<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>In treating short‐bowel syndrome (SBS), autonomy from parenteral nutrition (PN) relies upon intestinal adaptation, which can be augmented by glucagon‐like peptide‐2 (GLP‐2) analogues. In neonatal piglets with SBS, we compared intestinal adaptation following treatment with 2 GLP‐2 analogues: teduglutide (TED) and apraglutide (APRA)</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Following 75% distal small‐intestinal resection, piglets were allocated to 4 treatment groups: saline (CON: n = 8), twice weekly APRA (5 mg/kg/dose; n = 8), and TED once daily (TED, 0.05 mg/kg/dose; n = 8) or twice daily (TEDBID, 0.05 mg/kg/dose; n = 7). Pharmacokinetic (PK) studies were undertaken, and on day 7, small‐intestinal length and weight were measured and jejunal tissue collected for histology.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>PK profiles were different between the 2 analogues. To achieve a comparable exposure to APRA, TED requires twice daily injection (TEDBID). Compared with CON, APRA and TEDBID increased small‐bowel length (cm) (CON: 141, APRA: 166, TED: 153, TEDBID: 165; <jats:italic>P</jats:italic> = .004), whereas APRA increased small‐bowel weight (g) (CON: 26, APRA: 33, TED: 28, TEDBID: 31; <jats:italic>P</jats:italic> = .007) and villus height (mm) (CON: 0.59, APRA: 0.90, TED: 0.58, TEDBID: 0.74; <jats:italic>P</jats:italic> < .001).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>APRA injected only twice during the 7 consecutive days demonstrated a superior intestinotrophic effect compared with TED injected once daily. Even at more comparable drug exposure, when TED was injected twice a day, APRA showed superior trophic activity at the mucosal level. This is highly relevant for the treatment of pediatric SBS, given the markedly lower dose frequency by subcutaneous injection of APRA.</jats:p></jats:sec>