Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction

Abstract

Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist approved for the treatment of type 2 diabetes in the USA, Europe, and the UAE. Tirzepatide is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1-5) have shown that tirzepatide at 5-15 mg per week reduces both HbA_1c (1.24 to 2.58%) and body weight (5.4-11.7 kg) by amounts unprecedented for a single agent. A sizable proportion of patients (23.0 to 62.4%) reached an HbA_1c of < 5.7% (which is the upper limit of the normal range indicating normoglycaemia), and 20.7 to 68.4% lost more than 10% of their baseline body weight. Tirzepatide was significantly more effective in reducing HbA_1c and body weight than the selective GLP-1 RA semaglutide (1.0 mg per week), and titrated basal insulin. Adverse events related to tirzepatide were similar to what has been reported for selective GLP-1RA, mainly nausea, vomiting, diarrhoea, and constipation, that were more common at higher doses. Cardiovascular events have been adjudicated across the whole study program, and MACE-4 (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death and hospital admission for angina) events tended to be reduced over up to a 2 year-period, albeit with low numbers of events. For none of the cardiovascular events analysed (MACE-4, or its components) was a hazard ratio > 1.0 vs. pooled comparators found in a meta-analysis covering the whole clinical trial program, and the upper bounds of the confidence intervals for MACE were < 1.3, fulfilling conventional definitions of cardiovascular safety. Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, and this was associated with lower prandial insulin and glucagon concentrations. Both drugs caused similar reductions in appetite, although tirzepatide caused greater weight loss. While the clinical effects of tirzepatide have been very encouraging, important questions remain as to the mechanism of action. While GIP reduces food intake and body weight in rodents, these effects have not been demonstrated in humans. Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.

Keywords: Body weight; GIP/GLP-1 receptor co-agonists; GLP-1 receptor agonists; Glycemic control; HbA1c; Type 2 diabetes.

Fig. 1

Amino acid sequences of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), the GLP-1 receptor agonist exenatide, and tirzepatide, a GIP/GLP-1 receptor co-agonist. Colours indicate amino acids in the peptide sequence of tirzepatide which correspond to amino acids in the original primary structure of GLP-1 (green), GIP (blue), shared by both GLP-1 and GIP (blue-green), exenatide (orange). Amino acids not related to any of the parent peptides are shown in yellow. Amino-iso-butyric acid (AIB), a non-natural amino acid, is shown in grey with red letters. The primary amino acid sequence of tirzepatide has been taken from [13]; the sequences for human GIP, mammalian GLP-1, and exenatide for comparison are from [–24]

Fig. 2

Binding affinity of GIP, GLP-1, and the dual (GIP and GLP-1 receptor) co-agonist tirzepatide (formerly named LY3298176) to human embryonic kidney (HEK 293) cells transfected with human GIP and GLP-1 receptors, and potency in stimulating cyclic adenosine mono-phosphate (cAMP) accumulation. Data have been taken from Coskun et al. 2018 [13] and are expressed as EC50 (effective concentration resulting in half-maximal stimulation) or K_i (inhibitory constant, leading to half-maximal displacement of tracer)

Fig. 3

Efficacy of tirzepatide in phase 2 (GPGB; [14]) and phase 3 (SURPASS-1 to 5; [–19]) clinical trials, all according to the treatment estimand (SURPASS 1–5) or by Bayesian modified intention-to-treat analysis without considering data acquired post-rescue (GPWB). The upper row of panels depicts effects on HbA_1c (reduction vs. baseline). The lower row of panels shows effects on body weight (reduction vs. baseline). Asterisks (_*) indicate a significant difference (p < 0.05) vs. the respective comparator. Comparators were placebo and dulaglutide (1.5 mg per week) in phase 2 (GPGB), placebo (grey; SURPASS-1 and -5), semaglutide 1.0 mg (orange; SURPASS-2), basal insulin degludec (darker brown; SURPASS-3) and basal insulin glargine U100 (lighter brown; SURPASS-4). Patient numbers per arm are presented in the bottom of the lower panels

Fig. 4

Effects of tirzepatide on adjudicated cardiovascular events in SURPASS-4 [18] (A), a clinical trial recruiting subjects at high risk for cardiovascular events, and across the clinical trial program (phases 2 and 3) for tirzepatide [20] (B). MACE: Major adverse cardiovascular events. The line of identity (red, dashed) indicates an equal risk for CV events for tirzepatide and comparator(s). The blue, dashed line marks a hazard ratio of 1.3. An upper bound of the confidence interval for composite endpoints (MACE-3 and MACE-4, but not for individual endpoints) below 1.3 conventionally is interpreted as indicating a cardiovascular risk, which is not significantly elevated in comparison to the comparator(s). Comparators include placebo, insulin degludec, insulin glargine, dulaglutide 1.5 mg/week, and semaglutide 1.0 mg/week (GLP-1 receptor agonists). The numbers of patients at risk and the numbers of events observed are presented. The asterisk indicates a significant difference indirectly inferred from the 95% confidence interval completely being below the line of identity (= 1)