Tirzepatide: A Novel, Once-weekly Dual GIP and GLP-1 Receptor Agonist for the Treatment of Type 2 Diabetes

Gastrointestinal hormones are currently used to treat type 2 diabetes mellitus (T2D). Incretin preparations with gastric inhibitory polypeptide (GIP) activity or glucagon-like peptide-1 (GLP-1) provide new means for controlling blood glucose levels, body weight, and lipid metabolism. GIP, an incretin, has not been used due to lack of promising action against diabetes. However, recent studies have shown that GIP has an important effect on glucagon and insulin secretion under normoglycaemic conditions. Co-existence of GIP with GLP-1 and glucagon signalling leads to a stronger effect than that of GLP-1 stimulation alone. The development of a GIP/GLP-1R unimolecular dual agonist with affinity for both GIP and GLP-1 receptors is under investigation, and the drug is expected to be clinically available in the near future. Tirzepatide, a GIP/GLP-1R unimolecular dual agonist, regulates metabolism via both peripheral organs and the central nervous system. The SURPASS phase III clinical trials conducted for tirzepatide comprise 10 clinical trials, including five global trials and the global SURPASS-CVOT trial, with >13,000 patients with T2D (ClinicalTrials.gov Identifier: NCT04255433). The clinical application of tirzepatide as a therapy for T2D may provide new insights into diabetic conditions and help clarify the role of GIP in its pathogenesis.


touchREVIEWS in Endocrinology
GIP and GLP-1 are occasionally secreted by the same cell, also referred to as K/L or L/K cells ( Figure 1). [7][8][9][10][11][12][13][14] The influence of GIP and GLP-1 on the pancreatic α-cell function is inverse. GIP stimulates the α-cells to promote glucagon secretion, while GLP-1 reduces it. 10,15 Elevation of glucagon is associated with T2D. 16 Therefore, suppression of glucagon activity using a GLP-1 receptor (GLP-1R) agonist has been developed for treatment of T2D. 17 The use of gastrointestinal hormones, particularly GLP-1 and GIP, includes incretin preparations such as a novel GLP-1R agonist or a GIP/GLP-1 dual agonist, which is anticipated to provide new means for controlling T2D and body weight. [18][19][20] GLP-1R activity GLP-1R, a member of the class B family of G protein-coupled receptors, is found in various organs. 10 It is expressed mainly in pancreatic β-cells, various gut-cells, and also in the peripheral nervous system and CNS cells ( Figure 1). 20,21 Signal transduction occurs after GLP-1R agonists bind to GLP-1Rs, mirroring a GLP-1 bioactivity effect favourable for patients with T2D, where this incretin therapy lowers blood glucose levels by stimulating insulin secretion from β-cells. This therapy is effective when there is no complete loss of β-cell function. 10 Additionally, there is suppression of appetite induced through the CNS, leading to body weight reduction. Since GLP-1R is expressed in the cells of various organs including pancreatic β-cells, GLP-1R agonists manifest favourable effects during its circulation. 22 Some low molecular weight GLP-1R agonists can act on GLP-1R in the arcuate nucleus of the hypothalamus, crossing the blood-brain barrier, thereby regulating nerve cells. 23 In patients prescribed with a GLP-1R agonist as a personalized medicine (that could also reduce the body weight), longer adherence to such therapy with improved satisfaction is anticipated as the patient has chosen a therapy more suitable to their needs.

