CagriSema (Cagri+Sema)

One vial, two principles of action: CagriSema unites the amylin analog cagrilintide and the GLP-1 agonist semaglutide in a ready-made mixture. The two components engage independent cellular pathways whose effects on satiety and gastric emptying added up in preclinical studies.

The idea behind it: GLP-1 agonists alone reach sizeable effects on body weight in trials but hit a measurable plateau. When the amylin pathway is activated in parallel, the reduction goes beyond that in preclinical models. In the phase 1b work by Friedrichsen et al., the additive effect reached a magnitude close to the next generation of multi-agonists.

What the trials have shown since:

• Phase 1b, 95 participants: after 20 weeks, 17.1 percent weight loss with 2.4 mg cagrilintide, compared with 9.8 percent with semaglutide plus placebo.
• Phase 2 in type 2 diabetes, 92 participants, 32 weeks: minus 15.6 percent with the combination, minus 5.1 percent with semaglutide alone, minus 8.1 percent with cagrilintide alone; HbA1c fell by 2.2 percentage points.
• REDEFINE 1 (phase 3), 3417 adults without diabetes, 68 weeks: minus 20.4 percent versus minus 3.0 percent with placebo.
• REDEFINE 2 (phase 3), 1206 adults with type 2 diabetes, 68 weeks: minus 13.7 percent versus minus 3.4 percent.

The pre-mix saves a reconstitution step and fixes the ratio of the two constituents. Since both have half-lives of several days, the trials dosed weekly and raised the concentration slowly to keep nausea from the GLP-1 component low.

According to the studies, CagriSema is well tolerated overall. Because a GLP-1 agonist and an amylin analog meet here, the gut effects of both constituents add up; in REDEFINE 1, gastrointestinal adverse events occurred in 79.6 percent versus 39.9 percent on placebo.

• Stomach and bowel: nausea, vomiting, diarrhea and constipation come first, mainly early and during escalation; raising the concentration slowly lowered the rate.
• Fluids: two satiety pathways at once noticeably depress food and fluid intake in the studies, and the literature describes a higher risk of dehydration.
• Muscle mass: a portion of the weight lost in the studies is muscle.
• Gallbladder and injection site: gallbladder complaints during rapid weight loss and mild local irritation are documented.
• Evidence: the combination is young, and figures on very long use do not exist yet.

This summary is no substitute for medical advice.

• Cagrilintide with semaglutide 2.4 mg: randomised phase 1b trial - the first combination trial; mostly mild to moderate adverse events, semaglutide exposure unchanged.
• Co-administered cagrilintide 2.4 mg with semaglutide 2.4 mg in type 2 diabetes: phase 2 trial - the 32-week trial behind the three-arm figures and the HbA1c value.
• Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity - REDEFINE 1, phase 3 without diabetes.
• Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes - REDEFINE 2, phase 3 with type 2 diabetes.
• Once-weekly cagrilintide for weight management - cagrilintide on its own, as the baseline for the single component.