#EASD2025: Cagrilintide demonstrates encouraging results in obesity treatment

TouchENDOCRINOLOGY coverage from EASD 2025:

At the EASD 2025 congress (Vienna, Austria; 15–19 September), Dr W. Timothy Garvey presented findings from a post hoc analysis of the REDEFINE 1 (NCT05567796) trial, which evaluated cagrilintide 2.4 mg as a monotherapy in adults with overweight or obesity. Cagrilintide is a long-acting amylin analogue that acts on appetite-regulating centres in the brain, reducing caloric intake and supporting weight management.

The analysis demonstrated clinically meaningful reductions in body weight and waist circumference, alongside improvements in cardiometabolic risk factors, with a safety profile distinguished by lower rates of gastrointestinal side effects compared with GLP-1–based therapies. These findings highlight the potential role of cagrilintide as a well-tolerated monotherapy within the expanding treatment landscape for obesity.

We spoke with Dr Garvey to learn more about the mechanism of action of cagrilintide, the design and outcomes of the REDEFINE 1 analysis, and the future directions for this promising therapeutic option.

Q. Cagrilintide is a long-acting amylin analogue. Could you briefly explain its mechanism of action and why it might be an effective treatment for overweight/obesity?

Cagrilintide is a nutrient-stimulated hormone analogue. After eating, amylin is released from the pancreatic beta cells, the same cells that secrete insulin, into the bloodstream. It acts on regions of the brain such as the hypothalamus and the area postrema in the brainstem to reduce appetite. In this way, it functions as an anorexigenic agent, helping patients control appetite and caloric intake, which makes it a promising treatment for overweight and obesity.

Q. Could you outline the design and key objectives of this post hoc analysis of the REDEFINE 1 trial?

The REDEFINE 1 trial was a landmark phase 3 study evaluating the safety and efficacy of the combination of cagrilintide, an amylin analogue, with semaglutide, a GLP-1 receptor agonist. This combination, known as CagriSema, was compared with semaglutide alone, cagrilintide alone, and placebo. CagriSema was shown to be highly effective, achieving around 22% weight loss, though with the expected gastrointestinal side effects typical of GLP-1 receptor agonists.

In this post hoc analysis, we focused specifically on cagrilintide monotherapy. The clinical need we aimed to address is for therapies that can provide around 15% weight loss, enough to significantly improve health and quality of life, and sufficient to prevent or treat many obesity-related complications. Not all patients need 25–30% weight loss, and for many, that level may not be appropriate. Equally important is tolerability: GLP-1 receptor agonists are effective but often associated with gastrointestinal side effects, especially nausea, due to their action in brain regions that regulate both appetite and nausea. Patients shouldn’t have to feel unwell in order to benefit from obesity treatment, and improving tolerability is critical for long-term adherence.

Q. What were the most important efficacy and safety findings from this analysis, particularly regarding weight loss, waist circumference and gastrointestinal adverse events?

In this focused analysis of the cagrilintide arm, treatment produced around 11–12% weight loss, which is a clinically meaningful response. Gastrointestinal side effects were observed but were less frequent than with GLP-1–based medications. The incidence of nausea was approximately one-third to half that observed with GLP-1 therapies, while vomiting occurred at rates comparable to placebo, whereas GLP-1 therapies typically cause vomiting in about 25% of patients. Since vomiting is often the most troublesome side effect for patients, this difference is important.

In addition to weight reduction, we observed improvements in waist circumference, blood pressure, glucose levels, lipid profile, and reductions in C-reactive protein, an inflammatory marker. These benefits suggest cagrilintide may provide broad cardiometabolic improvements. Taken together, the efficacy and tolerability profile suggest that cagrilintide could fill an important gap as a well-tolerated, moderately effective monotherapy for obesity.

Q. How do you see these results shaping the potential role of cagrilintide as a monotherapy within the evolving treatment landscape for obesity, particularly compared with existing GLP-1–based therapies?

We are entering an era where multiple medications can achieve 20% or greater weight loss, what I call the second generation of obesity therapies, which include high dose semaglutide and tirzepatide. Many other agents with this level of efficacy are advancing through phase 2 and 3 trials.

However, almost all these agents act through GLP-1 receptor agonism and therefore share the gastrointestinal side effects of nausea and vomiting. Cagrilintide offers a different approach: as a non-GLP-1–based therapy, it has a more favourable tolerability profile. I see its role particularly for patients who need clinically meaningful weight loss but who may not tolerate GLP-1–based drugs, or for those who do not have comorbidities like cardiovascular disease, metabolic-associated steatohepatitis, or heart failure, conditions where GLP-1 therapies provide additional proven benefits. For patients without those complications, cagrilintide could represent a well-tolerated monotherapy option.

Q. What are the next steps for clinical research on cagrilintide and what unanswered questions remain about its long-term benefits and tolerability?

As with all anti-obesity medications, we need longer-term data. Cagrilintide also has a strong profile as part of combination therapy. One promising approach is pairing long-acting amylin analogues like cagrilintide with lower doses of GLP-1 receptor agonists, which could preserve efficacy while improving tolerability and maintaining the cardiometabolic benefits of GLP-1 agonism.

Beyond that, we are entering an era of nutrient-stimulated hormone combinations, GLP-1, GIP, glucagon and amylin, in dual and even triple agonist therapies. Cagrilintide adds another tool to this landscape, and its role in both monotherapy and combination therapy will become clearer as these studies progress.