infection over a three year period of time, do you throw that use of that medicine out or do you weigh it in the context? So I think an important article and hopefully it will help with some different guidelines for you and I who are very interested in using these medicines, but really want to use them with maybe a little bit more direction nationally.

A (30:57)

John before we close, I want to share some important news with our listeners. As you know, in addition to diabetes, we've been covering the full range of cardiometabolic conditions. And so this summer our name is going to be changing to meet that consistent mission. Starting this summer 2025, our podcast will be rebranded as Diabetes, Obesity and Cardiometabolic Update. I know, I know. You're already thinking and you're right. The new name is Doc Update Diabetes, Obesity and Cardiometabolic Update. You'll notice this when the change is made on your subscriber feed will have a new title and branding. Same great information. For more information and links to the articles that we discussed in this issue, just go to diabetesjournal.com word until next month, keep listening and keep learning.