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The New England Journal of Medicine commentary accompanying SURPASS-2 stated: "The dual incretin approach appears to exploit receptor crosstalk in ways that amplify downstream insulin secretion beyond what GLP-1 receptor agonism alone can achieve at comparable tolerability." [30] SURPASS-1: Monotherapy Benchmark SURPASS-1 (N=478) established monotherapy efficacy, with tirzepatide 15 mg reducing A1C by 2.07 percentage points and body weight by 9.5 kg at 40 weeks versus placebo [31]