TouchENDOCRINOLOGY coverage from EASD 2024:
Dapiglutide is a once-weekly, subcutaneous dual GLP-1/GLP-2 receptor agonist being investigated for the treatment of obesity. This first-in-class molecule is designed to take advantage of the weight-loss effects of GLP-1 agonists and the additional benefit of a GLP-2 agonists on improving intestinal barrier function and addressing co-morbidities associated with low-grade inflammation seen in obesity.
The dapiglutide for the treatment of obesity proof of concept study, presented at EASD 2024, is an investigator-initiated, randomized, double-blind, placebo-controlled clinical trial. It was designed to evaluate the weight-loss potential of dapiglutide in adults with obesity at doses of 4 mg and 6 mg, while also investigating dapiglutide’s effects on gut barrier function, systemic inflammation, body composition, patient-reported outcomes and safety/tolerability.
In this interview, we speak with Dr. Casper Nielsen (Gentofte Hospital, Hellerup, Denmark), the study’s co-investigator, to discuss the rationale behind investigating dapiglutide and review the key findings from the study so far. We also explore the promising results from a phase 1b dapiglutide trial, which offer hope for greater efficacy in the future, as well as the potential future research directions for this project
Associated abstract:
Nielsen C et al. Dapiglutide for the treatment of obesity: a double-blind, placebo-controlled, proof-of-concept study. LBA 07. EASD 24
Questions:
- What was the rationale for investigating dapiglutide as a treatment for obesity?
- Could you provide a brief summary of the study’s aims and design?
- What are the initial findings from the study?
- What factors might have contributed to these outcomes?
- What questions remain unanswered and what future studies are planned?
Disclosures: Casper Nielsen discloses grant/research support from Zealand Pharma A/S.
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Transcript:
Well, hello. So my name is Casper Nielson, and I’m a Postdoctoral Researcher at Gentofte Hospital at the Centre for Clinical Metabolic Research in Copenhagen, Denmark.
Q: What was the rationale for investigating dapiglutide as a treatment for obesity?
Obesity associated low-grade inflammation is highly, prevalent, 70-90% of all individuals with a BMI of 30 or greater, have low-grade inflammation as determined by a CRP of 200 mg/dL or greater. And the reason for this is, is speculated to be both adipose tissue dysfunction, but definitely also an impaired intestinal barrier function.
So, this is also coined the leaky gut theory. So this intestinal barrier function, or lack thereof is, leading to excess translocation of pro-inflammatory matter and pathogen species across the from the gut lumen into the circulation. And we know this, precipitates a lot of the comorbidities seen with people of, of the BMI of 30 or greater, such as cognitive decline and insulin resistance leading to type 2 diabetes, but also cardiovascular risk. It is an independent factor of that in itself. So that dapiglutide, which is a dual GLP-1/GLP-2 receptor agonist, targets both the GLP-1 components, which is predominantly reducing body weight, but GLP-2 is a pretty potent, intestinal traffic hormone that restores the intestinal barrier function by the means of improving mucus layer, but also improving the really high crypt depth ratio, which is pivotal in maintaining a an intestinal barrier function.
Q: Could you provide a brief summary of the study’s aims and design?
The study was aimed for weight reduction. It was a weight management, study, albeit only pharmacological driven. So there was no adjunct, to lifestyle intervention or, for example, instruction of a daily calorie deficit or an increased physical activity level, which is seen with all other weight management trials. So we wanted to see the pure pharmacological effects of a dual GLP-1/GLP-2 receptor agonist. That was the primary [endpoint] that was the weight management, subsequently to that was the intestinal trophic effects of diabetic leukocyte in the gut.
So we conducted gastric endoscopies, and collected duodenal biopsies, and we are currently looking at those biopsies to see whether or not the really high crypt depth ratio has been improved, and which should indicate an improved intestinal barrier function. The design was a, it was a parallel design, placebo-controlled, double-blinded, randomized study, phase 2a, I call it proof-of-concept as well, as it’s never been tested in this population before, it has been tested in a multiple ascending dose trial in lean young healthy men, and it is based on a 4.3% weight reduction seen in lean young healthy men a couple of years ago, over the course of just four weeks. So this was over the course of 12 weeks treatment with either 6mg of dapaglutide, 4mg dapaglutide, or placebo.
Q: What are the initial findings from the study?
So far, the study did not meet its primary endpoint. We observed indications towards that dapiglutide could be beneficial in reducing body weight in persons living with obesity. However, when comparing to placebo, we did not, the p-value did not meet the threshold for statistical significance, indicating that while there was there was a trend, a clear trend in reducing body weight, we could not definitively conclude treatment effect. We did observe indications towards a reduced weight circumference, which would support, of course, a body weight reduction. We’re still looking at the pending inflammatory panels and so on.
Q: What factors might have contributed to these outcomes?
Well, obviously, the lack of lifestyle modification might play, a certain role, either additive or synergistic, maybe also. That definitely has something to do with that. The dose might be in the lower therapeutic range. A few, or actually a couple of the participants stated the feeling of reduced appetite, rather, was sort of diminished by the end of the trial period, which could indicate a high dose might be more suitable, in inducing these weight reductions. It was a fairly small study, 18 participants in each arm, which makes it susceptible to, you know, variance, natural variance, which occur, but, definitely, also, a rather high placebo effect. There was a rather high placebo effect in the placebo group with a 2.2% weight reduction after 12 weeks. It’s almost twice as high as we typically see in other weight management trials, which actually uses lifestyle interventions as an adjunct.
What questions remain unanswered and what future studies are planned?
So, I’m not responsible for the compound that we could type that is Zealand Pharma, who are the owner of that compound. And I know that they are scheduling, larger and longer studies and just announced, this Monday that a phase 1b trial has been completed, demonstrating an 8.3% weight reduction after 13 weeks of 13mg dapiglutide, so one or twice a higher dose that we tested, And they’re planning doses up to 26mg, 28 weeks. So, that’s more than four times the dose that we tested. For us, at this centre we are very much interested in the gut and then how, the interplay is between the gut and the liver and the brain. So a lot of the biopsies that we collected during the sub study and a lot of inflammatory markers and also gut barrier markers are currently being analyzed at various labs. So, that’s pending.
Interviewer/Editor: Gina Furnival
Cite: Nieslen C. Dual GLP-1/GLP-2 receptor agonist, dapiglutide, shows similar weight loss to placebo but may aid weight reduction. touchENDOCRINOLOGY. September 19, 2024.
