A (5:27)

Joining us today to discuss two critically important articles published in the New England Journal is J. Rao, who is chief section of Endocrinology, Diabetes and Metabolism at the Lewis Katz School of Medicine at Temple University. The articles we're going to discuss are OR forglopron, an oral small molecule GLP1 receptor agonist in early type 2 diabetes and or forglipron for obesity treatment. Jay, welcome to our podcast.

C (6:02)

Thanks for having me on, Neil. I really appreciate being on.

A (6:06)

This is such a great topic. Let's start with background because a lot of people don't actually know what or Orglipron is. Can you tell us a little bit about it.

C (6:17)

Sure. Just another sort of added armamentarium for us in helping out people with diabetes, living with diabetes and obesity. Obviously we, I'm sure many of us all know the availability of the GLP1s that are available, the GLP1 receptor agonists, and a lot of us know of the injectable forms and some or many of us know about the, the oral form that's tried to mimic the compound that's given via injection. This is actually a molecule version of that peptide. So given by mouth and perhaps not riddled with the finickiness of the oral one that's already on formulary is the oral semaglutide.

A (6:58)

Yeah, and it's fascinating. So it's because it's a small molecule, it's absorbed more readily. Let's start with each of the articles in turn. First let's go over the diabetes article, tell us about the methods relatively briefly and then we'll get to results.

C (7:17)

Yeah, standard, sort of your standard phase three study in utilizing this molecule. So in the study that was focused on people living with diabetes, they really were harnessed against those who had early type 2 diabetes. So interestingly, individuals who are diet managed with type 2 diabetes, not on other agents and essentially they randomize these individuals into getting a variety of doses of the, the novel agent and of course placebo with the concept of obviously looking at, because it's diabetes, looking predominantly at how good did the drug do with a 1C lowering. And of course they also examined the potential changes in weight.

A (8:02)

And what did they find?

C (8:04)

So I think pretty fascinating, I think with the three different doses they found a pretty, pretty good drop in a 1Cs in less than a year. So they were looking at it about at the 40 week point, so a little bit about probably at the nine month point roughly or ten month point. And they were able to see a drop about 1 and a quarter to 1 and a half a 1c depending on the dose that was used. Because again, they used three different doses compared to maybe just about a half a point drop in those who were on the placebo arm. So clearly a nice drop in a 1C which was really nice to see. And also with the new diabetes medicine, it's also great to see the fact that they also had a nice drop in weight also.

A (8:45)

Yeah, that makes it pretty exciting. Let's move on now to the obesity trial methods first and then results.

C (8:55)

Yeah, so this one and again, same compound, same idea, but here the focus was for treatment for individuals with obesity. And again here It's a randomized double blind trial. And they looked at three different doses again of the same compound compared with placebo. And remember, it was an adjunct to healthy diet and physical activity for a little bit over than a year. All of the individuals in this study had obesity, but they did not have diabetes mellitus. And in this one, the focus was, the primary endpoint was essentially the change in body weight from baseline to week 72.

A (9:35)

And what did they find?

C (9:38)

Again, a pretty profound drop in weight, close to seven and a half to about eight and a half to 10% depending on where you started out with dose. And that's compared to only a 2% drop in body weight from baseline in the placebo group. So again, a really good effect on weight. And of course with that you saw a drop in other parameters such as blood pressure, triglyceride levels, cholesterol levels. They all did much better than those who were receiving sort of placebo.

A (10:12)

Very good. And side effect profile, any surprises here or usual GLP one sort of side effects?

C (10:19)

Yeah, great question, and I didn't comment on that on the both sides. I think you saw the similar sort of thing that we see on the GI side, nausea aspects related to the GI tract. And that did lead to some discontinuation, but nothing, I think surprising compared to even the available forms of the oral peptide or the injectable peptide of the GLP1.

A (10:42)

Great. So let's now go to clinical implications, which is always what people like you and I are most interested in. What do you see as the clinical implications of these trials?

C (10:53)

Yeah, I think just a great question and another added resource that we can turn to. I think we are all seeing these patients and they're all asking for assistance and we know that individuals with the overweight obesity represent a big, big problem for healthcare. I think starting out with the individuals with diabetes. I think it's another added potential option. I do want to say that this trial that we looked at was focused on those who are diet managed. So I think it would be interesting to see how this synergizes with other therapies that we typically think of first line. But this is usually the first type of study done in diabetes to just demonstrate that it's doing its job of a 1C lowering. So I would like to see how it synergizes with other available therapies like metformin and Shield 2 inhibitors and other types of regimens. But again, it's really nice to see that a 1C drop in a short period of time and with the known cardiovascular benefits of of GLP1 class. It's really nice to see that for the diabetes study, I think for the obesity study. This is such a huge population and surprisingly we have had oral agents on the diabetes side for the GLP1. But I must say the uptake has not been great. And I think if this molecule is not as finicky as the available one on the market, I think this will be a game changer for, for those who are really averse to the injection aspect of things.

