For people with type 2 diabetes whose basal insulin has stopped doing enough, the standard next move — more insulin — usually means more weight and more hypoglycemia. REIMAGINE 3, published June 7 in The Lancet, tests a different add-on: cagrilintide-semaglutide (CagriSema), Novo Nordisk’s once-weekly combination of the amylin analogue cagrilintide with the GLP-1 receptor agonist semaglutide.

The double-blind, placebo-controlled phase 3a trial randomized 274 adults across 46 centres in six countries (the USA, China, Japan, Serbia, Slovakia, and South Africa). All were on stable once-daily basal insulin, with or without metformin, and entered with a mean HbA1c of 8.8%. Participants were assigned 2:2:1:1 to CagriSema 2.4 mg/2.4 mg (n=90), CagriSema 1.0 mg/1.0 mg (n=93), or pooled dose-matched placebo (n=91) for 40 weeks.

What the trial found

On the primary endpoint — mean HbA1c change from baseline to week 40 — the high-dose arm fell 2.33 percentage points (SE 0.08) versus 0.66 points (SE 0.11) on placebo. The 1.0 mg arm fell 2.10 points. Against placebo, that is an estimated treatment difference of −1.68 percentage points (95% CI −1.95 to −1.41) at the higher dose and −1.44 points (95% CI −1.71 to −1.17) at the lower dose, both p<0.0001.

CagriSema “met the primary endpoint, with statistically significant and clinically relevant HbA1c reductions versus placebo,” the authors write, alongside “robust bodyweight reduction and no additional risk of hypoglycaemia.”

The signature for an insulin add-on is weight: rather than the gain insulin tends to cause, CagriSema produced bodyweight reductions of 10–12%, a key secondary endpoint.

Safety tracked the GLP-1 class. Adverse events — mostly mild-to-moderate gastrointestinal complaints — affected 80% of the high-dose arm (72/90), 71% of the low-dose arm (66/93), and 71% of the placebo arm (65/91). No group had any severe hypoglycemia. One participant in the 1.0 mg arm died of a malignancy that investigators judged unrelated to treatment.

Two caveats temper the readout. At 40 weeks and 274 participants, REIMAGINE 3 is short and small, and the comparator is placebo rather than intensified insulin — so it shows that CagriSema beats doing nothing more, not that it beats the standard escalation. The trial was funded by Novo Nordisk, which employs several of the authors. CagriSema remains investigational and is not approved for type 2 diabetes — or any other use — in the USA, EU, or elsewhere.