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.
Introduction: The glucagon-like peptide-1 receptor analogue (GLP-1RA) semaglutide is associated with improvements in glycaemia and cardiovascular risk factors in clinical trials. The aim of this study was to examine the real-world impact of semaglutide administered by injection in people with type 2 diabetes (T2D) across three secondary care sites in Wales. Methods: A retrospective evaluation of 189 patients with T2D initiated on semaglutide between January 2019 and June 2020 with at least one follow-up visit was undertaken. Results: At baseline, participants had a mean age of 61.1 years, mean glycated haemoglobin (HbA1c) of 77.8 mmol/mol (9.3%) and mean body weight of 101.8 kg. At 6 and 12 months of follow-up, mean HbA1c reductions of 13.3 mmol/mol (1.2%) and 16.4 mmol/mol (1.5%), respectively, were observed, and mean weight loss at 6 months was 3.0 kg (all p \ 0.001). At 12 months, there were significant reductions in total cholesterol (0.5 mmol/L) and alanine transaminase (4.8 IU/L). Patients naïve to GLP-1RAs or with higher baseline HbA1c at baseline had greater glycaemic reductions, although clinically significant HbA1c reductions were also observed in those who switched from other GLP-1RAs, whose body mass index was \ 35.0 and [ 35.0 kg/m 2 or who had lower baseline HbA1c. Semaglutide was generally well tolerated, although adverse-effects limited use in 18 patients (9.5%). Conclusion: Semaglutide provided clinically and statistically significant reductions in HbA1c, body weight, lipids and liver enzymes.
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