Dapiglutide

Dapiglutide (ZP 7570; CAS 2296814-85-0; molecular formula C192H302N46O57; molecular weight 4166.79 g/mol) is a synthetic 33-amino-acid peptide dual agonist of the human glucagon-like peptide 1 receptor (GLP-1R) and glucagon-like peptide 2 receptor (GLP-2R) bearing a C18 fatty acid acyl modification that extends plasma half-life to approximately 123 to 129 hours and permits subcutaneous administration [1, 2]. Developed by Zealand Pharma A/S (Copenhagen, Denmark) as a potential first-in-class agent for obesity and its inflammatory comorbidities, dapiglutide was designed to exploit the complementary pharmacology of the two incretin receptors: GLP-1R activation suppresses appetite, delays gastric emptying, and improves glucose homeostasis through cyclic adenosine monophosphate (cAMP)-dependent signaling in pancreatic beta cells, hypothalamic appetite circuits, and vagal afferents; GLP-2R activation promotes intestinal epithelial proliferation, enhances paracellular tight junction integrity, and suppresses mucosal inflammation through cAMP-dependent signaling in enteroendocrine cells, subepithelial myofibroblasts, and enteric neurons [3, 4]. At the molecular level, dapiglutide exhibits biased agonism at the GLP-1R, displaying full agonist activity for cAMP formation while producing significantly blunted beta-arrestin recruitment, a signaling profile associated with reduced receptor desensitization and sustained intracellular cAMP production for up to 12 hours in vitro [5]. The compound entered clinical development in 2020 with a Phase 1 single-ascending-dose and multiple-ascending-dose trial in healthy volunteers demonstrating dose-proportional pharmacokinetics, a favorable safety profile dominated by mild gastrointestinal adverse events, and dose-dependent body weight reductions of up to 4.3 percent from baseline after four weeks of dosing [1, 2]. A subsequent 13-week Phase 1b multiple-ascending-dose extension in 54 participants with overweight or obesity (BMI 27 to 40 kg/m2) reported placebo-adjusted body weight reductions of up to 8.3 percent, with no severe treatment-emergent adverse events [6]. A 28-week extension of the same trial (Part 2, 30 participants, doses up to 26 mg) reported mean body weight reduction of 11.6 percent versus 0.2 percent on placebo, with continued favorable tolerability [7]. An investigator-led mechanistic trial (DREAM; 54 participants with obesity, BMI greater than or equal to 30 kg/m2) evaluated lower doses (4 mg and 6 mg) over 12 weeks and reported body weight reductions of 2.9 and 4.3 percent respectively versus 2.2 percent on placebo; the primary endpoint did not achieve statistical significance, though HbA1c reduction was significant at 6 mg [8, 9]. The preclinical pharmacology of dapiglutide includes demonstration of intestinal barrier repair in murine short bowel syndrome models, where the compound promoted claudin-7 expression, tightened the paracellular leak pathway, improved oral glucose tolerance, reduced intestinal transit time, increased villus height and intestinal length, and reduced stool water losses [10, 11]. Zealand Pharma paused the dapiglutide program in 2025, citing portfolio prioritization in an increasingly competitive metabolic disease landscape, though the Phase 1b 28-week data were subsequently reported as positive [7, 12]. The compound is not approved in any jurisdiction. It is available from select research chemical suppliers for investigational use only.