Tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in the management of type 2 diabetes: the SURPASS trials

Ideally, innovative therapeutic approaches for the treatment of type 2 diabetes (T2D) should contribute to both reduction in glycated haemoglobin (HbA1c) and weight loss, and demonstrate superior efficacy over currently available treatment options. Tirzepatide (LY3298176) is an incretin hormone agonist that was developed to activate both glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptors and is approved in a number of countries, including the US and EU, for the treatment of T2D. The efficacy and safety of tirzepatide are being investigated in the SURPASS phase 3 clinical trial programme and are summarised herein. Tirzepatide 5, 10 and 15 mg was evaluated as monotherapy and in combination with accepted oral antidiabetes drugs and/or insulin in patients with T2D (SURPASS 1, versus placebo; SURPASS 2, versus semaglutide; SURPASS 3, versus insulin degludec; SURPASS 4, versus insulin glargine in patients with high cardiovascular risk; SURPASS 5, versus placebo). Across the SURPASS-1 to -5 studies, all dose regimens of tirzepatide were associated with mean reductions in HbA1c of 1.87-2.59% at either week 40 or 52 that were consistently significantly greater than changes seen in comparator groups. Tirzepatide showed superior effects on body weight reduction compared to all active comparators and placebo in these trials. Overall, available data indicate that tirzepatide is well tolerated with a gastrointestinal tolerability profile comparable to other incretin agonists, and a very low rate of hypoglycaemic events, which can be expected based on its mechanism of action. The novel dual mechanism of action and associated added clinical benefits has established tirzepatide as a first-in-class GIP/GLP-1 receptor agonist. It will also be of interest to see outcomes from the ongoing SURPASS-CVOT trial, which will assist understanding of what cardiovascular benefits tirzepatide may offer, given its benefits for improved glycaemic control and weight reduction.