Type 2 diabetes management has been revolutionized by improvements in glycemic control and cardiovascular complications mediated by glucagon-like peptide 1 (GLP-1) mimetics, like semaglutide. While single agonists can induce weight loss by targeting one entero-pancreatic hormonal pathway, an approach targeting multiple pathways, either within the same molecule or by combining different single agonists, may boost benefits.

In the symposium, Efficacy and Safety of CagriSema 2.4mg/2.4mg in Adults with Overweight/Obesity—The REDEFINE 1 and REDEFINE 2 Clinical Trials, on Sunday, June 22, at the 85^th Scientific Sessions, experts discussed findings from two phase 3 studies that evaluated the efficacy of combined treatment with an amylin analog and a GLP-1 receptor agonist in inducing weight loss in individuals living with obesity or overweight.

“More than one in five participants lost ≥30% body weight with CagriSema,” said W. Timothy Garvey, MD, MACE, Professor of Nutrition Science at the University of Alabama at Birmingham, who presented topline efficacy REDEFINE-1 findings. CagriSema is a combination of cagrilintide and semaglutide.

In the phase 3 REDEFINE-1 trial, 3,417 adults without concomitant diabetes, but with ≥1 non-diabetes comorbidity, were randomized to receive either CagriSema, cagrilintide alone, semaglutide alone, or placebo. In addition to the co-primary endpoints of relative change in body weight and proportion of patients achieving ≥5% weight reduction, the study evaluated other endpoints, including the proportion of patients achieving various levels of weight loss, change in waist circumference, body mass index (BMI), and glycemic parameters. In 250 patients across treatment arms, body composition was assessed.

REDFINE-1 participants in the CagriSema arm achieved a mean weight loss of 22.7%, making the results for CagriSema on par with tirzepatide (15 mg) in SURMOUNT-1, Dr. Garvey noted. Results for the semaglutide arm were on par with semaglutide (2.4 mg) in STEP-1.

CagriSema also improved secondary outcomes, including waist circumference, BMI, blood pressure and lipid profiles, and glycemia.

“Notably, at the end of the study, 56.4% of participants treated with CagriSema were no longer categorized as obese,” Dr. Garvey said.

Both the first amylin analog (pramlintide) and the first GLP-1 analog (exenatide) were licensed in 2005. In preclinical studies, combined treatment with amylin analogs and GLP-1 mimetics induced weight loss and reduced energy expenditure. This evidence supports clinical investigation of the combination approach in people living with obesity/overweight, said Thomas A. Lutz, DVM, PhD, Professor of Veterinary Physiology, Institut für Veterinärphysiologie, Universität Zürich, Switzerland, who discussed the rationale for combining semaglutide with cagrilintide.

Amylin, a peptide hormone that is co-secreted with insulin in the pancreas, acts on neurons in the area postrema in the hindbrain, mediating reduced food intake and slowed gastric emptying. GLP-1, which increases glucose-stimulated insulin secretion, has similar physiological effects, acting globally on similar brain regions as amylin.

The body composition analysis in 250 REDEFINE patients indicated that the weight reduction was driven primarily by loss of fat mass, and Dr. Garvey said there was an “impressive decline” in BMI, regardless of the dose received. These data were accompanied by improvements in patient-reported outcomes, including increased physical activity.

In REDFINE-2, patients also experienced notable weight loss, achieving a mean weight reduction of 15.7% with CagriSema.

REDEFINE-2, which enrolled 1,200 adults with type 2 diabetes living with obesity or overweight, compared the efficacy of Cargisema with placebo, with the same co-primary and secondary endpoints as REDEFINE-1. Continuous glucose monitoring (CGM) measures were included as glycemia endpoints.

“Nearly nine out of 10 patients in the CagriSema arm achieved ≥5% weight reduction,” said Melanie J. Davies, CBE, MB, ChB, MD, Professor of Diabetes Medicine at the University of Leicester Diabetes Research Centre, United Kingdom, adding that nearly one-third achieved weight loss ≥20% with CagriSema, compared to 0.2% with placebo.

Dr. Davies prefaced the REDEFINE-2 findings with the reminder that people living with type 2 diabetes and overweight/obesity tend to lose less weight with GLP-1−targeted therapies than those living with overweight/obesity without concomitant type 2 diabetes.

In addition to weight loss, CagriSema also improved glycemia outcomes, with over 80% of CagriSema-treated patients achieving A1C reduction thresholds and a mean A1C reduction of 2.07. CagriSema increased the time in tight glycemic range, based on CGM assessments; also, more patients achieved normoglycemia with CagriSema.

CagriSema was associated with a low incidence of hypoglycemia, with two severe hypoglycemia events reported, both in patients who were receiving concomitant sulfonylurea drugs.

CagriSema also improved cardiometabolic parameters and physical function in REDEFINE-2, including among patients who reported having very poor physical function at baseline.

“These are spectacular best-in-class results,” said Louis J. Aronne, MD, DABOM, Sanford I. Weill Professor of Metabolic Research at the Weil Cornell Medicine Comprehensive Weight Control Center, who reviewed the clinical implications of the REDEFINE findings.

The studies demonstrate the power of treating obesity and overweight to enable improvements beyond weight, across cardiometabolic risk factors, he said.

Baseline characteristics of the trial participants were balanced between treatment groups in both studies and reflected a wide population, allowing generalization of data findings, said Julio Rosenstock, MD, Senior Scientific Advisor for Velocity Clinical Research, Director of Velocity’s site at Medical City Dallas, and Clinical Professor of Medicine at the University of Texas Southwestern Medical Center. He reviewed the rationale and design of the REDEFINE trials, both of which had high rates of treatment completion.

“Overall, 75% of participants randomized to CagriSema reached the final 2.4 mg/2.4 mg dose during the trials,” he said.

Safety findings from the REDEFINE trials, shared by Sue D. Pedersen, MD, FRCPC, DABOM, C-ENDO, and Clinical Lecturer, Cumming School of Medicine, University of Calgary, Canada, indicated an adverse event (AE) profile for CagriSema consistent with those of cagrilintide and semaglutide individually.

In both studies, the most common AEs were gastrointestinal, the onset of which occurred mainly during dose-escalation. Nausea, the most common gastrointestinal complaint, was mostly mild/moderate and transient in nature.

The primary analyses of REDEFINE-1 and REDEFINE-2 were published in the New England Journal of Medicine, concurrent with the symposium.

On-demand access to recorded presentations will be available to registered participants following the conclusion of the 85^th Scientific Sessions, from June 25–August 25.