A (12:17)

And when you say finicky, what do you mean by finicky?

C (12:20)

Yeah, great, great question. I find the available one, it's a peptide, right? It's not a small molecule like this one. So that peptide, we're trying to do the same thing that you would do if you were getting it via injection and not let it get attacked by your own GI tract as it passes through. So I do think that as many for that available compound on the market, it has to be taken in a certain way on an empty stomach outside of these other meds. And that becomes, I think, really hard for Pat. And I'm hoping that this will be a little bit easier because it's a smaller molecule and doesn't maybe have that sort of regimented approach when you're taking it.

A (12:56)

I couldn't agree with you more. This is exciting. GLP1s have become a mainstay of our treatment for diabetes as well as treatment of obesity and oral options. And later in this podcast we are going to discuss oral semaglutide. Having two oral options potentially coming to market if they are FDA approved over the next year to year and a half really is exciting for patients. Not everyone loves injections and it just makes it hopefully easy to use and easy to move forward with. Jay, thank you so much for joining us.

C (13:35)

Anytime, Neil, thanks for having me on.

B (13:37)

Have a good one. Our next question, articles from Diabetes Care and it looked dementia risk in people with type 1 diabetes and associated risk factors and nationwide registered based cohort study. So this was a cohort study of over 43,000 individuals who had type 1 diabetes in Sweden and there were 217,000 plus age, sex and county match controls from the Swedish Total Population Register. They use Cox regression to study the relationship between type 1 diabetes and risk of all cause dementia and dementia subtypes. Alzheimer's vascular, non Alzheimer's, non vascular dementia. The researchers also examined the relationship between various risk factors and the risk of all cause dementia in patients with type 1 diabetes. The patients were followed for slightly over 14 years with a range of 7.9 to 20. The match was recorded in 1.2% of the individuals with type 1 diabetes and 0.9% of the patients who were in the control group. Age, sex and county match controls were brought into that Compared with the controls, individuals with type 1 diabetes had a higher risk of all cause dementia a hazard ratio of 2.02 Alzheimer's 1.38 hazard ratio vascular dementia has a ratio of 3.73 and non Alzheimer's non vascular dementia has a ratio of 1.87. The risk factors related to dementia and type 1 diabetes beyond age were patients with a lower education level, being single, having a higher systolic blood pressure, higher A1C, a history of a previous stroke or TIA, and a history of cardiovascular disease or a longer duration of having diabetes.

A (15:28)

Neil John, it's interesting. You and I have talked actually many times on this podcast about the relationship between type 2 diabetes and dementia that you have about twice the incidence of dementia in people with type 2 diabetes and that risk is related to A1C control. It's less in people with good A1C control. We don't think think of it as often in type 1 diabetes and this adds to the literature in that area. Dementia is just like nephropathy, neuropathy, retinopathy. It can be thought of as a downstream complication of diabetes and one of those things that we talk to people about as a reason to try and have tight control. Which brings us to modifiable risk factors and I don't think it's surprising, but it's important to emphasize that two modifiable risk factors identified in this paper were A1C Again, another reason to have good A1C control in people with type 1 diabetes and systolic blood pressure to aim for that type blood pressure control. Our next article from Diabetes Care is titled the impact of baseline GLP1 receptor agonist use on albuminuria reduction and safety with simultaneous initiation of phenirenone and empagliflozin in type 2 diabetes and chronic kidney disease. The Confidence Trial the Confidence trial demonstrated an additive benefit of simultaneous initiation of phenurenon, which is a non steroidal MRA and an SGLT2 inhibitor compared with monotherapy in reducing the urinary albumin to creatinine ratio. The uacr. This was a prespecified analysis that evaluated whether safety and efficacy of combination therapy varied by baseline GLP1 or receptor agonist use. Why is that important? Because these are medicines that are commonly used. So they looked at adults with CKD with a UACR greater than or equal to 100 but less than 5,000 and an EGFR 30 to 90 and type 2 diabetes with an A1C less than 11%. And individuals randomized 1 to 1 to once daily phenarinon, empagliflozin, or both. Phenarinon plus empagliflozin. Among 800 participants in the trial, 23% used a GLP1 receptor agonist at a baseline at day 180. UACR change from baseline in participants using a GLP1 receptor agonist was minus 50, 51% with combination therapy, minus 34% with phenerinon and minus 36% with empagliflozin. And corresponding results in those not using a GLP1 receptor agonist at baseline were essentially similar. Hyperkalemia incidence rates with combination therapy were 9% and 9.5% among individuals with and without baseline GLP1 receptor use. EGFR changes were consistent among individuals with and without baseline GLp1 use.

