Challenging Clinical Perspectives in Type 2 Diabetes with Tirzepatide, a First-in-Class Twincretin

Abstract

Tirzepatide is a first-in-class GIP/GLP-1 receptor agonist ('twincretin')-a single molecule that acts as an agonist at both glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. In the SURPASS clinical trial program in type 2 diabetes mellitus (T2D), tirzepatide was associated with unprecedented reductions in HbA1c, clinically significant weight loss and other metabolic benefits, combined with low rates of hypoglycaemia across a wide range of patient characteristics. The safety and adverse event rate for tirzepatide appears comparable to that of GLP-1 receptor agonists. Although results from dedicated cardiovascular (CV) and kidney trials are currently not available, information to date suggests that tirzepatide may have CV and kidney benefits in people with T2D. Tirzepatide has been approved for the treatment of T2D in the USA, United Arab Emirates, European Union, Japan and Australia. Here, we review how tirzepatide will fit into the T2D treatment continuum. We also consider future directions with tirzepatide in T2D, including its potential for targeting cardio-renal-metabolic disease in T2D, and discuss how tirzepatide-and other co-agonists in development-may challenge current approaches for management of T2D.

Keywords: Body weight/drug therapy; Cardio-renal-metabolic disease; GIP/GLP-1 receptor agonist; SURPASS clinical trials; Tirzepatide; Twincretin; Type 2 diabetes/drug therapy.

Fig. 1

HbA1c, body weight and combined endpoint data from SURPASS-1–5 [–12]. Data are estimated mean (SE) or percentage from the efficacy analysis set of the modified intent-to-treat population. A HbA1c change from baseline (primary efficacy endpoint) [–12]. B Body weight change from baseline [–12]. Figures A and B reproduced from Diabetes Obes Metab. De Block et al. 2022 [16]. ©2022 Eli Lilly and Company and The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. Reprinted with permission from John Wiley & Sons Ltd. This is an open-access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License. C Proportion of participants achieving a composite of HbA1c < 5.7% (39 mmol/mol) and ≥ 5% weight loss, without clinically significant or severe hypoglycaemia in SURPASS-1–5; Fig. C reproduced from Lingvay I et al. 2023 [20]. ©2022 Eli Lilly and Company. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License. Figure c has also been adapted from 718-P: Patients Achieving an HbA1c < 5.7% with = 5% Weight Loss and without Hypoglycemia: A Post Hoc Analysis of SURPASS 1 to 5, American Diabetes Association, 2022 [21]. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association. *p < 0.001 superiority vs comparator [8–12]; **p < 0.001 vs comparator [21]; ^†p < 0.05 vs comparator. Met metformin, SGLT2i sodium-glucose cotransporter 2 inhibitor, SU sulfonylurea

Fig. 2

Rate of eGFR decline and change in UACR in SURPASS-4. Changes in kidney function between baseline and end of treatment for the tirzepatide (pooled doses) versus insulin glargine groups in SURPASS-4 [22]. A Rate of decline in eGFR (mL/min/1.73 m²) per year. Mean baseline eGFR 81.3 mL/min/1.73 m². B Percentage change in UACR from baseline median baseline UACR 15.0 mg/g, median treatment duration 85 weeks. ACEi angiotensin-converting enzyme inhibitors, ARB angiotensin receptor blocker, eGFR estimated glomerular filtration rate, SGLT-2i sodium-glucose co-transporter 2 inhibitor, UACR urinary albumin-to-creatinine ratio. Created using data from Heerspink et al. [22]

Fig. 3

Will tirzepatide have a potential future in CRM disease? CV cardiovascular, T2D type 2 diabetes