GIP-R activity
GIP is an incretin secreted by the K cells in the upper segment of the small bowel in response to nutrient supply ( Figure 1). 24 Following GIP release from the gut endocrine K cells, rapid inactivation occurs by dipeptidyl peptidase-4 (DPP-4) through cleavage into non-insulinotropic truncated forms. [25][26][27] The postprandial level of GIP under normal physiological conditions is approximately four times that of GLP-1. 13 GIP receptors (GIPRs) are present   [10][11][12][13][14] Figure 1). 22,[28][29][30] In healthy people, GIP induces nutrient-stimulated insulin and glucagon secretion in a glucose-dependent manner. 14,27 The stimuli that induce insulin secretion in response to a 50 g oral glucose load are glucose alone (33%), GIP (44%) and GLP-1 (22%). 25,31 GIP has an augmented effect on insulin secretion, unlike GLP-1, and plays an important role in glucose metabolism in humans. 31 Moreover, GIP accompanied with insulin or GLP-1 signalling, leads to a reduction in blood glucose levels and body weight. Thus, GIP promotes insulin secretion in healthy individuals, however this effect is not observed in patients with T2D ( Figure 2). [31][32][33][34][35] Unlike GLP-1, GIP failed to stimulate glucagon secretion during hyperglycaemia. 33 Alternatively, stimulated glucagon secretion via GIP does occur during hypoglycaemic conditions accompanied by glucagonotropic enhanced activity. 15,29,30 The physiological significance of GIP-stimulated glucagon secretion remains unexplored. In contrast, in patients with T2D, glucose-dependency of GIP-stimulated glucagon secretion, such as in healthy people, does not remain ( Figure 2). 32  have been developed as treatments for T2D and obesity. 43 Additionally, enhancement of GIP activity, using agonists of GIPR or chronic elevation of GIP levels causing weight loss when coexisting with GLP-1 receptor activation, are useful treating obesity and T2D, leading to improved insulin secretion, glycaemic control, and an accompanying amelioration of β-cell function. [43][44][45][46][47] Further studies on clinical use of tirzepatide associated with GIPR activity will provide a platform for unravelling the pathogenesis and understanding GIPR activity in α-cells and regulation of glucagon secretion.

GIP (secreted by K-cells in the upper segment of the small intestine) and GLP-1 (secreted by L-cells throughout the intestine) in response to nutrient ingestion act on GIPRs and
GIP-based pharmacotherapy, which relies on CNS-GIPR signalling, is of importance, particularly in systemic metabolic control. 28,29 Apoptosis inhibition and osteoblast proliferation are also stimulated by GIP, resulting in bone formation and remodelling. 30

Protective effect of incretin on various organs
Any long-acting GLP-1R agonist exhibits the same anti-inflammatory effects as natural GLP-1, and is therefore demonstrated to protect organs such as the heart, kidneys and others ( Figure 1). [48][49][50][51][52] GLP-1 and other intestinal hormones are known to drive natriuresis via the gut-kidney axis. [53][54][55] Onset of apparent albuminuria in high-risk patients with T2D having cerebro-cardiovascular disease complications was significantly reduced by long-acting GLP-1R agonist administration. 49,54,55 The reduction in cerebrovascular events was significantly noted among Asian patients. 56 GIP has also been shown to reduce pro-inflammatory cytokine expression, thereby reducing the inflammatory response in the     In patients with T2D, the incidence of heart failure significantly increases due to ischaemic heart disease and also separately due to the diabetic condition itself. 58,59 Obesity, which is closely linked to T2D, is also often associated with heart failure. 60,61 It is expected that anti-diabetic drugs cause weight reduction, better glycaemic control and improvement in macrovascular outcomes such as cerebral cardiovascular risk factors, in addition to microvascular outcomes. 62,63 Since evidence suggests that GLP-1R agonists' have a protective effect on various organs (Figure 1), Pharmacological activation of GIPRs is anticipated to produce therapeutic effects regarding energy metabolism in peripheral tissues, whereas the chronic use of long-acting GIPR agonists did not reduce body weight. [44][45][46] Synergistic activation of GIP/GLP-1R produced higher therapeutic efficacy for T2D, leading to a greater body weight reduction, compared with GIP or GLP-1 alone. 43 Reinforced suppression of calorie intake, accompanied by a gradual increase in energy consumption, produces a reduction in body weight. Evidence suggests that GIP/GLP-1 synergism occurs in the CNS and reduces body weight, independent of insulin sensitivity and fat metabolism. 29 Compared to a GLP-1R agonist alone, a GIPR/GLP-1R unimolecular dual agonist has also shown restorative and neuroprotective properties. 67 Regarding the effects of increased antidiabetic action and decreased body weight by dual stimulation of GIP and GLP-1R, more than either GIP or GLP-1 alone, one of the reasons that might be postulated for this synergism is that GIP signals mediate insulinotropic and glucagonotropic effects through the brain or fat. Nevertheless, further research is needed concerning the links between the gut, brain and blood glucose levels which employ gastrointestinal hormones including dual, tri or more synergistic stimulations. Therefore, tirzepatide has the potential to be a key that unlocks the door to this conundrum. While many people have suggested that in vitro research has such potential, in fact the direct administration of tirzepatide in humans lends itself to a more timely revealing of the facts behind the system of blood glucose maintenance. 21 [1][2][3][4]20,68 In comparison to native GLP-1 with one-fifth affinity, tirzepatide has an affinity similar to that of native GIP. 20 Tirzepatide's once-weekly administration derives from its structure, which is based on the GIP sequence and includes a C20 fatty di-acid moiety, enabling it to bind to albumen and prolong its half-life of 5 days. 68 Tirzepatide has exhibited robust results in glycaemic control and body weight reduction compared to other alternatives. 68 1 and 2, Figure 4). 21,[70][71][72][73][74][76][77][78][79][80][81][82][83][84] Tirzepatide demonstrated robust glycaemic control ( Figure 4) and body weight reduction compared to the controls, which included the conventional GLP-1R agonist semaglutide.

