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Due to the high expression profile of GLP-1R in pancreatic -cells, GLP-1 analogs (such as exendin-4) have been modified by different methods (to prolong half-life, maintain receptor binding affinity and reduce renal drug accumulation) for theranostic purposes and serve as excellent templates for future cardiovascular drug development[178-184]

Traditional islet or pancreas transplantation can restore function but is limited by donor shortages and variable quality

Semaglutide emerged from Novo Nordisks systematic GLP-1 analogue optimisation programme as the successor to liraglutide , incorporating structural modifications addressing the three principal pharmacokinetic vulnerabilities of native GLP-1: DPP-IV susceptibility at position 8 addressed by Aib8 alpha-aminoisobutyric acid substitution, proteolytic cleavage at position 34 addressed by Arg34Lys substitution, and the short half-life of unmodified GLP-1 analogues addressed by the C18 fatty diacid conjugation providing tighter albumin binding and longer half-life than liraglutides C16 fatty acid, producing the approximately one-week half-life enabling once-weekly subcutaneous administration