Hi there, my name is Sue Pedersen. I'm a specialist in endocrinology and metabolism, and a diplomat of the American Board of Obesity Medicine, and I practise at C-endo Clinic in Calgary, Alberta, Canada. I'm also a clinical lecturer at the University of Calgary.

What were the primary objectives of the REDEFINE Trials?

The primary objective of the REDEFINE 1 trial was to investigate the efficacy and safety of CagriSema in people with overweight or obesity. The REDEFINE 2 trial investigated the efficacy of CagriSema for weight management in adults with type 2 diabetes. The co-primary endpoints in both trials were relative change in body weight and proportion of patients achieving at least 5% weight reduction at 68 weeks.

What was the rationale for combining cagrilintide and semaglutide, and how does this dual mechanism approach differ from existing therapies?

Our natural human biology vigorously defends our body weight in part because we have many satiety hormones that decrease with weight loss. So in development of highly efficacious weight management medications, it makes sense to combine more than one satiety hormone with complementary mechanisms of action so as to provide a better sense of fullness, thereby facilitating weight loss and improving weight-related health issues.

Semaglutide of course is a GLP-1 receptor agonist, and we know that GLP-1 receptor agonists reduce appetite centrally. GLP-1 can also reduce cravings for some people. Cagrilintide is an amylin analogue. Amylin is a satiety hormone released by the pancreas in response to nutrient intake. It also works to decrease appetite centrally and both hormones also slow gastric emptying.

Combining cagrilintide and semaglutide differs from existing therapies in that there are no currently available treatments that include amylin analogue therapy for weight management. Amylin analogue therapy has the potential for unique benefits beyond weight loss which are currently under exploration.

What was the study design and patient population?

The REDEFINE 1 trial was a randomised study of 3,417 adults with BMI 30 or greater or BMI of 27 or greater with obesity-related health complications without diabetes. Patients were randomised in a 21:3:3:7 ratio to receive either CagriSema 2.4/2.4 milligrammes weekly, semaglutide monotherapy 2.4 milligrammes weekly, cagrilintide monotherapy 2.4 milligrammes weekly or placebo for 68 weeks.

The REDEFINE 2 trial was a randomised study of 1,206 adults with BMI 27 or greater with type 2 diabetes, randomised to receive either kegrisema 2.4/2.4 milligrammes weekly or placebo in a 3:1 ratio.

Our study was the first phase 3 weight management study in people with type 2 diabetes to include continuous glucose monitoring in a subset of patients so we could have an in-depth assessment of glucose profiles with CagriSema verses placebo.

What were the key findings?

In REDEFINE 1 at 68 weeks, weight loss was 20.4% with CagriSema, 14.9% with semaglutide 2.4 milligrammes, 11.5% with cagrilintide 2.4 milligrams weekly, verses 3% with Placebo. Weight loss of at least 25% was seen in 35% of people in the CagriSema group, 15% of people in the semaglutide group, 7% in the cagrilintide group, and 1% of those with placebo.

Health improvements were seen with CagriSema including impressive improvements in blood pressure, a 9.9 millimetre reduction in systolic BP with CagriSema, versus 3.2 millimetres of mercury with placebo. Improvement in metabolic health parameters and physical function were also seen.

The most common side effects were gastrointestinal, numerically a little more common with CagriSema than in the other treatment groups, and mostly mild to moderate in severity. These were most commonly seen during dose escalation and decline thereafter. GI side effects with cagrilintide monotherapy were generally less than with either CagriSema or semaglutide but a little more than placebo. A slightly greater proportion of people in CagriSema group had hepatobiliary adverse events such as gallstones.

The need to stop treatment due to adverse events was quite low in all groups: 6% with CagriSema, 3.6% with semaglutide, 2.6 with cagrilintide, and 3.7% with placebo.

Now in the REDEFINE 2 trial at 68 weeks, weight loss was 13.7% with CagriSema versus 3.4% with placebo. Weight loss of at least 20% was seen in 29% of people with CagriSema versus just 0.2% with placebo. Haemoglobin A1C was reduced by 1.8% with CagriSema versus 0.4% with placebo.

In our continuous glucose monitoring data, we found that time and range at the end of the study was 88% with CagriSema versus 51% with placebo. Greater improvements in blood pressure, metabolic health parameters and physical function were seen with CagriSema.

In terms of safety, the most common side effects with CagriSema were again gastrointestinal, mostly mild to moderate and transient with dose escalation. The need to stop treatment due to adverse events, mostly gastrointestinal, occurred in 8% of the CagriSema group and 3% of the placebo group.

Severe low blood sugars were seen in two people in the CagriSema group. These two people were also on Sulfonylureas which is a medication known to cause low blood sugar.

How does CagriSema potentially fit into existing obesity treatment algorithms alongside lifestyle interventions and other pharmacotherapies?

The weight loss results with CagriSema are similar to the results in studies of other highly efficacious therapies such as tirzepatide, known as Mounjaro or Zeppbound, in similar patient groups, and tolerability is similar to that of other GLP-1 based medications.

Different treatments work for different people, so CagriSema will present an additional option in the toolbox as a highly effective obesity pharmacotherapy. It will be interesting and important to see how CagriSema might benefit health conditions associated with obesity. It's currently being studied in a cardiovascular outcome trial in people with and without type 2 diabetes and for potential benefit to nerve pain.

I'm also really keen to see if there may be any benefit in terms of preservation of bone with weight loss.

How might these findings influence obesity treatment guidelines and clinical practice?

Should CagriSema become approved by regulatory bodies? CagriSema will present a new treatment option as a highly efficacious pharmacotherapy for obesity. In determining the appropriate pharmacotherapy for our patients, our Obesity Canada guidelines recommend partnering with the patient to identify treatment goals which may include improvement in obesity-related health issues and values based goals that are important to the patient, which may or may not include magnitude of weight loss.

We recommend selection of pharmacotherapy taking into consideration which obesity-related health issues that individual has and recommending pharmacotherapy that has shown benefit for that particular health concern. For some patients their value is to achieve a larger magnitude of weight loss.

That's what's important to them, and CagriSema would certainly fall into that category as highly efficacious treatment. As we learn more about new and emerging pharmacotherapies and their benefits to obesity related health issues, this will help us to further refine our selection of pharmacotherapy as appropriate to each patient.