ADA 2025: Clinical Trial Data on Incretin Therapies
At the ADA meetings this year, incretin therapies were a big topic. There were many, many different studies presented on all sorts of new drugs and older drugs, and a large amount of interest in this. What I'm going to try to do is make it simple, and you're going to have to forgive me because many of these drugs have names that are almost impossible to pronounce.
As far as I can tell, there were three main areas that involved incretins. One was newer agents that were different combinations of different kinds of drugs. I'm going to touch on those main areas where there were differences. The second is in terms of the forms for delivery, specifically a new oral form of incretin therapy that might be easier for patients to take. Third, longer duration of activity of these agents that might make it even easier for our patients to adhere to.
First, I'm going to go to different combinations. The first is CagriSema, which is semaglutide plus cagrilintide, which is a long-acting human amylin analog. We all were familiar with amylin from a long while ago, as we had pramlintide. This takes that amylin analog and mixes it with a dose of 2.4 mg of semaglutide.
The studies that they did are called REDEFINE, and they presented the full results of the phase 3 REDEFINE trials. In most of the studies on these newer agents, they basically study them in people who are overweight or obese without type 2 diabetes, as well as in people who are overweight or obese with type 2 diabetes.
REDEFINE 1 looked at 3417 people who were overweight or obese and who didn't have type 2 diabetes. They saw 20% weight loss with this new agent compared to 15% with semaglutide 2.4 mg, or 12% weight loss with cagrilintide alone.
In REDEFINE 2, there were 1206 people with obesity and type 2 diabetes compared to placebo. CagriSema conferred a 13.7% weight loss vs 3.4% with placebo.
That's fairly standard for many of these drugs. You get weight loss and A1c reduction, and it's always a bit more in people without diabetes than those who have diabetes.
Moving on to the next combination. There was the DREAMS-1 trial, looking at a once-weekly GLP-1 receptor agonist combined with a glucagon receptor agonist, which is called mazdutide. It was studied in people in China with type 2 diabetes. This showed a nice A1c reduction and significant weight loss at 24 weeks.
This was a study in 319 individuals who were living in China. They had a number of different arms to this study, so they had a 4-mg dose, a 6-mg dose, and placebo. The study lasted for 24 weeks, and they saw A1c reductions of 1.4%-2%. There was weight loss that varied depending on the dose, at 5.6% or 7.8% in the two different arms.
There were similar side effects. I think one of the truths of all of these trials is that the GI side effects occur with nearly all of these agents, some to a greater degree than others, but those were the major side effects in terms of this agent.
They're now studying it in other individuals with type 2 diabetes. They compared it to dulaglutide and found a greater A1c reduction than with dulaglutide in one trial. They're also looking at it for weight loss in people without diabetes. There are a number of trials that are ongoing that will give us more data in terms of what this combination does in people with obesity and type 2 diabetes.
The next trial is one that I find oddly fascinating, which is called the BELIEVE trial. Believe it or not, this is a trial in which they took semaglutide and mixed it with a monoclonal antibody that blocks activin type II receptors, with the hopes that that will improve muscle mass, maintain lean body mass, and decrease fat mass as people lose weight with this combination.
They studied it in people who were living with obesity or overweight without type 2 diabetes, and they basically had a number of different comparisons. The monoclonal antibody is called bimagrumab. It's something that I'm not familiar with, but it was really interesting in terms of its effect.
They had a number of different groups: a placebo group, a low-dose bimagrumab group, a high-dose bimagrumab group, a low-dose semaglutide group, and a high-dose semaglutide group, and then they had four different combination groups with low-dose or high-dose bimagrumab. They looked at all of these different permutations in a study sample size that was 507 individuals.
They were hoping to see less loss of lean body mass, and they basically showed this. There was a 7.9% reduction in lean body mass with semaglutide alone, but if you gave them the monoclonal antibody, there was a 2.3% gain in lean body mass. When you combined the monoclonal antibody with semaglutide, you got a lesser reduction in lean body mass, a 2.6% reduction, which was compared to the 7.9% reduction with semaglutide alone.
This is hopeful in the sense that this specific combination helps people lose less lean body mass. There were a whole bunch of other analyses they did to see about people being stronger and feeling better. It really does matter to not lose so much lean body mass.
I'm still old fashioned and I really want to encourage people to exercise and eat well in order to help preserve lean body mass. We'll see what happens with this. I think it's a fascinating concept, but I also don't want to forget about lifestyle.
The next trial was called ACHIEVE-1, and this was looking at an oral form of a GLP-1 receptor agonist known as orforglipron. They studied this in people with type 2 diabetes.
What's different about this is that this is a small molecule. It's not a peptide GLP-1, so it's really easy to give. It's like any old pill that people take, so it doesn't have restrictions around how much water and when it's taken, etc.
They did see benefit in terms of A1c reduction, some weight loss, about 8%, and it seemed like it worked, but it did have GI side effects and it didn't cause the same sort of A1c reduction or weight loss we see with some of the other injectable compounds. Still, it might be an interesting first step for people as they get used to GLP-1 receptor agonist therapy, and it may be easier for patients to take.
The final compound I'm going to discuss is MariTide. This is a compound that is a GLP-1 receptor agonist and a GIP antagonist. This is a once-a-month agent. This was a 52-week trial in individuals who were obese or overweight without type 2 diabetes. They basically had three different doses they were studying and they did a bunch of different dosing frequencies.
It seemed to me to be effective in terms of weight loss, as most of these drugs are, but it did have an incredibly high rate of GI side effects. When you look at that study in individuals without type 2 diabetes, the rates of nausea and vomiting were really high.
At baseline, 25% of placebo patients reported nausea. In the treatment group, nausea was reported in 77%-87% of participants and vomiting was reported in 68%-92%. It usually occurred after the very first dose of the drug, with an incidence decreasing over time. I've never used a drug that had such a high rate of vomiting — nausea, potentially, but not vomiting. GI side effects were the main reason for people stopping it, and 14%-29% of individuals discontinued the drug due to adverse events.
They also did a study in people with type 2 diabetes. It's interesting because they used a different survey to assess GI side effects, but they still had a very high rate of GI side effects, at 94% in the MariTide group vs 81% in the placebo group. Again, the most common GI side effects were nausea, vomiting, constipation, and diarrhea. Nausea rates ranged from 41% to 59% of people taking the MariTide, with vomiting in 45%-75% of participants.
These GI side effects are really clear here, and I don't know that this is going to be something people are going to want to take. Once a month is nice, but it's not fun to vomit. I think it depends on how quickly people habituate to this and how one goes up on the dose.
These GI side effects are an issue for all of us and our patients as we prescribe these drugs. I tend to start as low as I possibly can. I'm a fan of microdosing as much as possible to get people to tolerate these drugs because I think that the incretin class of drugs is so beneficial, not only in terms of glucose and weight loss, but also in its nonglycemic effects.
I also don't want people to lose weight too fast because I think that it isn't healthy. I know that there are studies that are coming out that show that there are people who respond by very rapid weight loss, more commonly in women than in men. I think we need to be mindful of how we use these drugs, how quickly people lose weight, and how we encourage people in terms of leading a healthier lifestyle to avoid some of the side effects that can be associated with that sort of rapid weight loss.
This has been Dr Anne Peters for Medscape.
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