The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type?2 Diabetes: The SURPASS Clinical Trials

摘要

Glucagon-like peptide?1 (GLP-1) based therapy is an established treatment option for the management of type?2 diabetes mellitus (T2DM) and is recommended early in the treatment algorithm owing to glycaemic efficacy, weight reduction and favourable cardiovascular outcomes. Glucose-dependent insulinotropic polypeptide (GIP), on the other hand, was thought to have no potential as a glucose-lowering therapy because of observations showing no insulinotropic effect from supraphysiological infusion in people with T2DM. However, emerging evidence has illustrated that co-infusion of GLP-1 and GIP has a synergetic effect, resulting in significantly increased insulin response and glucagonostatic response, compared with separate administration of each hormone. These observations have led to the development of a dual GIP/GLP-1 receptor agonist, known as a ‘twincretin’. Tirzepatide is a novel dual GIP/GLP-1 receptor agonist formulated as a synthetic peptide containing 39?amino acids, based on the native GIP sequence. Pre-clinical trials and phase?1 and 2 clinical trials indicate that tirzepatide has potent glucose lowering and weight loss with adverse effects comparable to those of established GLP-1 receptor agonists. The long-term efficacy, safety and cardiovascular outcomes of tirzepatide will be investigated in the SURPASS phase?3 clinical trial programme. In this paper, we will review the pre-clinical and phase?1 and 2 trials for tirzepatide in the management of T2DM and give an overview of the SURPASS clinical trials.