Glycaemic control and weight reduction in type 2 diabetes with weekly tirzepatide, a novel GIP/GLP-1 agonist

Results from the SURPASS-2 trial

Incretins are a group of metabolic hormones secreted by the gut during a meal, which convey insulinotropic signals to the pancreatic islet cells, thereby potentiating glucose-induced insulin secretion and modulating blood glucose levels—termed the ‘incretin effect’.

The two predominant incretin hormones are glucagon-like peptide-1 (GLP-1), which is secreted by L-cells in the jejunal mucosa, and glucose-dependent insulinotropic polypeptide (GIP), secreted by the duodenal K-cells in the duodenal mucosa. 1, 4-6 Together, these incretins are responsible for most of the incretin effect in response to oral glucose loading. 4, 7 In terms of relative importance, recent evidence suggests that GIP may be the more important incretin hormone, being responsible for approximately two-thirds of the incretin effect in healthy individuals.

Both the GLP-1 and GIP receptors are present on the pancreatic α and β cells, as well as in the brain, vasculature, heart, immune cells, gut and kidney. Interestingly, GIP receptors are also prominent on adipocytes, and are involved in enhancing their lipid-buffering capacity. 8-10

Role of incretin receptor agonists in T2D

In individuals with type 2 diabetes (T2D), the overall incretin effect is markedly impaired or absent— referred to as ‘incretin defect’. GLP-1 secretion is diminished, but with only slight impairment of its insulinotropic effects; while GIP secretion is largely maintained but with greatly reduced GIP-induced potentiation of insulin secretion. 2, 9, 11

GLP-1 and GIP receptors have thus gained increasing interest as therapeutic targets in adults with T2D. Among the established pharmacotherapy options are injectable GLP-1 receptor agonists, which bind to GLP-1 receptors and enhance the body’s natural response to food ingestion, improving glycaemic control. 12 GLP-1 receptor agonists, including semaglutide, dulaglutide and exenatide, have demonstrated efficacy in normalising plasma glucose and reducing glycated haemoglobin (HbA1c, a well-established indicator of long-term glycaemic control13), as well as enhancing weight reduction in adults with T2D. 14-17 GLP-1 receptor agonists are thus recommended early in the treatment algorithm. 18

Given the even more prominent role of GIP receptor signalling in the enteropancreatic axis, it stands to reason that GIP receptor agonists would help mitigate the severe metabolic consequences of a major loss of GIP receptor signalling in individuals with T2D.4 While human studies employing exogenous GIP have shown a very limited effect on postprandial blood glucose, 19, 20 the focus is now shifting to GIP receptor agonism.

Emerging evidence now suggests that dual agonism of both the GLP-1 receptor and the GIP receptor may be associated with a distinct mechanism of glycaemic control via a synergistic effect on β cell function and mechanisms of insulin sensitivity. 18, 21

A single molecule targeting GIP/GLP-1 receptors

Tirzepatide is a novel, first-in-class synthetic incretin recently approved in Australia for the treatment of patients with insufficiently controlled T2D, as an adjunct to exercise and a healthy diet. 8 This incretin-like drug is a longacting, injectable, single molecule with high affinity to both the GLP-1 and GIP receptors. As well as mimicking GLP-1, it demonstrates similar activity on the GIP receptor compared with the native GIP hormone. 8

Tirzepatide - a novel, long-acting, single molecule with high affinity to both the GLP-1 and GIP receptors - was recently approved – was recently approved in Australia for patients with insufficiently controlled T2D 8

Evidence supporting the use of tirzepatide in T2D is building. A meta-analysis of seven clinical trials in over 6,600 patients with T2D demonstrated a dose-dependent superiority in glycaemic control and body weight reduction with tirzepatide compared with placebo, GLP-1 receptor agonists, or basal insulin alone, without an increased risk of hypoglycaemia. 22

Notably, in the Phase 3 SURPASS series of clinical trials, tirzepatide (5–15 mg/week) was well tolerated, with a similar safety profile to that of the GLP-1 receptor agonist class of drugs. 23 Tirzepatide was associated with marked mean reductions in HbA1c of –20 to –28 mmol/mol and mean body weight reductions of –6.2 to –12.9 kg. These reductions were dose-dependent and significantly greater than that demonstrated with semaglutide 1 mg, insulin degludec, insulin glargine, or placebo with or without background insulin. In addition, markers of cardiometabolic risk including weight circumference, blood pressure, visceral adiposity and circulating triglycerides, were significantly improved in relation to baseline and versus placebo or active controls. 23 In the phase 3 SURPASS-4 trial, tirzepatide therapy in patients with T2D (with increased cardiovascular risk) reduced triglycerides and LDL cholesterol and increased HDL cholesterol compared with baseline and versus insulin glargine, on top of the benefits of background lipid-lowering therapy. 23, 24

Across the SURPASS trial series, tirzepatide was associated with marked dose dependent mean improvements from baseline in HbA1c, body weight, and markers of cardiometabolic risk, which were significant compared with placebo and/or active controls including semaglutide 1 mg or insulin 23, 24

SURPASS-2 trial

The SURPASS-2 trial (NCT03987919) was published in the New England Journal of Medicine. This 40-week, open-label, international phase 3 trial was designed to compare glycaemic control with tirzepatide versus semaglutide 1 mg in adults with T2D who were inadequately controlled on metformin ≥1500 mg/day (i.e. HbA1c of 7.0%–10.5%), and had a body mass index (BMI) of ≥25 with stable bodyweight over the preceding 3 months. 25

A total of 1,879 patients were randomly assigned (1:1:1:1) to receive weekly subcutaneous (SC) tirzepatide at a dose of 5 mg, 10 mg or 15 mg; or SC semaglutide 1 mg for 40 weeks, followed by a 4-week safety follow-up. Tirzepatide was initiated at 2.5 mg weekly, increasing in 2.5 mg increments every 4 weeks until the assigned dose was reached; semaglutide was initiated at 0.25 mg weekly, then doubled every 4 weeks until 1 mg was reached. Randomisation was stratified according to country and baseline HbA1c (≤8.5%>). The primary endpoint was HbA1c change from baseline at 40 weeks. 25

Baseline characteristics were well balanced across the cohorts; the mean age was approximately 56 years, the mean body weight was approximately 93 kg, and the mean baseline HbA1c was 8.3%. 25

Primary endpoint

At all dose levels, tirzepatide was noninferior and superior to semaglutide 1 mg in terms of HbA1c change from baseline at 40 weeks (Figure 1 ). Estimated percentage point differences between the semaglutide group and the 5 mg, 10 mg, and 15 mg tirzepatide groups were –0.15 (95% CI, –0.28 to –0.03; p=0.02), –0.39 (95% CI, –0.51 to –0.26; p<0.001), and –0.45 (95% CI, –0.57 to –0.32; p<0.001), respectively. 25

Tirzepatide demonstrated superior HbA1c reductions from baseline at 40 weeks, compared with semaglutide 25