Type 2 diabetes and obesity are responsible for a large global burden of morbidity and mortality in the form of cardiovascular disease, kidney disease, and retinopathy. Analogues of the incretin GLP-1 have helped to transform the face of type 2 diabetes treatment, combining effective reductions in glycaemia with clinically useful weight loss. More importantly, GLP-1 analogues are proven to reduce mortality, the risk of cardiovascular events, and progression of diabetic kidney disease. 1 Kristensen SL Rørth R Jhund PS et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.

Lancet Diabetes Endocrinol. 2019; 7: 776-785

However, the achievable doses and efficacy of GLP-1 analogues can be limited by their adverse effects, mainly gastrointestinal in nature, such as nausea, vomiting, gastro-oesophageal reflux, and alterations in bowel habit. 2 Sorli C Harashima SI Tsoukas GM et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.

Lancet Diabetes Endocrinol. 2017; 5: 251-260

In the search for the next step beyond GLP-1, researchers have explored suitable companion treatments to obtain enhanced efficacy. 3 Combination gut hormones: prospects and questions for the future of obesity and diabetes therapy.

J Endocrinol. 2020; 246: R65-R74

The other incretin, glucose-dependent insulinotropic polypeptide (GIP), is, on first look, a natural partner to GLP-1 and is the more dominant insulinotropic hormone in normal physiology. 4 Holst JJ Gasbjerg LS Rosenkilde MM The role of incretins on insulin function and glucose homeostasis.

Endocrinology. 2021; 162bqab065

Tirzepatide, a unimolecular dual agonist of GLP-1 and GIP receptors, was developed with this so-called twincretin concept in mind. 5 Coskun T Sloop KW Loghin C et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept.

Mol Metab. 2018; 18: 3-14