Visual Abstract

HISHS-2001 is a novel long-acting, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual receptor (R) agonist. In in vitro cAMP assays in human GIP/GLP-1 receptor-expressing cells, HISHS-2001 exerted half-maximal effects at concentrations of 2.3 nM and 4.1 nM on the receptors for GIP (GIPR) and GLP-1 (GLP-1R) respectively. After SC dosing every third day for four weeks, HISHS-2001 at 3, 10 and 21 nmol/kg demonstrated robust effects on HbA1c in db/db mice which were superior to semaglutide and tirzepatide (Table). The effect on body weight was more pronounced with HISHS-2001 than semaglutide and similar to tirzepatide which was associated with a reduction in food intake. Interestingly, HISHS-2001 led to a significant increase in uncoupling protein-1 (UCP-1) levels in intrascapular brown adipose tissue, in inguinal white adipose tissue and serum and liver fibroblast growth factor-21 (FGF-21) levels. A decrease in serum interleukin-6 (IL-6) level was also observed.

In conclusion, HISHS-2001 is a potent, long acting GIP/GLP-1R dual agonist, which provides improved control of glucose homeostasis in diabetic mice compared to an existing GLP-1 agonist and a GIP/GLP-1R dual agonist.


V. S. Burade: None. A. Garcia-ocana: Consultant; Self; Sun Pharmaceutical Industries Ltd. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. G. A. Rutter: Advisory Panel; Self; Sun Pharmaceutical Industries Ltd. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. B. Thorens: Advisory Panel; Self; Sun Pharmaceutical Industries Ltd. R. Thennati: None.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at