SURPASS clinical trials
In particular, in the SURPASS-1 trial, tirzepatide was reported to be a curative drug in patients with early stage T2D. In all studies, over 90% of the patients taking tirzepatide achieved HbA1c levels <7%; between 40% and 52% of patients achieved HbA1c levels <5.7% (Figure 4). [70][71][72][73][74] Weight reduction ranged from 6.2-12.9 kg (6.6-13.9%) depending on   The global SURPASS-CVOT (A study of tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with type 2 diabetes; ClinicalTrials.gov Identifier: NCT04255433) assesses the noninferiority and superiority of tirzepatide against dulaglutide (1.5 mg dose weekly) with a confirmed cardio-protective effect. 80 Patients with T2D and increased CV risk were enrolled. 80 This trial was started in June 2020, with an expected read-out in 2024. The phase III SUMMIT study (A study of tirzepatide (LY3298176) in participants with heart failure with preserved ejection fraction and obesity; ClinicalTrials.gov identifier: NCT04847557) was initiated in 2021 ( Table 3). [86][87][88] The main purpose of this study is to assess the efficacy and safety of tirzepatide in participants suffering from heart failure with preserved ejection fraction and obesity.

Other tirzepatide trials
The other trials into tirzepatide are as follows (

Safety profile
There are no specific signs in a serious adverse event.
When tirzepatide was not combined with sulfonylurea or insulin, the occurrence of hypoglycaemia remained low. [70][71][72][73][74] Conclusion Tirzepatide, a dual GIP/GLP-1R agonist, demonstrated robust reductions in glycaemic control and body weight for the patients in the SURPASS studies, without causing hypoglycaemia. The current focus areas for research are preventative factors to combat accelerated β-cell deterioration -a critical cause of diabetes -and exploring the benefits of GIPR. The novel drugs represented by tirzepatide seem promising in revealing new pathogenic insights. It is also believed that unexploited anti-diabetic drugs with GIP and GLP-1 signal activation will unravel undiscovered avenues of treatment for T2D and its complications. The clinical success of this dual GIP/GLP-1R agonist will inspire the development of multiple agonists, such as other dual agonists or triagonists consisting of multiple ligands, including hormones with wider applications. ❑