B (19:06)

John so Neil, I think an interesting study, so you and I are involved, you know, once a year in the top articles kind of presentation to a primary care audience. The confidence trial was one of the articles we talked about as a top article of the year. It was in the late August New England Journal of Medicine. And in that combining empagliflozin and phenerinone in a patient population with diabetes and kidney disease showed an additive effect of adding in those two medicines versus either one as monotherapy. I think if you look at what are our challenges here in primary care and taking care of people who have kidney disease, the numbers for survival for people with stage five kidney disease hasn't changed a ton. And you know, the average lifespan in that population is and has been around five years without transplantation or something else going on. And that number really hasn't moved a lot despite all these kind of great advances we've had. So the challenge is really for you and I, you know, when we have people who are CKD3, CKD4, can we stop the line? Can we reverse the line a little bit and stop people from progressing into CKD5? A lot of our patients are on GLP1s right? They are a really good workhorse, strong medicine for a 1C reduction. So the context of this is if you have populations and you look at people who are on baseline GLP1 versus not on a baseline GLP1, does this kind of peanut butter and jelly combination added into a GLP1 present or absent patient. Does it really screw up that synergy? And it really doesn't seem to. So whether someone's on a GLP1 didn't really affect some of the positives that you saw. Our next article is from the New England Journal of Medicine and it was a study looking at oral semaglutide at a dose of 25 milligrams in adults with overweight or obesity. So this was a 71 week double blind randomized placebo controlled trial that was conducted at 22 sites in four countries. The researchers enrolled patients without diabetes who had a BMI of 30 or higher or a BMI of 27 or higher with at least one obesity related complication. Participants were randomly assigned in the 2 to 1 ratio to receive oral semaglutide 25mg or placebo once daily. Both groups were given lifestyle interventions. The co primary endpoints at week 64 were the percentage change in body weight and a reduction in 5% or more body weight. Confirmatory secondary endpoints included reduction in body weight of 10% or more, 15% or more and 20% or more and the change in the impact of weight on quality of life. Clinical Trials version the IWQoL LATECT physical function score. So there were a total of 205 participants that were randomly assigned to receive either oral semaglutide and 102 were getting placebo. The estimated meat change in body weight from baseline to week 64 was a decrease in 13.6% in the oral semaglutide group and a decrease in 2.2% in the placebo controlled group, an estimated difference of 11.4 percentage points. Participants that were in the oral semaglutide group were significantly more likely than those in the placebo group to have body weight reductions of 5% or more, 10% or more, 15% or more and 20% or more and have an improved physical function score. The GI adverse events much more common in the oral semaglutide than placebo 74% vs 42% Neil John, I gotta tell.

A (23:06)

You I think this is exciting. Looks like we may have an oral effective option for treatment of obesity and that would be very welcome. So oral semaglutide at a dose of 25mg achieving a 13.5% mean weight loss is about what we saw in the step one trial of subcusamaglutide. In the BIG trial in people with obesity without diabetes where they achieved approximately 15% weight loss so in terms of weight loss efforts can see these are about the same. In this trial we saw a third of people lost greater than 20% of their body weight and very important we saw improved physical function. Based on this trial, NOVO submitted oral semaglutide to the FDA in May just a few months ago for approval for treatment of obesity. Also interestingly, just about a week and a half ago, oral semaglutide 14 milligrams which is the dose for diabetes, not for weight loss. The 14 milligram dose received FDA approval for an indication of cardiovascular risk reduction in people with diabetes and elevated cardiovascular risk based on the SOLE trial which showed a 14% reduction in mace, which is what we see with GLP1s in general and the CVOTs. Also interestingly in the FDA application back In May, this 25 milligram dose, the application also included an application for reducing the risk of MACE in adults with obesity and established ASCVD. Remember the SELECT trial which we've talked about? It's two years ago already fall of 2023 that was the large trial of semaglutide sub Q1 milligram in people with obesity and cardiovascular disease, either MI, stroke or peripheral vascular disease, decreasing MACE by 20% over about three years. So we're going to see a lot happening in this space. Earlier in this podcast we talked about another oral GLP one as well. It is very possible at the end of the next year to year and a half, in addition to our injection armamentarium, we will have one and perhaps two oral GLP1s to help our patients who have obesity. 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 our name is going to be changing. To meet that consistent mission. 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.org until next month.

B (26:47)

Keep listening and keep learning. SA.

C (27:38)

SAM.