Authors: Michael A. Nauck, David A. D‘Alessio
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.
The redundancy of the system to regulate food intake and body weight led to suggestions that multiple signaling pathways would need to be targeted for effective medical treatment of obesity. Proof-of-concept studies were reported using simultaneous administration of peptides, e.g. leptin and amylin, to cause greater weight loss in rodent models. In 2009, Day and colleagues reported the development of novel peptides engineered to agonize both the GLP-1 and glucagon receptors (GLP-1R and GCGR). The rationale for these agents was that combining the satiety effects of GLP-1 signaling with purported effects of glucagon to increase energy expenditure would lead to a more effective weight loss agent. In fact, this was demonstrated quite convincingly in obese mice, with some variability in effect depending on the relative balance of potency at the GLP-1R and GCGR. Of perhaps greater importance was the establishment of the process of iterative chemical refinement as a means of modifying the amino acid sequence of a known peptide to add agonism for multiple receptors. Using this model an obvious strategy was to combine activity for GLP-1 with that of glucose-dependent insulinotropic polypeptide (GIP) to treat diabetes. Together GLP-1 and GIP account for the bulk of the incretin effect, a physiologic system evolved to augment insulin secretion following the ingestion of nutrients. Both the GLP-1R and the GIP receptor (GIPR) are expressed on pancreatic β-cells and activation of these in the context of even modest elevations of blood glucose potently stimulate insulin secretion. Activation of the GLP-1R lowers blood glucose in persons with type 2 diabetes while the GIPR is much less effective for this. Nonetheless, an engineered peptide with activity at both the GIPR and GLP-1R was more effective at reducing body weight and blood glucose in obese mice than a selective GLP-1R agonist (GLP-1RA). This compound was also superior to a GLP-1RA for stimulating insulin secretion in non-human primates, and reduced blood glucose in humans with diabetes. While the insulinotropic properties of a GIPR/GLP-1R co-agonist were expected, the effects on food intake and weight loss were not. However, recent work in rodents has demonstrated that the GIPR is expressed on neurons in the arcuate nucleus and other parts of the hypothalamus, and their activation reduces food intake and body weight, in particular when co-administered with GLP-1. This initial work, and other studies, heralded the development of a number of different multi-receptor peptides that have become the latest advances in therapeutics of diabetes and obesity.
This review is based primarily on information from preclinical studies in animal models and clinical trials in humans; a secondary analysis of the trial data has been included to highlight specific points. For this purpose, a PubMed literature search was performed using EndNote X7.1, using the search terms “tirzepatide”, “LY3298176 “, "dual GIP/GLP-1” and “GIP/GLP-1 receptor co-agonist”. Data in Tables 1 and 2 were taken from publications of phase 2 (GPWB) and 3 (SURPASS 1–5) trials. Data presented as Fig.1 (molecular structure of tirzepatide and its relationship to GIP, GLP-1, and exendin-4) have been adopted from publications quoted in the respective legend. Data presented as Fig.2 were taken from Coscun et al. 2018. Data presented as Fig.3 have been taken from publications of phase 2 (GPWB) and phase 3 (SURPASS 1–5) trials, strictly presenting the treatment estimand (or, in the case of GPWB, a Bayesian analysis according to a modified intention-to-treat approach excluding data gathered post-rescue, which is most similar to the treatment estimand, but, however, does not exclude data after treatment discontinuation). Data presented as Fig.4 are redrawn from the SURPASS-4 publication and
